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    Clinical Trial Results:
    A Multicenter, Global, Randomized, Double-Blind Study of Axitinib plus Best Supportive Care Versus Placebo plus Best Supportive Care in Patients with Advanced Hepatocellular Carcinoma Following Failure of One Prior Antiangiogenic Therapy

    Summary
    EudraCT number
    2010-021590-37
    Trial protocol
    DE   HU   SK   GB   BE   IT  
    Global end of trial date
    20 Dec 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Jan 2018
    First version publication date
    05 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A4061058
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01210495
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of non-randomized portion was to evaluate, in subjects with advanced hepatocellular carcinoma (HCC) following failure of one prior antiangiogenic therapy, the pharmacokinetics (PK) of axitinib, and the tolerability and starting dose in subjects with Child-Pugh Class B disease (Score 7); and the objective of randomized portion was to compare the overall survival (OS) of subjects with advanced HCC receiving axitinib+best supportive care (BSC) versus placebo+BSC following failure of one prior antiangiogenic therapy.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Dec 2010
    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
    Slovakia: 4
    Country: Number of subjects enrolled
    Taiwan: 19
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    United States: 19
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    China: 20
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hong Kong: 13
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Japan: 44
    Country: Number of subjects enrolled
    Korea, Republic of: 44
    Worldwide total number of subjects
    224
    EEA total number of subjects
    65
    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)
    131
    From 65 to 84 years
    93
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Total 224 subjects were enrolled in the study. Randomized portion enrolled 202 subjects in 2 arms (134 in axitinib, 68 in placebo) in 70 centres (13 countries). Non-randomized portion enrolled 22 subjects in 2 cohorts (15 in Child-Pugh Class A, 7 in Child-Pugh Class B score 7) according to Child-Pugh score in 13 centers (4 countries).

    Pre-assignment
    Screening details
    Subjects with Child-Pugh Class A (score 5 or 6) could have been enrolled into either non-randomized or to randomized portion. Subjects with Child-Pugh Class B (score 7) were initially enrolled into non-randomized portion but following determination of recommended axitinib starting dose they could have been enrolled in randomized portion.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Child-Pugh Class A
    Arm description
    Subjects with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 milligrams (mg) twice daily (BID).
    Arm type
    Experimental

    Investigational medicinal product name
    Axitinib
    Investigational medicinal product code
    AG-013736
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Axitinib will be administered as per the dose and schedule specified in the arm group description.

    Arm title
    Child-Pugh Class B
    Arm description
    Subjects with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.
    Arm type
    Experimental

    Investigational medicinal product name
    Axitinib
    Investigational medicinal product code
    AG-013736
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Axitinib will be administered as per the dose and schedule specified in the arm group description.

    Arm title
    Axitinib
    Arm description
    Subjects in this group received axitinib + best supportive care. Subjects with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Subjects with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non-randomized portion. Study treatment was administered in cycles of 4 weeks in duration.
    Arm type
    Experimental

    Investigational medicinal product name
    Axitinib
    Investigational medicinal product code
    AG-013736
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Axitinib will be administered as per the dose and schedule specified in the arm group description.

    Arm title
    Placebo
    Arm description
    Subjects in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration. The starting dose of placebo for subjects with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Subjects with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, subjects with Child-Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    AG-013736
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to axitinib will be administered as per the dose and schedule specified in the arm group description.

    Number of subjects in period 1
    Child-Pugh Class A Child-Pugh Class B Axitinib Placebo
    Started
    15
    7
    134
    68
    Completed
    0
    0
    0
    0
    Not completed
    15
    7
    134
    68
         Study Terminated by Sponsor
    -
    -
    4
    11
         Death
    14
    7
    112
    54
         Subject Refused Further Follow-Up
    1
    -
    11
    2
         Other unspecified
    -
    -
    6
    -
         Lost to follow-up
    -
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Child-Pugh Class A
    Reporting group description
    Subjects with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 milligrams (mg) twice daily (BID).

    Reporting group title
    Child-Pugh Class B
    Reporting group description
    Subjects with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.

    Reporting group title
    Axitinib
    Reporting group description
    Subjects in this group received axitinib + best supportive care. Subjects with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Subjects with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non-randomized portion. Study treatment was administered in cycles of 4 weeks in duration.

    Reporting group title
    Placebo
    Reporting group description
    Subjects in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration. The starting dose of placebo for subjects with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Subjects with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, subjects with Child-Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.

    Reporting group values
    Child-Pugh Class A Child-Pugh Class B Axitinib Placebo Total
    Number of subjects
    15 7 134 68 224
    Age, Customized
    Units: Subjects
        <18 years|
    0 0 0 0 0
        18-44 years|
    4 0 7 4 15
        45-64 years|
    5 5 74 32 116
        >=65 years|
    6 2 53 32 93
    Sex: Female, Male
    Units: Subjects
        Female
    3 2 24 12 41
        Male
    12 5 110 56 183

    End points

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    End points reporting groups
    Reporting group title
    Child-Pugh Class A
    Reporting group description
    Subjects with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 milligrams (mg) twice daily (BID).

    Reporting group title
    Child-Pugh Class B
    Reporting group description
    Subjects with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non-randomized portion of this study to determine the recommended starting dose of axitinib for this population. The initial starting dose for this group was 2 mg BID.

    Reporting group title
    Axitinib
    Reporting group description
    Subjects in this group received axitinib + best supportive care. Subjects with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Subjects with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non-randomized portion. Study treatment was administered in cycles of 4 weeks in duration.

    Reporting group title
    Placebo
    Reporting group description
    Subjects in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration. The starting dose of placebo for subjects with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Subjects with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, subjects with Child-Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.

    Primary: Overall Survival (OS) - Stratified Analysis, Randomized Portion

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    End point title
    Overall Survival (OS) - Stratified Analysis, Randomized Portion [1]
    End point description
    OS was defined as the time from the date of randomization to the date of death due to any cause. OS (in months) was calculated as (date of death − first randomization date +1)/30.4. For subjects still alive at the time of the analysis, the OS time was censored on the last date they were known to be alive. All subjects were followed up for survival at least every 3 months after discontinuing study treatment until at least two years after randomization of the last subjects. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Primary
    End point timeframe
    From randomization until at least two years after the last subject has been randomized (up to 6 years)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: months
        median (confidence interval 95%)
    12.7 (10.2 to 14.9)
    9.7 (5.9 to 11.8)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The study was designed to test the null hypothesis that the true median OS was 5 months vs. the alternative hypothesis that the true median OS was at least 8.3 months (i.e., 66 percent [%] improvement in median OS).
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.2872 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.907
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.646
         upper limit
    1.274
    Notes
    [2] - Assuming proportional hazards, a hazard ratio less than (<) 1 indicated reduction in hazard rate to favor Axitinib; hazard ratio greater than (>) 1 indicated reduction to favor Placebo.
    [3] - For the overall stratified analysis the p-value is from a 1-sided log-rank test of treatment stratified by tumor invasion and geographic region.

    Secondary: Progression-Free Survival (PFS) - Stratified Analysis, Randomized Portion

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    End point title
    Progression-Free Survival (PFS) - Stratified Analysis, Randomized Portion [4]
    End point description
    PFS was defined as time from randomization to first documented objective tumor progression or to death due to any cause, whichever occurred first. PFS was calculated as(first event date − first randomization date +1)/30.4. Tumor progression was determined from oncologic assessment data (data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where outcome was death). As per response evaluation criteria in solid tumors (RECIST) 1.1, progression was defined as greater than or equal to (>=) 20% increase in sum of longest dimensions of target lesions or appearance of one or more new target lesions, unequivocal progression of existing non-target lesions, or appearance of 1 new non-target lesions. Subjects discontinuing study treatment without documented evidence of PD were to be followed up at least every 8 weeks after discontinuing study treatment until disease progression, or initiation of another anticancer treatment. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks until disease progression/death or start of new treatment or until at least two years after the last subject has been randomized, whatever occurs first
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: months
        median (confidence interval 95%)
    3.6 (2.3 to 4.6)
    1.9 (1.9 to 3.5)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Assuming proportional hazards, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Placebo.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0039 [5]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.618
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.438
         upper limit
    0.871
    Notes
    [5] - For the overall stratified analysis the p-value is from a 1-sided log-rank test of treatment stratified by tumor invasion and geographic region.

    Secondary: Objective Response Rate (ORR) - Percentage of Subjects With Objective Response by Stratified Analysis, Randomized Portion

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    End point title
    Objective Response Rate (ORR) - Percentage of Subjects With Objective Response by Stratified Analysis, Randomized Portion [6]
    End point description
    ORR was defined as the percentage of subjects with confirmed complete response (CR) or confirmed partial response (PR) according to the RECIST 1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must decrease to normal (short axis <10 millimetres [mm]). PR was defined as a 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks until at least two years after the last subject has been randomized
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: percentage of subjects
        number (confidence interval 95%)
    9.7 (5.3 to 16.0)
    2.9 (0.4 to 10.2)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Risk ratio and confidence interval (CI) were based on the Mantel-Haenszel estimator; risk ratio was adjusted for geographical region and vascular invasion and extra hepatic spread.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0914 [7]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk ratio (RR)
    Point estimate
    3.172
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.759
         upper limit
    13.265
    Notes
    [7] - ORR for the 2 treatment arms was compared with a significance level of 0.025 using Cochran-Mantel-Haenszel (CMH) test for stratified analyses.

    Secondary: Time to Tumor Progression (TTP) - Stratified Analysis, Randomized Portion

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    End point title
    Time to Tumor Progression (TTP) - Stratified Analysis, Randomized Portion [8]
    End point description
    TTP was defined as the time from randomization to first documentation of objective tumor progression. If tumor progression data included more than 1 date, the first date was used. TTP (in months) was calculated as (first event date − first randomization date +1)/30.4. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks until disease progression/death or start of new treatment or until at least two years after the last subject has been randomized, whatever occurs first
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: months
        median (confidence interval 95%)
    3.7 (2.8 to 5.6)
    1.9 (1.9 to 3.6)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Assuming proportional hazards, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Placebo.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006 [9]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.621
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.434
         upper limit
    0.889
    Notes
    [9] - For the overall stratified analysis the p-value is from a 1-sided log-rank test of treatment stratified by tumor invasion and geographic region.

