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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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

A4061058

ISRCTN number

US NCT number

NCT01210495

WHO universal trial number (UTN)

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

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

20 Mar 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

20 Dec 2016

Was the trial ended prematurely?

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

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Hong Kong: 13

Country: Number of subjects enrolled

Japan: 44

Country: Number of subjects enrolled

Korea, Republic of: 44

Country: Number of subjects enrolled

United States: 19

Country: Number of subjects enrolled

China: 20

Country: Number of subjects enrolled

Taiwan: 19

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

France: 33

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Hungary: 3

Country: Number of subjects enrolled

Italy: 8

Country: Number of subjects enrolled

Slovakia: 4

Country: Number of subjects enrolled

United Kingdom: 8

Worldwide total number of subjects

224

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

131

From 65 to 84 years

85 years and over

Subject disposition

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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).

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 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

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.

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.

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.

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
Other unspecified	-	-	6	-
Death	14	7	112	54
Subject Refused Further Follow-Up	1	-	11	2
Study Terminated by Sponsor	-	-	4	11
Lost to follow-up	-	-	1	1

Baseline characteristics

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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

Reporting group title

Axitinib

Reporting group description

Reporting group title

Placebo

Reporting group description

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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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

Reporting group title

Axitinib

Reporting group description

Reporting group title

Placebo

Reporting group description

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 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 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 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 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 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: nanogramshour per milliliter (nghr/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

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

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

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

Top of page

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 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

Top of page

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 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

Top of page

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 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

Top of page

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 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 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 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 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

Top of page

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 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

Top of page

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 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

Top of page

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 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

Top of page

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 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

Top of page

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 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

Top of page

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

Top of page

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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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 name

MedDRA

Dictionary version

17.0

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

Reporting group title

Placebo

Reporting group description

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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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