    Secondary: Duration of Response (DR) by Unstratified Analysis, Randomized Portion

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    End point title
    Duration of Response (DR) by Unstratified Analysis, Randomized Portion [10]
    End point description
    DR was defined as the time from the first documentation of objective tumor response (CR or PR) that was subsequently confirmed to the first documentation of PD or to death due to any cause, whichever occurs first. If tumor progression data included more than 1 date, the first date was to be used. DR (in months) was to be calculated as (the end date for DR − first CR or PR that was subsequently confirmed +1)/30.4. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received. DR was calculated for the subgroup of FAS subjects with objective response. Here, '99999' represents 'value not reached'.
    End point type
    Secondary
    End point timeframe
    From objective response to date of progression or death
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    13
    2
    Units: months
        median (confidence interval 95%)
    6.4 (3.7 to 9.3)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Overall Clinical Benefit Response (CBR) - Stratified Analysis, Randomized Portion

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    End point title
    Percentage of Subjects With Overall Clinical Benefit Response (CBR) - Stratified Analysis, Randomized Portion [11]
    End point description
    CBR was defined as the percentage of subjects with confirmed CR or confirmed PR or a best response of stable disease >=8 weeks according to RECIST 1.1 criteria, relative to all randomized subjects who had baseline measurable disease. Confirmed responses were defined as those that persisted on repeat imaging study >=4 weeks after the initial documentation of response. Subjects who did not have on study radiographic tumor re-evaluation or who died, progressed, or dropped out for any reason prior to reaching a CR, PR, or stable disease were counted as non-responders in the assessment of CBR. A subject who initially met the criteria for a PR and then subsequently became a confirmed CR was to be assigned a best response of CR. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    From Baseline up to end of treatment
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: percentage of subjects
        number (confidence interval 95%)
    31.3 (23.6 to 39.9)
    11.8 (5.2 to 21.9)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Risk Ratio and CI based on the Mantel-Haenszel estimator; risk ratio was adjusted for geographical region and vascular invasion and extra hepatic spread.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0025 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk ratio (RR)
    Point estimate
    2.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.319
         upper limit
    5.326
    Notes
    [12] - For the overall stratified analysis the p-value is from Cochran-Mantel-Haenszel test of treatment stratified by geographical region and vascular invasion and extra hepatic spread.

    Secondary: Axitinib Steady-State Pharmacokinetic (PK) Parameter - Maximum Observed Plasma Concentration (Cmax), Non-Randomized Portion

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    End point title
    Axitinib Steady-State Pharmacokinetic (PK) Parameter - Maximum Observed Plasma Concentration (Cmax), Non-Randomized Portion [13]
    End point description
    Axitinib samples were to be collected from all subjects on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. The PK concentration set included all subjects who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all subjects treated who had at least 1 estimated PK parameter of primary interest.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Child-Pugh Class A Child-Pugh Class B
    Number of subjects analysed
    12
    7
    Units: nanograms per milliliter (ng/mL)
        geometric mean (confidence interval 95%)
    35.74 (21.84 to 58.50)
    21.16 (11.10 to 40.33)
    No statistical analyses for this end point

    Secondary: Axitinib Steady-State PK Parameter - Area Under the Plasma Concentration Versus Time Curve From 0 to 24 Hour (AUC0-24), Non-Randomized Portion

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    End point title
    Axitinib Steady-State PK Parameter - Area Under the Plasma Concentration Versus Time Curve From 0 to 24 Hour (AUC0-24), Non-Randomized Portion [14]
    End point description
    Axitinib samples were to be collected from all subjects on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. In the below table, 4 subjects in Child-Pugh A and 1 subject in Child-Pugh B were not reported due to nonestimable half-life. The PK concentration set included all subjects who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all subjects treated who had at least 1 estimated PK parameter of primary interest.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Child-Pugh Class A Child-Pugh Class B
    Number of subjects analysed
    8
    6
    Units: nanograms*hour per milliliter (ng*hr/mL)
        geometric mean (confidence interval 95%)
    310.76 (175.02 to 551.75)
    316.20 (162.96 to 613.55)
    No statistical analyses for this end point

    Secondary: Axitinib Steady-State Pharmacokinetic Parameter - Time to First Occurrence of Cmax (Tmax), Non-Randomized Portion

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    End point title
    Axitinib Steady-State Pharmacokinetic Parameter - Time to First Occurrence of Cmax (Tmax), Non-Randomized Portion [15]
    End point description
    Axitinib samples were to be collected from all subjects on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. The PK concentration set included all subjects who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all subjects treated who had at least 1 estimated PK parameter of primary interest.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Child-Pugh Class A Child-Pugh Class B
    Number of subjects analysed
    12
    7
    Units: hours
        median (full range (min-max))
    2.50 (0.00 to 7.98)
    1.05 (0.00 to 4.00)
    No statistical analyses for this end point

    Secondary: Axitinib Steady-State Pharmacokinetic Parameter - Apparent Oral Clearance (CL/F), Non-Randomized Portion

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    End point title
    Axitinib Steady-State Pharmacokinetic Parameter - Apparent Oral Clearance (CL/F), Non-Randomized Portion [16]
    End point description
    Axitinib samples were to be collected from all subjects on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. In the below table, 4 subjects in Child-Pugh A and 1 subject in Child-Pugh B were not reported due to nonestimable half-life. The PK concentration set included all subjects who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all subjects treated who had at least 1 estimated PK parameter of primary interest.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Child-Pugh Class A Child-Pugh Class B
    Number of subjects analysed
    8
    6
    Units: liters per hour (L/hr)
        geometric mean (confidence interval 95%)
    32.18 (18.12 to 57.13)
    12.65 (6.52 to 24.55)
    No statistical analyses for this end point

    Secondary: Axitinib Steady-State Pharmacokinetic Parameter - Terminal Plasma Elimination Half-Life (t1/2), Non-Randomized Portion

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    End point title
    Axitinib Steady-State Pharmacokinetic Parameter - Terminal Plasma Elimination Half-Life (t1/2), Non-Randomized Portion [17]
    End point description
    Axitinib samples were to be collected from all subjects on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. In the below table, 4 subjects in Child-Pugh A and 1 subject in Child-Pugh B were not reported due to nonestimable half-life. The PK concentration set included all subjects who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all subjects treated who had at least 1 estimated PK parameter of primary interest.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Child-Pugh Class A Child-Pugh Class B
    Number of subjects analysed
    8
    6
    Units: hours
        arithmetic mean (standard deviation)
    4.12 ± 3.55
    4.79 ± 2.42
    No statistical analyses for this end point

    Secondary: Axitinib Steady-State Pharmacokinetic Parameter - Apparent Oral Volume of Distribution of the Drug During the Elimination Phase (Vz/F), Non-Randomized Portion

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    End point title
    Axitinib Steady-State Pharmacokinetic Parameter - Apparent Oral Volume of Distribution of the Drug During the Elimination Phase (Vz/F), Non-Randomized Portion [18]
    End point description
    Axitinib samples were to be collected from all subjects on Cycle 1 Day 15 at the following time points: pre-dose, 1, 2, 3, 4, 6 and 8 hours after axitinib dosing. The PK parameter, Vz/F has been presented in this outcome measure. In the below table, 4 subjects in Child-Pugh A and 1 subject in Child-Pugh B were not reported due to nonestimable half-life. The PK concentration set included all subjects who were treated and had at least 1 measured concentration on at least 1 day of PK assessment. The PK parameter analysis set included all subjects treated who had at least 1 estimated PK parameter of primary interest.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Child-Pugh Class A Child-Pugh Class B
    Number of subjects analysed
    8
    6
    Units: liters
        geometric mean (confidence interval 95%)
    150.01 (94.67 to 237.68)
    81.16 (47.70 to 138.08)
    No statistical analyses for this end point

    Secondary: Concentration of Soluble Proteins at Baseline in Randomized Portion

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    End point title
    Concentration of Soluble Proteins at Baseline in Randomized Portion [19]
    End point description
    Plasma soluble proteins interleukin-6 (IL-6), E-Selectin, interleukin-8 (IL-8), hepatocyte growth factor (HGF), matrix metalloproteinase-2 (MMP-2), stem cell factor (SCF), angiopoietin-2 (Ang-2), vascular endothelial growth factor-A (VEGF-A), vascular endothelial growth factor-C (VEGF-C), soluble vascular endothelial growth factor receptor 2 (sVEGFR2), sVEGFR3, stromal cell-derived factor-1 (SDF1), neutrophil gelatinase-associated lipocalin (NGAL), migration inhibitory factor (MIF), c-MET, regulated upon activation normal T cell expressed and presumably secreted (RANTES), monocyte chemotactic protein-3 (MCP-3) were only measured in randomized subjects. Soluble protein analysis set included all subjects in safety analysis set who had a Baseline soluble protein assessment. Here, '99999' represents ‘data not available as % < lower limit of quantification (LLQ) was greater than 75%’.
    End point type
    Secondary
    End point timeframe
    Baseline
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    120
    61
    Units: picograms per milliliter (pg/mL)
    arithmetic mean (standard deviation)
        IL-6
    50.67 ± 102.86
    50.72 ± 106.74
        E-Selectin
    52313.94 ± 32603.18
    55430.76 ± 26723.43
        IL-8
    33.35 ± 47.72
    27.23 ± 44.46
        HGF
    478.84 ± 712.43
    406.06 ± 376.04
        MMP-2
    355715.66 ± 137663.04
    350979.72 ± 146323.29
        SCF
    1352.75 ± 1534.41
    1439.71 ± 2260.89
        Ang-2
    662.40 ± 623.87
    577.82 ± 354.42
        VEGF-A
    102.56 ± 128.09
    173.59 ± 472.19
        VEGF-C
    99999 ± 99999
    99999 ± 99999
        sVEGFR2
    17675.76 ± 7218.95
    18273.65 ± 6836.16
        sVEGFR3
    287429.28 ± 117583.24
    290338.69 ± 97830.36
        SDF1
    1190.08 ± 823.03
    1150.10 ± 681.04
        NGAL
    134861.80 ± 152492.96
    141383.00 ± 121747.35
        MIF
    33057.15 ± 28256.00
    32302.99 ± 21485.01
        c-MET ELISA
    1664.96 ± 834.36
    1641.08 ± 704.38
        RANTES
    26412.12 ± 38682.81
    26917.76 ± 27094.12
        MCP-3
    99999 ± 99999
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Specific Micro-Ribonucleic Acid (miRNA) Transcript Present in Circulation in Randomized Portion

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    End point title
    Percentage of Subjects With Specific Micro-Ribonucleic Acid (miRNA) Transcript Present in Circulation in Randomized Portion [20]
    End point description
    A 5 millilitres (mL) whole blood sample was collected from all randomized subjects to evaluate the miRNA transcripts. The miRNA analysis set included all subjects in the safety analysis set who had a baseline miRNA assessment. Safety analysis population included all randomized subjects who received at least 1 dose of study drug with treatment assignments designated according to actual study treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    111
    59
    Units: percentage of subjects
    number (not applicable)
        hsa-let-7a-5p
    100.0
    100.0
        hsa-let-7b-5p
    100.0
    100.0
        hsa-let-7c
    100.0
    100.0
        hsa-let-7d-5p
    100.0
    100.0
        hsa-let-7f-5p
    100.0
    100.0
        hsa-let-7g-5p
    100.0
    100.0
        hsa-let-7i-5p
    100.0
    100.0
        hsa-miR-103a-3p
    100.0
    100.0
        hsa-miR-106b-5p
    100.0
    100.0
        hsa-miR-107
    100.0
    100.0
        hsa-miR-1202
    100.0
    100.0
        hsa-miR-1207-5p
    100.0
    100.0
        hsa-miR-1225-5p
    100.0
    100.0
        hsa-miR-1234-5p
    100.0
    100.0
        hsa-miR-1246
    100.0
    100.0
        hsa-miR-125b-5p
    100.0
    100.0
        hsa-miR-126-3p
    100.0
    100.0
        hsa-miR-1260a
    100.0
    100.0
        hsa-miR-1260b
    100.0
    100.0
        hsa-miR-1268a
    100.0
    100.0
        hsa-miR-1273g-3p
    100.0
    100.0
        hsa-miR-1275
    100.0
    100.0
        hsa-miR-128
    100.0
    100.0
        hsa-miR-130a-3p
    100.0
    100.0
        hsa-miR-130b-3p
    100.0
    100.0
        hsa-miR-140-3p
    100.0
    100.0
        hsa-miR-142-3p
    100.0
    100.0
        hsa-miR-145-5p
    100.0
    100.0
        hsa-miR-148a-3p
    100.0
    100.0
        hsa-miR-148b-3p
    100.0
    100.0
        hsa-miR-150-5p
    100.0
    100.0
        hsa-miR-151a-3p
    100.0
    100.0
        hsa-miR-151a-5p
    100.0
    100.0
        hsa-miR-151b
    100.0
    100.0
        hsa-miR-1587
    100.0
    100.0
        hsa-miR-15a-5p
    100.0
    100.0
        hsa-miR-15b-5p
    100.0
    100.0
        hsa-miR-16-5p
    100.0
    100.0
        hsa-miR-17-5p
    100.0
    100.0
        hsa-miR-181a-5p
    100.0
    100.0
        hsa-miR-182-5p
    100.0
    100.0
        hsa-miR-183-5p
    100.0
    100.0
        hsa-miR-185-5p
    100.0
    100.0
        hsa-miR-186-5p
    100.0
    100.0
        hsa-miR-191-5p
    100.0
    100.0
        hsa-miR-1914-3p
    100.0
    100.0
        hsa-miR-1915-3p
    100.0
    100.0
        hsa-miR-192-5p
    100.0
    100.0
        hsa-miR-194-5p
    100.0
    100.0
        hsa-miR-197-3p
    100.0
    100.0
        hsa-miR-197-5p
    100.0
    100.0
        hsa-miR-19a-3p
    100.0
    100.0
        hsa-miR-19b-3p
    100.0
    100.0
        hsa-miR-20a-5p
    100.0
    100.0
        hsa-miR-20b-5p
    100.0
    100.0
        hsa-miR-21-5p
    100.0
    100.0
        hsa-miR-210
    100.0
    100.0
        hsa-miR-215
    100.0
    100.0
        hsa-miR-22-3p
    100.0
    100.0
        hsa-miR-222-3p
    100.0
    100.0
        hsa-miR-223-3p
    100.0
    100.0
        hsa-miR-23a-3p
    100.0
    100.0
        hsa-miR-23b-3p
    100.0
    100.0
        hsa-miR-24-3p
    100.0
    100.0
        hsa-miR-25-3p
    100.0
    100.0
        hsa-miR-26a-5p
    100.0
    100.0
        hsa-miR-26b-5p
    100.0
    100.0
        hsa-miR-2861
    100.0
    100.0
        hsa-miR-29a-3p
    100.0
    100.0
        hsa-miR-29b-3p
    100.0
    100.0
        hsa-miR-29c-3p
    100.0
    100.0
        hsa-miR-29c-5p
    100.0
    100.0
        hsa-miR-30b-5p
    100.0
    100.0
        hsa-miR-30c-5p
    100.0
    100.0
        hsa-miR-30d-5p
    100.0
    100.0
        hsa-miR-30e-5p
    100.0
    100.0
        hsa-miR-3135b
    100.0
    100.0
        hsa-miR-3162-5p
    100.0
    100.0
        hsa-miR-3180-3p
    100.0
    100.0
        hsa-miR-3195
    100.0
    100.0
        hsa-miR-320a
    100.0
    100.0
        hsa-miR-320b
    100.0
    100.0
        hsa-miR-320c
    100.0
    100.0
        hsa-miR-320d
    100.0
    100.0
        hsa-miR-320e
    100.0
    100.0
        hsa-miR-324-3p
    100.0
    100.0
        hsa-miR-324-5p
    100.0
    100.0
        hsa-miR-331-3p
    100.0
    100.0
        hsa-miR-339-5p
    100.0
    100.0
        hsa-miR-342-3p
    100.0
    100.0
        hsa-miR-361-3p
    100.0
    100.0
        hsa-miR-361-5p
    100.0
    100.0
        hsa-miR-362-5p
    100.0
    100.0
        hsa-miR-363-3p
    100.0
    100.0
        hsa-miR-3651
    100.0
    100.0
        hsa-miR-3656
    100.0
    100.0
        hsa-miR-365a-3p
    100.0
    100.0
        hsa-miR-3665
    100.0
    100.0
        hsa-miR-3676-5p
    100.0
    100.0
        hsa-miR-374b-5p
    100.0
    100.0
        hsa-miR-378a-3p
    100.0
    100.0
        hsa-miR-378i
    100.0
    100.0
        hsa-miR-3940-5p
    100.0
    100.0
        hsa-miR-3960
    100.0
    100.0
        hsa-miR-423-3p
    100.0
    100.0
        hsa-miR-425-5p
    100.0
    100.0
        hsa-miR-4281
    100.0
    100.0
        hsa-miR-4284
    100.0
    100.0
        hsa-miR-4286
    100.0
    100.0
        hsa-miR-4299
    100.0
    100.0
        hsa-miR-4306
    100.0
    100.0
        hsa-miR-4318
    100.0
    100.0
        hsa-miR-4323
    100.0
    100.0
        hsa-miR-4428
    100.0
    100.0
        hsa-miR-4442
    100.0
    100.0
        hsa-miR-4443
    100.0
    100.0
        hsa-miR-4454
    100.0
    100.0
        hsa-miR-4459
    100.0
    100.0
        hsa-miR-4466
    100.0
    100.0
        hsa-miR-4497
    100.0
    100.0
        hsa-miR-4505
    100.0
    100.0
        hsa-miR-4507
    100.0
    100.0
        hsa-miR-4516
    100.0
    100.0
        hsa-miR-451a
    100.0
    100.0
        hsa-miR-4530
    100.0
    100.0
        hsa-miR-4687-3p
    100.0
    100.0
        hsa-miR-4713-3p
    100.0
    100.0
        hsa-miR-4721
    100.0
    100.0
        hsa-miR-4728-5p
    100.0
    100.0
        hsa-miR-4732-3p
    100.0
    100.0
        hsa-miR-4739
    100.0
    100.0
        hsa-miR-4763-3p
    100.0
    100.0
        hsa-miR-4787-5p
    100.0
    100.0
        hsa-miR-4788
    100.0
    100.0
        hsa-miR-484
    100.0
    100.0
        hsa-miR-486-5p
    100.0
    100.0
        hsa-miR-494
    100.0
    100.0
        hsa-miR-5001-5p
    100.0
    100.0
        hsa-miR-500a-3p
    100.0
    100.0
        hsa-miR-500a-5p
    100.0
    100.0
        hsa-miR-501-3p
    100.0
    100.0
        hsa-miR-501-5p
    100.0
    100.0
        hsa-miR-502-3p
    100.0
    100.0
        hsa-miR-505-5p
    100.0
    100.0
        hsa-miR-5100
    100.0
    100.0
        hsa-miR-532-3p
    100.0
    100.0
        hsa-miR-532-5p
    100.0
    100.0
        hsa-miR-550a-3-5p
    100.0
    100.0
        hsa-miR-550a-3p
    100.0
    100.0
        hsa-miR-5739
    100.0
    100.0
        hsa-miR-574-3p
    100.0
    100.0
        hsa-miR-574-5p
    100.0
    100.0
        hsa-miR-5787
    100.0
    100.0
        hsa-miR-584-5p
    100.0
    100.0
        hsa-miR-6085
    100.0
    100.0
        hsa-miR-6087
    100.0
    100.0
        hsa-miR-6088
    100.0
    100.0
        hsa-miR-6089
    100.0
    100.0
        hsa-miR-6090
    100.0
    100.0
        hsa-miR-6125
    100.0
    100.0
        hsa-miR-6127
    100.0
    100.0
        hsa-miR-625-5p
    100.0
    100.0
        hsa-miR-638
    100.0
    100.0
        hsa-miR-642a-3p
    100.0
    100.0
        hsa-miR-642b-3p
    100.0
    100.0
        hsa-miR-652-3p
    100.0
    100.0
        hsa-miR-660-5p
    100.0
    100.0
        hsa-miR-664a-3p
    100.0
    100.0
        hsa-miR-664b-3p
    100.0
    100.0
        hsa-miR-6717-5p
    100.0
    100.0
        hsa-miR-6724-5p
    100.0
    100.0
        hsa-miR-7-5p
    100.0
    100.0
        hsa-miR-762
    100.0
    100.0
        hsa-miR-766-3p
    100.0
    100.0
        hsa-miR-92a-3p
    100.0
    100.0
        hsa-miR-93-3p
    100.0
    100.0
        hsa-miR-93-5p
    100.0
    100.0
        hsa-miR-937-5p
    100.0
    100.0
        hsa-miR-940
    100.0
    100.0
        hsa-miR-1228-3p
    99.1
    100.0
        hsa-miR-1268b
    99.1
    100.0
        hsa-miR-142-5p
    100.0
    98.3
        hsa-miR-27a-3p
    99.1
    100.0
        hsa-miR-296-5p
    99.1
    100.0
        hsa-miR-3196
    99.1
    100.0
        hsa-miR-3198
    99.1
    100.0
        hsa-miR-342-5p
    100.0
    98.3
        hsa-miR-3653
    100.0
    98.3
        hsa-miR-4465
    99.1
    100.0
        hsa-miR-4515
    99.1
    100.0
        hsa-miR-4653-3p
    99.1
    100.0
        hsa-miR-4665-3p
    99.1
    100.0
        hsa-miR-4746-3p
    99.1
    100.0
        hsa-miR-505-3p
    100.0
    98.3
        hsa-miR-6073
    99.1
    100.0
        hsa-miR-6126
    99.1
    100.0
        hsa-miR-6132
    99.1
    100.0
        hsa-miR-6165
    99.1
    100.0
        hsa-miR-744-5p
    100.0
    98.3
        hsa-miR-874
    99.1
    100.0
        hsa-miR-942
    100.0
    98.3
        hsa-miR-96-5p
    99.1
    100.0
        hsa-miR-1238-3p
    98.2
    100.0
        hsa-miR-1285-3p
    99.1
    98.3
        hsa-miR-1305
    98.2
    100.0
        hsa-miR-146a-5p
    98.2
    100.0
        hsa-miR-15b-3p
    99.1
    98.3
        hsa-miR-17-3p
    98.2
    100.0
        hsa-miR-195-5p
    99.1
    98.3
        hsa-miR-199a-5p
    99.1
    98.3
        hsa-miR-28-5p
    99.1
    98.3
        hsa-miR-30a-5p
    99.1
    98.3
        hsa-miR-340-3p
    99.1
    98.3
        hsa-miR-3679-5p
    99.1
    98.3
        hsa-miR-374a-5p
    99.1
    98.3
        hsa-miR-378a-5p
    99.1
    98.3
        hsa-miR-4433-5p
    98.2
    100.0
        hsa-miR-454-3p
    99.1
    98.3
        hsa-miR-4685-5p
    99.1
    98.3
        hsa-miR-575
    98.2
    100.0
        hsa-miR-6068
    98.2
    100.0
        hsa-miR-6124
    98.2
    100.0
        hsa-miR-6131
    98.2
    100.0
        hsa-miR-939-5p
    98.2
    100.0
        hsa-miR-1234-3p
    99.1
    96.6
        hsa-miR-1249
    98.2
    98.3
        hsa-miR-132-3p
    99.1
    96.6
        hsa-miR-30e-3p
    98.2
    98.3
        hsa-miR-326
    99.1
    96.6
        hsa-miR-374c-5p
    98.2
    98.3
        hsa-miR-4270
    97.3
    100.0
        hsa-miR-4672
    97.3
    100.0
        hsa-miR-4741
    98.2
    98.3
        hsa-miR-6515-3p
    97.3
    100.0
        hsa-miR-371b-5p
    97.3
    98.3
        hsa-miR-4485
    96.4
    100.0
        hsa-miR-4513
    98.2
    96.6
        hsa-miR-454-5p
    98.2
    96.6
        hsa-miR-4716-3p
    96.4
    100.0
        hsa-miR-5006-5p
    97.3
    98.3
        hsa-miR-6069
    98.2
    96.6
        hsa-miR-101-3p
    97.3
    96.6
        hsa-miR-155-5p
    97.3
    96.6
        hsa-miR-16-2-3p
    98.2
    94.9
        hsa-miR-27b-3p
    98.2
    94.9
        hsa-miR-328
    98.2
    94.9
        hsa-miR-4486
    96.4
    98.3
        hsa-miR-513a-5p
    96.4
    98.3
        hsa-miR-92b-3p
    98.2
    94.9
        hsa-miR-98-5p
    98.2
    94.9
        hsa-miR-18b-5p
    96.4
    96.6
        hsa-miR-191-3p
    97.3
    94.9
        hsa-miR-3200-5p
    97.3
    94.9
        hsa-miR-4313
    97.3
    94.9
        hsa-miR-4532
    96.4
    96.6
        hsa-miR-4787-3p
    97.3
    94.9
        hsa-miR-513b
    95.5
    98.3
        hsa-miR-550a-5p
    97.3
    94.9
        hsa-miR-5581-5p
    94.6
    100.0
        hsa-miR-629-3p
    97.3
    94.9
        hsa-miR-629-5p
    94.6
    100.0
        hsa-miR-7-1-3p
    98.2
    93.2
        hsa-miR-125a-3p
    94.6
    98.3
        hsa-miR-1281
    97.3
    93.2
        hsa-miR-140-5p
    95.5
    96.6
        hsa-miR-144-5p
    96.4
    94.9
        hsa-let-7b-3p
    96.4
    93.2
        hsa-let-7f-1-3p
    95.5
    94.9
        hsa-miR-125a-5p
    96.4
    93.2
        hsa-miR-183-3p
    96.4
    93.2
        hsa-miR-3162-3p
    97.3
    91.5
        hsa-miR-33b-3p
    97.3
    91.5
        hsa-miR-4669
    94.6
    96.6
        hsa-miR-502-5p
    96.4
    93.2
        hsa-miR-1304-3p
    97.3
    89.8
        hsa-miR-1306-5p
    95.5
    93.2
        hsa-miR-221-3p
    93.7
    96.6
        hsa-miR-4649-3p
    96.4
    91.5
        hsa-miR-4690-5p
    94.6
    94.9
        hsa-miR-627
    95.5
    93.2
        hsa-miR-99a-5p
    96.4
    91.5
        hsa-miR-18a-5p
    94.6
    93.2
        hsa-miR-211-3p
    94.6
    93.2
        hsa-miR-4430
    95.5
    91.5
        hsa-miR-6508-5p
    95.5
    91.5
        hsa-miR-933
    95.5
    91.5
        hsa-miR-339-3p
    94.6
    91.5
        hsa-miR-624-5p
    95.5
    89.8
        hsa-miR-425-3p
    95.5
    88.1
        hsa-miR-5194
    91.9
    93.2
        hsa-miR-6511b-3p
    92.8
    91.5
        hsa-let-7d-3p
    92.8
    89.8
        hsa-miR-129-2-3p
    92.8
    89.8
        hsa-miR-1825
    92.8
    89.8
        hsa-miR-362-3p
    93.7
    88.1
        hsa-miR-665
    91.0
    93.2
        hsa-miR-149-5p
    92.8
    88.1
        hsa-miR-3620-5p
    91.0
    91.5
        hsa-miR-4478
    90.1
    91.5
        hsa-miR-4484
    92.8
    86.4
        hsa-miR-4656
    90.1
    91.5
        hsa-miR-602
    91.9
    88.1
        hsa-miR-1233-1-5p
    89.2
    91.5
        hsa-miR-3125
    89.2
    91.5
        hsa-miR-4725-5p
    91.0
    88.1
        hsa-miR-4732-5p
    91.0
    88.1
        hsa-miR-146b-5p
    92.8
    83.1
        hsa-miR-4659a-3p
    91.0
    86.4
        hsa-miR-6510-5p
    88.3
    91.5
        hsa-miR-1225-3p
    91.0
    84.7
        hsa-miR-1539
    90.1
    86.4
        hsa-miR-188-5p
    88.3
    89.8
        hsa-miR-4758-3p
    91.0
    84.7
        hsa-miR-550b-2-5p
    91.9
    83.1
        hsa-miR-144-3p
    89.2
    86.4
        hsa-miR-4310
    89.2
    84.7
        hsa-miR-4749-3p
    89.2
    84.7
        hsa-miR-1229-5p
    87.4
    86.4
        hsa-miR-1288
    86.5
    88.1
        hsa-miR-3156-5p
    84.7
    91.5
        hsa-miR-2116-3p
    89.2
    81.4
        hsa-miR-4664-3p
    87.4
    84.7
        hsa-miR-23c
    87.4
    83.1
        hsa-miR-3652
    85.6
    86.4
        hsa-miR-424-5p
    88.3
    81.4
        hsa-miR-4745-5p
    85.6
    86.4
        hsa-miR-1973
    83.8
    88.1
        hsa-miR-4291
    84.7
    86.4
        hsa-miR-3200-3p
    86.5
    81.4
        hsa-miR-4436b-5p
    84.7
    84.7
        hsa-miR-6512-5p
    82.9
    88.1
        hsa-miR-3613-3p
    86.5
    78.0
        hsa-miR-4793-5p
    81.1
    88.1
        hsa-miR-628-3p
    83.8
    83.1
        hsa-miR-1181
    82.9
    83.1
        hsa-miR-3646
    82.0
    84.7
        hsa-miR-4317
    82.9
    83.1
        hsa-miR-5684
    83.8
    81.4
        hsa-miR-1227-5p
    81.1
    84.7
        hsa-miR-3180-5p
    84.7
    78.0
        hsa-miR-4665-5p
    82.9
    81.4
        hsa-miR-129-1-3p
    82.0
    81.4
        hsa-miR-4652-3p
    82.9
    79.7
        hsa-miR-500b
    82.0
    79.7
        hsa-miR-181b-5p
    83.8
    74.6
        hsa-miR-3676-3p
    82.9
    76.3
        hsa-miR-671-5p
    77.5
    86.4
        hsa-miR-1185-1-3p
    78.4
    83.1
        hsa-miR-378d
    78.4
    83.1
        hsa-miR-1271-5p
    81.1
    76.3
        hsa-miR-4433-3p
    78.4
    81.4
        hsa-miR-564
    81.1
    76.3
        hsa-miR-6723-5p
    81.1
    76.3
        hsa-miR-100-5p
    82.9
    71.2
        hsa-miR-135a-3p
    77.5
    81.4
        hsa-miR-181a-2-3p
    80.2
    76.3
        hsa-miR-4666b
    78.4
    79.7
        hsa-miR-98-3p
    79.3
    76.3
        hsa-miR-3940-3p
    77.5
    74.6
        hsa-miR-513c-5p
    74.8
    79.7
        hsa-miR-634
    79.3
    71.2
        hsa-miR-4769-3p
    77.5
    72.9
        hsa-miR-6507-3p
    76.6
    72.9
        hsa-miR-3907
    72.1
    79.7
        hsa-miR-4634
    73.0
    78.0
        hsa-miR-563
    73.9
    74.6
        hsa-miR-892b
    73.9
    74.6
        hsa-miR-103a-2-5p
    74.8
    71.2
        hsa-miR-2392
    73.9
    72.9
        hsa-miR-3127-5p
    72.1
    76.3
        hsa-miR-338-5p
    73.0
    74.6
        hsa-miR-3614-5p
    73.9
    72.9
        hsa-miR-4499
    70.3
    79.7
        hsa-miR-3667-5p
    74.8
    69.5
        hsa-miR-1290
    68.5
    78.0
        hsa-miR-130b-5p
    75.7
    62.7
        hsa-miR-4449
    73.0
    67.8
        hsa-miR-4695-5p
    70.3
    67.8
        hsa-miR-4271
    67.6
    71.2
        hsa-miR-4651
    69.4
    67.8
        hsa-miR-340-5p
    63.1
    74.6
        hsa-miR-133b
    67.6
    61.0
        hsa-miR-199b-5p
    70.3
    55.9
        hsa-miR-200c-3p
    67.6
    61.0
        hsa-miR-4257
    63.1
    69.5
        hsa-miR-150-3p
    62.2
    69.5
        hsa-miR-30c-1-3p
    68.5
    57.6
        hsa-miR-139-3p
    64.9
    62.7
        hsa-miR-625-3p
    62.2
    67.8
        hsa-miR-106b-3p
    67.6
    54.2
        hsa-miR-409-3p
    63.1
    62.7
        hsa-miR-1237-3p
    63.1
    61.0
        hsa-miR-5571-5p
    66.7
    54.2
        hsa-miR-652-5p
    63.1
    61.0
        hsa-miR-196b-5p
    61.3
    62.7
        hsa-miR-22-5p
    64.9
    55.9
        hsa-miR-338-3p
    64.0
    55.9
        hsa-miR-26b-3p
    62.2
    55.9
        hsa-miR-4261
    55.9
    67.8
        hsa-miR-345-5p
    60.4
    57.6
        hsa-miR-10a-5p
    58.6
    59.3
        hsa-miR-3176
    56.8
    62.7
        hsa-miR-1224-5p
    56.8
    61.0
        hsa-miR-4462
    55.9
    62.7
        hsa-miR-4728-3p
    58.6
    57.6
        hsa-miR-193a-5p
    59.5
    54.2
        hsa-miR-664b-5p
    55.9
    61.0
        hsa-miR-3141
    53.2
    64.4
        hsa-miR-6075
    55.9
    59.3
        hsa-miR-6086
    55.0
    61.0
        hsa-miR-99b-5p
    55.9
    59.3
        hsa-miR-1307-3p
    58.6
    52.5
        hsa-miR-148b-5p
    56.8
    55.9
        hsa-miR-15a-3p
    59.5
    50.8
        hsa-miR-6513-3p
    61.3
    47.5
        hsa-miR-590-5p
    54.1
    57.6
        hsa-miR-199a-3p
    52.3
    59.3
        hsa-miR-301a-3p
    55.0
    52.5
        hsa-miR-4698
    51.4
    59.3
        hsa-miR-491-5p
    56.8
    49.2
        hsa-miR-4701-5p
    53.2
    54.2
        hsa-miR-572
    53.2
    54.2
        hsa-let-7e-5p
    52.3
    54.2
        hsa-miR-134
    52.3
    54.2
        hsa-miR-335-5p
    51.4
    54.2
        hsa-miR-4646-3p
    54.1
    49.2
        hsa-miR-4463
    51.4
    52.5
        hsa-miR-5690
    56.8
    39.0
        hsa-miR-1972
    46.8
    50.8
        hsa-miR-769-5p
    48.6
    47.5
        hsa-miR-126-5p
    43.2
    55.9
        hsa-miR-192-3p
    52.3
    39.0
        hsa-miR-4800-5p
    42.3
    52.5
        hsa-miR-212-3p
    42.3
    50.8
        hsa-miR-5010-3p
    43.2
    49.2
        hsa-miR-641
    48.6
    39.0
        hsa-miR-3648
    40.5
    50.8
        hsa-miR-548ai
    45.9
    40.7
        hsa-miR-3663-3p
    42.3
    44.1
        hsa-miR-4298
    38.7
    49.2
        hsa-miR-4707-3p
    41.4
    44.1
        hsa-miR-1273e
    38.7
    47.5
        hsa-miR-487b
    36.9
    49.2
        hsa-miR-1227-3p
    40.5
    40.7
        hsa-miR-18a-3p
    43.2
    35.6
        hsa-miR-769-3p
    40.5
    39.0
        hsa-miR-598
    39.6
    39.0
        hsa-miR-1273f
    38.7
    37.3
        hsa-miR-663a
    38.7
    37.3
        hsa-miR-2110
    36.9
    39.0
        hsa-miR-371a-5p
    34.2
    42.4
        hsa-miR-483-3p
    36.0
    39.0
        hsa-miR-5195-3p
    37.8
    35.6
        hsa-miR-654-3p
    35.1
    35.6
        hsa-miR-877-3p
    34.2
    37.3
        hsa-miR-3190-5p
    34.2
    35.6
        hsa-miR-4697-5p
    34.2
    35.6
        hsa-miR-617
    36.0
    32.2
        hsa-miR-4324
    35.1
    30.5
        hsa-miR-4534
    31.5
    35.6
        hsa-miR-4633-5p
    28.8
    39.0
        hsa-miR-4538
    27.9
    39.0
        hsa-miR-664a-5p
    29.7
    35.6
        hsa-miR-4312
    26.1
    37.3
        hsa-miR-6076
    25.2
    35.6
        hsa-miR-5585-3p
    28.8
    27.1
        hsa-miR-125b-1-3p
    25.2
    32.2
        hsa-miR-4632-5p
    27.0
    28.8
        hsa-miR-139-5p
    27.9
    25.4
        hsa-miR-4767
    33.3
    15.3
        hsa-miR-34a-5p
    27.9
    22.0
        hsa-miR-4455
    25.2
    27.1
        hsa-miR-330-3p
    28.8
    18.6
        hsa-miR-1180
    25.2
    23.7
        hsa-miR-193b-3p
    28.8
    16.9
        hsa-miR-4784
    20.7
    30.5
        hsa-miR-4667-5p
    23.4
    23.7
        hsa-miR-660-3p
    23.4
    23.7
        hsa-miR-4731-3p
    22.5
    23.7
        hsa-miR-503-5p
    24.3
    20.3
        hsa-miR-378g
    18.0
    27.1
        hsa-miR-4481
    19.8
    23.7
        hsa-miR-138-2-3p
    18.9
    23.7
        hsa-miR-1469
    20.7
    20.3
        hsa-miR-4327
    21.6
    18.6
        hsa-miR-1236-5p
    17.1
    23.7
        hsa-miR-152
    18.0
    22.0
        hsa-miR-21-3p
    18.9
    20.3
        hsa-miR-4697-3p
    16.2
    25.4
        hsa-miR-548aa
    17.1
    23.7
        hsa-miR-636
    19.8
    18.6
        hsa-miR-767-3p
    18.0
    22.0
        hsa-miR-4689
    23.4
    8.5
        hsa-miR-3679-3p
    19.8
    13.6
        hsa-miR-4326
    15.3
    22.0
        hsa-miR-2276
    17.1
    16.9
        hsa-miR-3137
    17.1
    16.9
        hsa-miR-4734
    16.2
    18.6
        hsa-miR-181c-5p
    18.0
    13.6
        hsa-miR-921
    17.1
    15.3
        hsa-miR-3688-3p
    15.3
    16.9
        hsa-miR-4274
    15.3
    16.9
        hsa-miR-4758-5p
    16.2
    13.6
        hsa-miR-5010-5p
    15.3
    15.3
        hsa-miR-4488
    13.5
    16.9
        hsa-miR-483-5p
    14.4
    15.3
        hsa-miR-542-5p
    15.3
    13.6
        hsa-miR-623
    11.7
    20.3
        hsa-miR-650
    9.9
    23.7
        hsa-miR-3188
    11.7
    18.6
        hsa-miR-378b
    10.8
    20.3
        hsa-miR-576-5p
    12.6
    16.9
        hsa-miR-20a-3p
    15.3
    10.2
        hsa-miR-4487
    15.3
    10.2
        hsa-miR-1976
    12.6
    13.6
        hsa-miR-3605-3p
    12.6
    13.6
        hsa-miR-4647
    9.9
    18.6
        hsa-miR-4700-3p
    11.7
    15.3
        hsa-miR-6503-3p
    12.6
    13.6
        hsa-miR-3615
    10.8
    13.6
        hsa-miR-424-3p
    10.8
    13.6
        hsa-miR-4636
    11.7
    11.9
        hsa-miR-4646-5p
    9.0
    16.9
        hsa-miR-3610
    12.6
    8.5
        hsa-miR-557
    9.9
    13.6
        hsa-miR-718
    14.4
    5.1
        hsa-miR-193b-5p
    9.0
    13.6
        hsa-miR-3692-5p
    12.6
    6.8
        hsa-miR-509-3-5p
    11.7
    8.5
        hsa-miR-1470
    10.8
    8.5
        hsa-miR-28-3p
    8.1
    13.6
        hsa-miR-378f
    10.8
    8.5
        hsa-miR-4252
    6.3
    16.9
        hsa-miR-4417
    11.7
    6.8
        hsa-miR-4498
    10.8
    8.5
        hsa-miR-491-3p
    8.1
    13.6
        hsa-miR-495-3p
    7.2
    15.3
        hsa-miR-5096
    12.6
    5.1
        hsa-miR-1229-3p
    6.3
    15.3
        hsa-miR-299-5p
    6.3
    15.3
        hsa-miR-3138
    6.3
    15.3
        hsa-miR-335-3p
    8.1
    11.9
        hsa-miR-3682-3p
    8.1
    11.9
        hsa-miR-485-3p
    8.1
    11.9
        hsa-miR-630
    7.2
    13.6
        hsa-miR-936
    9.0
    10.2
        hsa-miR-101-5p
    10.8
    5.1
        hsa-miR-122-5p
    9.9
    6.8
        hsa-miR-4446-3p
    5.4
    15.3
        hsa-miR-4518
    8.1
    10.2
        hsa-miR-4640-3p
    6.3
    13.6
        hsa-miR-5189
    8.1
    10.2
        hsa-miR-6129
    8.1
    10.2
        hsa-miR-1471
    8.1
    8.5
        hsa-miR-29b-2-5p
    8.1
    8.5
        hsa-miR-5003-5p
    5.4
    13.6
        hsa-miR-1273c
    6.3
    10.2
        hsa-miR-190a
    9.0
    5.1
        hsa-miR-3675-3p
    8.1
    6.8
        hsa-miR-6511b-5p
    5.4
    11.9
        hsa-miR-1291
    4.5
    11.9
        hsa-miR-3934-5p
    4.5
    11.9
        hsa-miR-4737
    7.2
    6.8
        hsa-miR-486-3p
    6.3
    8.5
        hsa-miR-5580-3p
    2.7
    15.3
        hsa-miR-671-3p
    7.2
    6.8
        hsa-miR-154-5p
    6.3
    6.8
        hsa-miR-3158-5p
    7.2
    5.1
        hsa-miR-337-3p
    3.6
    11.9
        hsa-miR-363-5p
    4.5
    10.2
        hsa-miR-376a-3p
    3.6
    11.9
        hsa-miR-5190
    3.6
    11.9
        hsa-miR-5701
    6.3
    6.8
        hsa-miR-770-5p
    3.6
    11.9
        hsa-miR-1226-5p
    3.6
    10.2
        hsa-miR-1267
    6.3
    5.1
        hsa-miR-1306-3p
    6.3
    5.1
        hsa-miR-3154
    4.5
    8.5
        hsa-miR-329
    3.6
    10.2
        hsa-miR-4659b-3p
    7.2
    3.4
        hsa-miR-6134
    3.6
    10.2
        hsa-miR-181a-3p
    4.5
    6.8
        hsa-miR-1827
    5.4
    5.1
        hsa-miR-3926
    2.7
    10.2
        hsa-miR-662
    4.5
    6.8
        hsa-miR-127-3p
    4.5
    5.1
        hsa-miR-148a-5p
    3.6
    6.8
        hsa-miR-18b-3p
    3.6
    6.8
        hsa-miR-202-3p
    2.7
    8.5
        hsa-miR-4325
    2.7
    8.5
        hsa-miR-4673
    5.4
    3.4
        hsa-miR-4730
    6.3
    1.7
        hsa-miR-489
    4.5
    5.1
        hsa-miR-584-3p
    4.5
    5.1
        hsa-miR-6720-3p
    1.8
    10.2
        hsa-let-7i-3p
    5.4
    1.7
        hsa-miR-1307-5p
    3.6
    5.1
        hsa-miR-204-5p
    4.5
    3.4
        hsa-miR-218-5p
    4.5
    3.4
        hsa-miR-378e
    3.6
    5.1
        hsa-miR-3911
    2.7
    6.8
        hsa-miR-543
    3.6
    5.1
        hsa-miR-5703
    3.6
    5.1
        hsa-miR-589-3p
    3.6
    5.1
        hsa-miR-885-5p
    1.8
    8.5
        hsa-let-7g-3p
    3.6
    3.4
        hsa-miR-1185-2-3p
    4.5
    1.7
        hsa-miR-1238-5p
    3.6
    3.4
        hsa-miR-19b-1-5p
    3.6
    3.4
        hsa-miR-3130-5p|
    2.7
    5.1
        hsa-miR-3163
    3.6
    3.4
        hsa-miR-377-3p
    2.7
    5.1
        hsa-miR-421
    2.7
    5.1
        hsa-miR-4419a
    2.7
    5.1
        hsa-miR-4425
    3.6
    3.4
        hsa-miR-4470
    3.6
    3.4
        hsa-miR-4539
    2.7
    5.1
        hsa-miR-516a-5p
    3.6
    3.4
        hsa-miR-610
    4.5
    1.7
        hsa-miR-628-5p
    3.6
    3.4
        hsa-miR-99b-3p
    2.7
    5.1
        hsa-let-7f-2-3p
    2.7
    3.4
        hsa-miR-193a-3p
    0.9
    6.8
        hsa-miR-195-3p
    2.7
    3.4
        hsa-miR-221-5p
    3.6
    1.7
        hsa-miR-223-5p
    4.5
    0.0
        hsa-miR-23a-5p
    1.8
    5.1
        hsa-miR-25-5p
    1.8
    5.1
        hsa-miR-3616-3p
    0.9
    6.8
        hsa-miR-376c-3p
    1.8
    5.1
        hsa-miR-4701-3p
    2.7
    3.4
        hsa-miR-4743-5p
    1.8
    5.1
        hsa-miR-5008-5p
    1.8
    5.1
        hsa-miR-570-3p
    2.7
    3.4
        hsa-miR-595
    1.8
    5.1
        hsa-miR-6716-3p
    3.6
    1.7
        hsa-miR-887
    2.7
    3.4
        hsa-miR-1299
    0.9
    5.1
        hsa-miR-133a
    2.7
    1.7
        hsa-miR-198
    1.8
    3.4
        hsa-miR-3622b-5p
    0.9
    5.1
        hsa-miR-373-5p
    3.6
    0.0
        hsa-miR-3917
    0.9
    5.1
        hsa-miR-409-5p
    1.8
    3.4
        hsa-miR-4440
    2.7
    1.7
        hsa-miR-4514
    0.9
    5.1
        hsa-miR-4535
    0.9
    5.1
        hsa-miR-4668-5p
    0.9
    5.1
        hsa-miR-4776-5p
    0.9
    5.1
        hsa-miR-4793-3p
    2.7
    1.7
        hsa-miR-542-3p
    0.9
    5.1
        hsa-miR-548am-5p
    1.8
    3.4
        hsa-miR-548q
    1.8
    3.4
        hsa-miR-582-5p
    2.7
    1.7
        hsa-miR-654-5p
    1.8
    3.4
        hsa-miR-758-3p
    2.7
    1.7
        hsa-miR-760
    0.0
    6.8
        hsa-miR-765
    1.8
    3.4
        hsa-miR-875-5p
    1.8
    3.4
        hsa-miR-106a-3p
    2.7
    0.0
        hsa-miR-1236-3p
    0.0
    5.1
        hsa-miR-1255b-5p
    1.8
    1.7
        hsa-miR-181c-3p
    2.7
    0.0
        hsa-miR-26a-2-3p
    0.9
    3.4
        hsa-miR-298
    0.9
    3.4
        hsa-miR-3194-5p
    0.9
    3.4
        hsa-miR-3620-3p
    1.8
    1.7
        hsa-miR-374a-3p
    1.8
    1.7
        hsa-miR-411-3p
    1.8
    1.7
        hsa-miR-4475
    0.9
    3.4
        hsa-miR-4476
    0.9
    3.4
        hsa-miR-4716-5p
    1.8
    1.7
        hsa-miR-4762-3p
    1.8
    1.7
        hsa-miR-544a
    1.8
    1.7
        hsa-miR-548d-5p
    1.8
    1.7
        hsa-miR-561-3p
    1.8
    1.7
        hsa-miR-5695
    2.7
    0.0
        hsa-miR-580
    1.8
    1.7
        hsa-miR-612
    1.8
    1.7
        hsa-miR-622
    0.9
    3.4
        hsa-miR-670
    1.8
    1.7
        hsa-miR-744-3p
    1.8
    1.7
        hsa-let-7a-3p
    0.9
    1.7
        hsa-miR-1255a
    0.9
    1.7
        hsa-miR-1270
    0.9
    1.7
        hsa-miR-185-3p
    0.0
    3.4
        hsa-miR-186-3p
    0.0
    3.4
        hsa-miR-187-5p
    0.9
    1.7
        hsa-miR-194-3p
    1.8
    0.0
        hsa-miR-200b-5p
    0.9
    1.7
        hsa-miR-2052
    0.0
    3.4
        hsa-miR-224-5p
    0.9
    1.7
        hsa-miR-2964a-5p
    0.9
    1.7
        hsa-miR-29b-1-5p
    0.9
    1.7
        hsa-miR-30d-3p
    0.0
    3.4
        hsa-miR-3150b-5p
    1.8
    0.0
        hsa-miR-3184-3p
    0.9
    1.7
        hsa-miR-32-3p
    0.9
    1.7
        hsa-miR-323a-3p
    1.8
    0.0
        hsa-miR-3663-5p
    1.8
    0.0
        hsa-miR-370
    0.9
    1.7
        hsa-miR-376a-5p
    0.9
    1.7
        hsa-miR-381-3p
    0.9
    1.7
        hsa-miR-3924
    0.0
    3.4
        hsa-miR-3945
    0.9
    1.7
        hsa-miR-422a
    1.8
    0.0
        hsa-miR-4289
    0.9
    1.7
        hsa-miR-432-3p
    0.0
    3.4
        hsa-miR-4468
    0.9
    1.7
        hsa-miR-452-3p
    0.9
    1.7
        hsa-miR-452-5p
    0.0
    3.4
        hsa-miR-4714-5p
    0.9
    1.7
        hsa-miR-504
    1.8
    0.0
        hsa-miR-5088
    0.0
    3.4
        hsa-miR-518b
    0.9
    1.7
        hsa-miR-545-3p
    0.9
    1.7
        hsa-miR-545-5p
    0.9
    1.7
        hsa-miR-548at-5p
    0.9
    1.7
        hsa-miR-556-3p
    0.9
    1.7
        hsa-miR-559
    0.0
    3.4
        hsa-miR-5686
    0.9
    1.7
        hsa-miR-5692a
    0.0
    3.4
        hsa-miR-586
    0.9
    1.7
        hsa-miR-590-3p
    1.8
    0.0
        hsa-miR-601
    0.9
    1.7
        hsa-miR-607
    0.9
    1.7
        hsa-miR-619
    0.0
    3.4
        hsa-miR-624-3p
    1.8
    0.0
        hsa-miR-642a-5p
    0.9
    1.7
        hsa-miR-645
    0.9
    1.7
        hsa-miR-668
    0.9
    1.7
        hsa-miR-6722-3p
    1.8
    0.0
        hsa-miR-675-5p
    0.9
    1.7
        hsa-miR-888-3p
    0.9
    1.7
        hsa-miR-937-3p
    0.9
    1.7
        hsa-miR-939-3p
    0.9
    1.7
        hsa-miR-10b-3p
    0.0
    1.7
        hsa-miR-10b-5p
    0.0
    1.7
        hsa-miR-1183
    0.0
    1.7
        hsa-miR-1208
    0.0
    1.7
        hsa-miR-1226-3p
    0.0
    1.7
        hsa-miR-1228-5p
    0.0
    1.7
        hsa-miR-124-3p
    0.9
    0.0
        hsa-miR-124-5p
    0.0
    1.7
        hsa-miR-1247-3p
    0.9
    0.0
        hsa-miR-1261
    0.0
    1.7
        hsa-miR-1269a
    0.0
    1.7
        hsa-miR-1273d
    0.9
    0.0
        hsa-miR-1285-5p
    0.0
    1.7
        hsa-miR-1287
    0.0
    1.7
        hsa-miR-1296
    0.0
    1.7
        hsa-miR-143-3p
    0.9
    0.0
        hsa-miR-1538
    0.0
    1.7
        hsa-miR-16-1-3p
    0.9
    0.0
        hsa-miR-184
    0.9
    0.0
        hsa-miR-188-3p
    0.9
    0.0
        hsa-miR-1909-5p
    0.0
    1.7
        hsa-miR-1910
    0.0
    1.7
        hsa-miR-196a-3p
    0.9
    0.0
        hsa-miR-19a-5p
    0.0
    1.7
        hsa-miR-19b-2-5p
    0.9
    0.0
        hsa-miR-205-5p
    0.9
    0.0
        hsa-miR-206
    0.0
    1.7
        hsa-miR-20b-3p
    0.9
    0.0
        hsa-miR-2115-5p
    0.9
    0.0
        hsa-miR-218-1-3p
    0.0
    1.7
        hsa-miR-218-2-3p
    0.9
    0.0
        hsa-miR-2277-3p
    0.0
    1.7
        hsa-miR-2681-3p
    0.9
    0.0
        hsa-miR-26a-1-3p
    0.9
    0.0
        hsa-miR-27b-5p
    0.0
    1.7
        hsa-miR-297
    0.0
    1.7
        hsa-miR-29a-5p
    0.0
    1.7
        hsa-miR-300
    0.9
    0.0
        hsa-miR-301b
    0.9
    0.0
        hsa-miR-302b-3p
    0.0
    1.7
        hsa-miR-30a-3p
    0.9
    0.0
        hsa-miR-3132
    0.0
    1.7
        hsa-miR-3149
    0.0
    1.7
        hsa-miR-3157-5p
    0.0
    1.7
        hsa-miR-3161
    0.0
    1.7
        hsa-miR-32-5p
    0.9
    0.0
        hsa-miR-330-5p
    0.9
    0.0
        hsa-miR-33a-3p
    0.9
    0.0
        hsa-miR-33b-5p
    0.0
    1.7
        hsa-miR-34c-3p
    0.0
    1.7
        hsa-miR-3591-3p
    0.0
    1.7
        hsa-miR-3607-3p
    0.9
    0.0
        hsa-miR-3654
    0.0
    1.7
        hsa-miR-3666
    0.0
    1.7
        hsa-miR-367-5p
    0.9
    0.0
        hsa-miR-374b-3p
    0.9
    0.0
        hsa-miR-379-3p
    0.9
    0.0
        hsa-miR-380-5p
    0.9
    0.0
        hsa-miR-3935
    0.0
    1.7
        hsa-miR-3937
    0.0
    1.7
        hsa-miR-3942-3p
    0.9
    0.0
        hsa-miR-3976
    0.0
    1.7
        hsa-miR-410
    0.0
    1.7
        hsa-miR-4259
    0.0
    1.7
        hsa-miR-4272
    0.0
    1.7
        hsa-miR-4290
    0.0
    1.7
        hsa-miR-4294
    0.0
    1.7
        hsa-miR-431-5p
    0.0
    1.7
        hsa-miR-4420
    0.9
    0.0
        hsa-miR-4422
    0.0
    1.7
        hsa-miR-4489
    0.0
    1.7
        hsa-miR-4500
    0.9
    0.0
        hsa-miR-450a-5p
    0.9
    0.0
        hsa-miR-450b-3p
    0.0
    1.7
        hsa-miR-451b
    0.9
    0.0
        hsa-miR-4520b-3p
    0.0
    1.7
        hsa-miR-4639-3p
    0.9
    0.0
        hsa-miR-4648
    0.0
    1.7
        hsa-miR-4657
    0.0
    1.7
        hsa-miR-4677-3p
    0.9
    0.0
        hsa-miR-4677-5p
    0.9
    0.0
        hsa-miR-4685-3p
    0.9
    0.0
        hsa-miR-4694-3p
    0.0
    1.7
        hsa-miR-4695-3p
    0.0
    1.7
        hsa-miR-4707-5p
    0.0
    1.7
        hsa-miR-4710
    0.0
    1.7
        hsa-miR-4723-3p
    0.9
    0.0
        hsa-miR-4726-5p
    0.0
    1.7
        hsa-miR-4733-3p
    0.0
    1.7
        hsa-miR-4733-5p
    0.9
    0.0
        hsa-miR-4736
    0.0
    1.7
        hsa-miR-4740-5p
    0.0
    1.7
        hsa-miR-4755-3p
    0.0
    1.7
        hsa-miR-4762-5p
    0.0
    1.7
        hsa-miR-4763-5p
    0.0
    1.7
        hsa-miR-4785
    0.0
    1.7
        hsa-miR-4792
    0.9
    0.0
        hsa-miR-4800-3p
    0.9
    0.0
        hsa-miR-493-5p
    0.0
    1.7
        hsa-miR-5007-3p
    0.9
    0.0
        hsa-miR-5011-5p
    0.9
    0.0
        hsa-miR-5087
    0.0
    1.7
        hsa-miR-5093
    0.0
    1.7
        hsa-miR-513a-3p
    0.0
    1.7
        hsa-miR-513c-3p
    0.0
    1.7
        hsa-miR-517c-3p
    0.0
    1.7
        hsa-miR-518a-5p
    0.0
    1.7
        hsa-miR-5196-3p
    0.9
    0.0
        hsa-miR-520c-3p
    0.9
    0.0
        hsa-miR-541-3p
    0.0
    1.7
        hsa-miR-548a-3p
    0.9
    0.0
        hsa-miR-548ap-3p
    0.9
    0.0
        hsa-miR-548d-3p
    0.9
    0.0
        hsa-miR-548e
    0.9
    0.0
        hsa-miR-552
    0.9
    0.0
        hsa-miR-558
    0.0
    1.7
        hsa-miR-5591-3p
    0.0
    1.7
        hsa-miR-5681b
    0.9
    0.0
        hsa-miR-5692b
    0.9
    0.0
        hsa-miR-5692c
    0.9
    0.0
        hsa-miR-571
    0.0
    1.7
        hsa-miR-588
    0.9
    0.0
        hsa-miR-589-5p
    0.9
    0.0
        hsa-miR-593-3p
    0.9
    0.0
        hsa-miR-597
    0.0
    1.7
        hsa-miR-609
    0.9
    0.0
        hsa-miR-615-3p
    0.0
    1.7
        hsa-miR-615-5p
    0.0
    1.7
        hsa-miR-616-5p
    0.9
    0.0
        hsa-miR-618
    0.0
    1.7
        hsa-miR-621
    0.9
    0.0
        hsa-miR-631
    0.0
    1.7
        hsa-miR-633
    0.0
    1.7
        hsa-miR-637
    0.0
    1.7
        hsa-miR-639
    0.9
    0.0
        hsa-miR-642b-5p
    0.9
    0.0
        hsa-miR-646
    0.9
    0.0
        hsa-miR-6509-3p
    0.9
    0.0
        hsa-miR-651
    0.9
    0.0
        hsa-miR-6511a-3p
    0.0
    1.7
        hsa-miR-657
    0.9
    0.0
        hsa-miR-6722-5p
    0.0
    1.7
        hsa-miR-708-5p
    0.9
    0.0
        hsa-miR-767-5p
    0.9
    0.0
        hsa-miR-875-3p
    0.0
    1.7
        hsa-miR-876-5p
    0.9
    0.0
        hsa-miR-877-5p
    0.9
    0.0
        hsa-miR-891a
    0.9
    0.0
        hsa-miR-920
    0.9
    0.0
        hsa-miR-922
    0.9
    0.0
        hsa-miR-924
    0.0
    1.7
        hsa-miR-92a-2-5p
    0.9
    0.0
        hsa-miR-935
    0.9
    0.0
        hsa-miR-938
    0.0
    1.7
        hsa-miR-943
    0.9
    0.0
        hsa-miR-423-5p
    100.0
    100.0
    No statistical analyses for this end point

    Secondary: Functional Assessment of Cancer Therapy – Hepatobiliary Questionnaire (FACT-Hep) in Randomized portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model

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    End point title
    Functional Assessment of Cancer Therapy – Hepatobiliary Questionnaire (FACT-Hep) in Randomized portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model [21]
    End point description
    FACT-Hep consists of 27-item FACT-G, and 18-item Hepatobiliary Subscale. FACT-Hep questionnaire uses 5-point Likert rating scale, range '0'-not at all to '4'. FACT-Hep total score ranges from 0 to 180, where highest score represents maximum achievable quality of life. Domains of FACT-G include Physical Well-Being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB) and Functional Well-Being (FWB). Hepatobiliary disease specific items include: swelling or cramps, losing weight, gastrointestinal (GI)-related questions, lack of energy, side effects, pain, fatigue, usual activities, jaundice, fevers, itching, taste of food and chills. Eight of the items (pain, back pain, stomach pain/discomfort, lack of energy, fatigue, nausea, weight loss and jaundice) make up FACT-Hepatobiliary Symptom Index (FHSI-8), and are considered to be symptoms specific to hepatobiliary cancer. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: units on a scale
        least squares mean (confidence interval 95%)
    123.33 (120.17 to 126.50)
    135.22 (129.17 to 141.27)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006 [22]
    Method
    Longitudinal mixed effect analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -11.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.7
         upper limit
    -5.08
    Notes
    [22] - No adjustment made for multiple comparisons.

    Secondary: Functional Assessment of Cancer Therapy - General (FACT-G) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model

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    End point title
    Functional Assessment of Cancer Therapy - General (FACT-G) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model [23]
    End point description
    FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate QoL in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general Health-Related QoL (HRQoL): PWB, SWB, EWB and FWB; each ranging from 0 (not at all) to 4 (very much). FACT-G ranged between 0 and 108. Since questions could be reversed coded, as appropriate, before calculating FACT-G, 0 and 108 could be considered worst and best health states. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: units on a scale
        least squares mean (confidence interval 95%)
    71.20 (69.00 to 73.41)
    78.81 (74.68 to 82.93)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0014 [24]
    Method
    Longitudinal mixed effect analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.27
         upper limit
    -2.94
    Notes
    [24] - No adjustment made for multiple comparisons.

    Secondary: Functional Assessment of Cancer Therapy (FACT)-Hepatobiliary Symptom Index-8 (FHSI-8) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model

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    End point title
    Functional Assessment of Cancer Therapy (FACT)-Hepatobiliary Symptom Index-8 (FHSI-8) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model [25]
    End point description
    The FACT-Hep includes the FACT-G and a hepatobiliary module. The hepatobiliary disease specific items include: swelling or cramps, losing weight, GI related questions, lack of energy, side effects, pain, fatigue, usual activities, jaundice, fevers, itching, taste of food and chills. Eight of the items (pain, back pain, stomach pain/discomfort, lack of energy, fatigue, nausea, weight loss, and jaundice) make up the FHSI-8, and are considered to be symptoms specific to hepatobiliary cancer. FHSI-8 total score ranges from 0 to 32 where “0” is a severely symptomatic subject and the highest score indicates an asymptomatic subject. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: units on a scale
        least squares mean (confidence interval 95%)
    23.42 (22.77 to 24.07)
    26.69 (25.35 to 28.03)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [26]
    Method
    Longitudinal mixed effect analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.76
         upper limit
    -1.78
    Notes
    [26] - No adjustment made for multiple comparisons.

    Secondary: Functional Assessment of Cancer Therapy-G (FACT-G) Subscales in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model

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    End point title
    Functional Assessment of Cancer Therapy-G (FACT-G) Subscales in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model [27]
    End point description
    FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate QoL in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general HRQoL: PWB, SWB, EWB and FWB. Each of the individual subscale, except EWB has 7 items and each integer scored 0 to 4 making a maximum possible score of 28 (range 0 to 28). EWB has 6 items and each integer scored 0 to 4 making a maximum possible score of 24 (range 0 to 24). For all the 4 scales, higher values correspond to better health. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: units on a scale
    least squares mean (confidence interval 95%)
        PWB
    19.39 (18.72 to 20.07)
    23.13 (21.76 to 24.50)
        SWB
    18.94 (18.05 to 19.83)
    20.21 (18.66 to 21.77)
        EWB
    17.23 (16.63 to 17.84)
    17.71 (16.54 to 18.89)
        FWB
    15.76 (14.88 to 16.65)
    17.83 (16.19 to 19.47)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis presented above is for FACT-G PWB. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [28]
    Method
    Longitudinal mixed effect analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.26
         upper limit
    -2.21
    Notes
    [28] - No adjustment made for multiple comparisons.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis presented above is for FACT-G SWB. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1642 [29]
    Method
    Longitudinal mixed effect analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.07
         upper limit
    0.52
    Notes
    [29] - No adjustment made for multiple comparisons.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Analysis presented above is for FACT-G EWB. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4759 [30]
    Method
    Longitudinal mixed effect analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    0.84
    Notes
    [30] - No adjustment made for multiple comparisons.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Analysis presented above is for FACT-G FWB. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0288 [31]
    Method
    Longitudinal mixed effect analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.92
         upper limit
    -0.21
    Notes
    [31] - No adjustment made for multiple comparisons.

    Secondary: Functional Assessment of Cancer Therapy - Hepatobiliary Cancer Subscale (FACT Hep-CS18) Questionnaire in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model

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    End point title
    Functional Assessment of Cancer Therapy - Hepatobiliary Cancer Subscale (FACT Hep-CS18) Questionnaire in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model [32]
    End point description
    This subscale consists of 18 items rated on a scale from ‘0’ - not at all to ‘4’ - very much regarding how much each item was present in the last 7 days. FACT-Hep-CS18 total score ranges from 0 to 72. The higher score reflects better QoL or fewer symptoms. The 18 items of this scale are associated with hepatocellular carcinoma. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: units on a scale
        least squares mean (confidence interval 95%)
    51.78 (50.46 to 53.10)
    56.74 (54.08 to 59.39)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011 [33]
    Method
    Longitudinal mixed effect analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.93
         upper limit
    -1.99
    Notes
    [33] - No adjustment made for multiple comparisons.

    Secondary: Functional Assessment of Cancer Therapy - Hepatobiliary Cancer Trial Outcome Index (FACT Hep-TOI) Questionnaire in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model

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    End point title
    Functional Assessment of Cancer Therapy - Hepatobiliary Cancer Trial Outcome Index (FACT Hep-TOI) Questionnaire in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model [34]
    End point description
    The trial outcome index is defined to be the sum (PWB+FWB+HepCS), making it 32 items altogether. Each ranges from '0' – not at all to '4' - very much regarding how much each item was present in the last 7 days. FACT Hep –TOI total score ranges from 0 to 128, where the highest score represents a maximum achievable quality of life. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: units on a scale
        least squares mean (confidence interval 95%)
    87.28 (84.98 to 89.58)
    97.73 (93.24 to 102.23)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [35]
    Method
    Longitudinal mixed effect analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -10.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.49
         upper limit
    -5.42
    Notes
    [35] - No adjustment made for multiple comparisons.

    Secondary: Time to Deterioration (TTD) Based on the Composite Endpoint in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model

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    End point title
    Time to Deterioration (TTD) Based on the Composite Endpoint in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model [36]
    End point description
    A time to deterioration (TTD) analysis was performed for FHSI-8. Time to deterioration was defined as the time between date of randomization and date of the event. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    From randomization to death or tumor progression or FHSI-8 mean score decrease >=3 points, whichever comes first
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: months
        median (confidence interval 95%)
    1.9 (1.8 to 1.9)
    1.9 (1.8 to 2.7)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Assuming proportional hazards, a hazard ratio <1 indicates reduction in hazard rate to favor Axitinib, hazard ratio >1 indicates reduction to favor Placebo.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9182 [37]
    Method
    1-sided, unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.252
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.923
         upper limit
    1.698
    Notes
    [37] - The p-value is from a 1-sided log-rank test.

    Secondary: EuroQoL (EQ-5D)- Health State Profile Utility Score in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model

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    End point title
    EuroQoL (EQ-5D)- Health State Profile Utility Score in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model [38]
    End point description
    EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state. Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: units on a scale
        least squares mean (confidence interval 95%)
    0.67 (0.63 to 0.70)
    0.79 (0.72 to 0.86)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0024
    Method
    Longitudinal mixed effect analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    -0.04

    Secondary: EuroQoL Visual Analogue Scale (EQ-VAS) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model

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    End point title
    EuroQoL Visual Analogue Scale (EQ-VAS) in Randomized Portion: Overall Between-Treatment Comparison Based on the Repeated Measures Mixed Effects Model [39]
    End point description
    EQ-5D VAS in rates the subject's overall health status using values from 0 (worst imaginable) to 100 (best imaginable). The below table included the model estimated average based on all the observed values/time points. The mixed effect model was used. FAS included all randomized subjects, and subjects were classified according to the randomized treatment arm regardless of what treatment, if any, was received.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 pre-dose and before any other clinical assessments, every 4 weeks thereafter while on study, at end of study treatment/withdrawal, and follow-up and at Day 28 after last dose date
    Notes
    [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    134
    68
    Units: units on a scale
        least squares mean (confidence interval 95%)
    68.67 (66.11 to 71.23)
    75.70 (70.40 to 81.00)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Axitinib v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0193
    Method
    Longitudinal mixed effect analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.91
         upper limit
    -1.15

    Secondary: Number of Subjects With Dose-Limiting Toxicities (DLTs) in Non-Randomized Portion

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    End point title
    Number of Subjects With Dose-Limiting Toxicities (DLTs) in Non-Randomized Portion [40]
    End point description
    Number of Child-Pugh Class B (score 7) subjects with DLT was evaluated during Cycle 1 of treatment in the non-randomized portion of the study. Subjects with Child-Pugh Class B, score 7 are only included in this analysis.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (4 weeks)
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Child-Pugh Class B
    Number of subjects analysed
    7
    Units: subjects
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) in Non-Randomized Portion

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (AEs) in Non-Randomized Portion [41]
    End point description
    An AE was an untoward medical occurrence in a subject who received study treatment without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. The grade of an AE was determined according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. The safety analysis population included subjects who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.
    End point type
    Secondary
    End point timeframe
    Up to 28 days after last dose of study drug (up to 6 years)
    Notes
    [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Child-Pugh Class A Child-Pugh Class B
    Number of subjects analysed
    15
    7
    Units: subjects
        Subjects with AEs
    15
    7
        Subjects with SAEs
    10
    3
        Subjects ≥Grade 3 AEs
    13
    5
        Subjects Grade 5 AEs
    4
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Related Adverse Events (AEs) in Non-Randomized Portion

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    End point title
    Number of Subjects With Treatment-Related Adverse Events (AEs) in Non-Randomized Portion [42]
    End point description
    Treatment-related AE was any untoward medical occurrence in a subject with causal relationship to the study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The grade of an AE was determined according to CTCAE Version 3.0. The safety analysis population included subjects who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.
    End point type
    Secondary
    End point timeframe
    Up to 28 days after last dose of study drug (up to 6 years)
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Child-Pugh Class A Child-Pugh Class B
    Number of subjects analysed
    15
    7
    Units: subjects
        Subjects with AEs
    14
    6
        Subjects with SAEs
    2
    2
        Subjects ≥Grade 3 AEs
    9
    4
        Subjects Grade 5 AEs
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) in Randomized Portion

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (AEs) in Randomized Portion [43]
    End point description
    An AE was an untoward medical occurrence in a subject who received study treatment without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes: death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. The grade of an AE was determined according to CTCAE Version 3.0. The safety analysis population included all randomized subjects who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.
    End point type
    Secondary
    End point timeframe
    Up to 28 days after last dose of study drug (up to 6 years)
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    133
    68
    Units: subjects
        Subjects with AEs
    131
    63
        Subjects with SAEs
    62
    16
        Subjects with Grade ≥3 AEs
    109
    26
        Subjects with Grade 5 AEs
    16
    8
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Related Adverse Events (AEs) in Randomized Portion

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    End point title
    Number of Subjects With Treatment-Related Adverse Events (AEs) in Randomized Portion [44]
    End point description
    Treatment-related AE was any untoward medical occurrence in a subject with causal relationship to the study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The grade of an AE was determined according to CTCAE Version 3.0. The safety analysis population included all randomized subjects who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.
    End point type
    Secondary
    End point timeframe
    Up to 28 days after last dose of study drug (up to 6 years)
    Notes
    [44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Axitinib and Placebo arm only.
    End point values
    Axitinib Placebo
    Number of subjects analysed
    133
    68
    Units: subjects
        Subjects with AEs
    128
    40
        Subjects with SAEs
    24
    1
        Subjects with Grade ≥3 AEs
    90
    12
        Subjects with Grade 5 AEs
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to follow-up visit (up to 6 years)
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Child-Pugh Class A
    Reporting group description
    Subjects with Child-Pugh Class A disease (score 5 or 6) were enrolled into the non-randomized portion at selected sites only at a starting axitinib dose of 5 mg BID.

    Reporting group title
    Axitinib
    Reporting group description
    Subjects in this group received axitinib + best supportive care. Subjects with Child-Pugh Class A disease (score 5 or 6) were enrolled into the randomized portion at a starting axitinib dose of 5 mg BID orally. Subjects with Child-Pugh Class B disease (score 7) were to begin enrollment into the randomized portion of the study following determination of the recommended axitinib starting dose in the non-randomized portion. Study treatment was administered in cycles of 4 weeks in duration.

    Reporting group title
    Placebo
    Reporting group description
    Subjects in this group received placebo + best supportive care. Treatment was administered in cycles of 4 weeks in duration. The starting dose of placebo for subjects with Child Pugh Class A disease (score 5 or 6) was chosen as 5 mg BID. Subjects with Child-Pugh Class B, score 7 received placebo that was determined from the non-randomized portion of the study until the recommended starting dose was determined, subjects with Child-Pugh Class B, score 7, were not permitted to enter the randomized portion of the study.

    Reporting group title
    Child-Pugh Class B
    Reporting group description
    Subjects with Child-Pugh Class B disease (score 7) at selected sites were initially enrolled only into the non randomized portion of this study to determine the recommended starting dose of axitinib for this population.

    Serious adverse events
    Child-Pugh Class A Axitinib Placebo Child-Pugh Class B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 15 (66.67%)
    62 / 133 (46.62%)
    16 / 68 (23.53%)
    3 / 7 (42.86%)
         number of deaths (all causes)
    14
    100
    52
    6
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Tumour rupture
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 133 (3.01%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    3 / 15 (20.00%)
    8 / 133 (6.02%)
    4 / 68 (5.88%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 12
    0 / 6
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 133 (2.26%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Dysthymic disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 133 (2.26%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 133 (1.50%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem infarction
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma hepatic
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 133 (1.50%)
    0 / 68 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 133 (3.01%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 133 (2.26%)
    2 / 68 (2.94%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    2 / 68 (2.94%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 15 (0.00%)
    7 / 133 (5.26%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 9
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 133 (3.01%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 133 (1.50%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising myositis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 133 (2.26%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 133 (1.50%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess rupture
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 133 (1.50%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian abscess
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 133 (0.75%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 133 (0.75%)
    1 / 68 (1.47%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 133 (2.26%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Child-Pugh Class A Axitinib Placebo Child-Pugh Class B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    130 / 133 (97.74%)
    55 / 68 (80.88%)
    7 / 7 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 15 (46.67%)
    72 / 133 (54.14%)
    9 / 68 (13.24%)
    3 / 7 (42.86%)
         occurrences all number
    10
    128
    9
    5
    Hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour associated fever
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 15 (0.00%)
    27 / 133 (20.30%)
    3 / 68 (4.41%)
    2 / 7 (28.57%)
         occurrences all number
    0
    59
    3
    5
    Chest pain
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    7
    0
    0
    0
    Chills
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    1
    Face oedema
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Fatigue
         subjects affected / exposed
    12 / 15 (80.00%)
    46 / 133 (34.59%)
    18 / 68 (26.47%)
    2 / 7 (28.57%)
         occurrences all number
    23
    81
    25
    2
    Malaise
         subjects affected / exposed
    0 / 15 (0.00%)
    13 / 133 (9.77%)
    1 / 68 (1.47%)
    2 / 7 (28.57%)
         occurrences all number
    0
    19
    1
    3
    Influenza like illness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 15 (6.67%)
    8 / 133 (6.02%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    11
    0
    0
    Oedema peripheral
         subjects affected / exposed
    4 / 15 (26.67%)
    14 / 133 (10.53%)
    10 / 68 (14.71%)
    1 / 7 (14.29%)
         occurrences all number
    6
    21
    13
    1
    Oedema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    1
    Pain
         subjects affected / exposed
    5 / 15 (33.33%)
    0 / 133 (0.00%)
    0 / 68 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    6