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%)
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
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
General disorders and administration site conditions
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 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
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
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
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
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
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
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
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	0	0	0
Pyrexia
subjects affected / exposed	3 / 15 (20.00%)	16 / 133 (12.03%)	3 / 68 (4.41%)	1 / 7 (14.29%)
occurrences all number	5	21	3	1
Catheter site pain
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 15 (20.00%)	16 / 133 (12.03%)	6 / 68 (8.82%)	0 / 7 (0.00%)
occurrences all number	7	17	7	0
Dysphonia
subjects affected / exposed	6 / 15 (40.00%)	33 / 133 (24.81%)	0 / 68 (0.00%)	3 / 7 (42.86%)
occurrences all number	11	48	0	3
Dyspnoea
subjects affected / exposed	3 / 15 (20.00%)	13 / 133 (9.77%)	6 / 68 (8.82%)	1 / 7 (14.29%)
occurrences all number	8	15	6	1
Epistaxis
subjects affected / exposed	1 / 15 (6.67%)	10 / 133 (7.52%)	2 / 68 (2.94%)	0 / 7 (0.00%)
occurrences all number	4	10	2	0
Haemoptysis
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
Interstitial lung disease
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Nasal congestion
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Oropharyngeal pain
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
Nasal inflammation
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Productive cough
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
Upper respiratory tract inflammation
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Agitation
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Depression
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Insomnia
subjects affected / exposed	2 / 15 (13.33%)	12 / 133 (9.02%)	3 / 68 (4.41%)	1 / 7 (14.29%)
occurrences all number	2	16	5	1
Irritability
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 15 (13.33%)	8 / 133 (6.02%)	2 / 68 (2.94%)	0 / 7 (0.00%)
occurrences all number	2	10	3	0
Alpha 1 foetoprotein increased
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Ammonia increased
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 15 (13.33%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	3	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	4 / 15 (26.67%)	10 / 133 (7.52%)	4 / 68 (5.88%)	0 / 7 (0.00%)
occurrences all number	6	13	6	0
Blood bilirubin increased
subjects affected / exposed	1 / 15 (6.67%)	7 / 133 (5.26%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	19	0	0
Blood creatinine increased
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
Blood thyroid stimulating hormone increased
subjects affected / exposed	1 / 15 (6.67%)	9 / 133 (6.77%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	10	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	3 / 15 (20.00%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	3	0	0	0
Neutrophil count decreased
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Platelet count decreased
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
Weight decreased
subjects affected / exposed	5 / 15 (33.33%)	36 / 133 (27.07%)	2 / 68 (2.94%)	3 / 7 (42.86%)
occurrences all number	12	77	2	3
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Fall
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Laceration
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Procedural pain
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Congenital, familial and genetic disorders
Hydrocele
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
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Nervous system disorders
Dysgeusia
subjects affected / exposed	0 / 15 (0.00%)	9 / 133 (6.77%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	9	0	0
Dizziness
subjects affected / exposed	6 / 15 (40.00%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	8	0	0	0
Headache
subjects affected / exposed	5 / 15 (33.33%)	21 / 133 (15.79%)	3 / 68 (4.41%)	2 / 7 (28.57%)
occurrences all number	10	21	4	3
Hepatic encephalopathy
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
Neuropathy peripheral
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Peripheral sensory neuropathy
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
Tremor
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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Thrombocytopenia
subjects affected / exposed	0 / 15 (0.00%)	8 / 133 (6.02%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	13	0	0
Ear and labyrinth disorders
Ear disorder
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
Eye disorders
Ocular surface disease
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	2 / 15 (13.33%)	5 / 133 (3.76%)	7 / 68 (10.29%)	0 / 7 (0.00%)
occurrences all number	3	6	7	0
Abdominal pain
subjects affected / exposed	6 / 15 (40.00%)	45 / 133 (33.83%)	12 / 68 (17.65%)	1 / 7 (14.29%)
occurrences all number	12	72	16	1
Abdominal pain upper
subjects affected / exposed	2 / 15 (13.33%)	17 / 133 (12.78%)	3 / 68 (4.41%)	1 / 7 (14.29%)
occurrences all number	9	20	4	1
Anal inflammation
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
Ascites
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
Constipation
subjects affected / exposed	5 / 15 (33.33%)	21 / 133 (15.79%)	8 / 68 (11.76%)	2 / 7 (28.57%)
occurrences all number	6	25	9	2
Diarrhoea
subjects affected / exposed	9 / 15 (60.00%)	71 / 133 (53.38%)	8 / 68 (11.76%)	1 / 7 (14.29%)
occurrences all number	30	201	10	1
Dry mouth
subjects affected / exposed	1 / 15 (6.67%)	7 / 133 (5.26%)	2 / 68 (2.94%)	0 / 7 (0.00%)
occurrences all number	1	7	2	0
Dyspepsia
subjects affected / exposed	5 / 15 (33.33%)	10 / 133 (7.52%)	6 / 68 (8.82%)	2 / 7 (28.57%)
occurrences all number	9	14	6	3
Enterocolitis
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
Gastritis erosive
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	2
Glossitis
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
Nausea
subjects affected / exposed	5 / 15 (33.33%)	35 / 133 (26.32%)	7 / 68 (10.29%)	3 / 7 (42.86%)
occurrences all number	7	54	8	4
Stomatitis
subjects affected / exposed	3 / 15 (20.00%)	19 / 133 (14.29%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	9	34	0	0
Varices oesophageal
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
Vomiting
subjects affected / exposed	3 / 15 (20.00%)	26 / 133 (19.55%)	7 / 68 (10.29%)	0 / 7 (0.00%)
occurrences all number	3	41	13	0
Hepatobiliary disorders
Hyperbilirubinaemia
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	2
Skin and subcutaneous tissue disorders
Alopecia
alternative assessment type: Systematic
subjects affected / exposed	0 / 15 (0.00%)	6 / 133 (4.51%)	7 / 68 (10.29%)	0 / 7 (0.00%)
occurrences all number	0	6	8	0
Blister
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
Dry skin
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Facial wasting
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Nail disorder
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Night sweats
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	8 / 15 (53.33%)	45 / 133 (33.83%)	4 / 68 (5.88%)	2 / 7 (28.57%)
occurrences all number	33	135	4	2
Petechiae
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Pruritus
subjects affected / exposed	0 / 15 (0.00%)	11 / 133 (8.27%)	8 / 68 (11.76%)	1 / 7 (14.29%)
occurrences all number	0	12	10	1
Rash
subjects affected / exposed	2 / 15 (13.33%)	23 / 133 (17.29%)	2 / 68 (2.94%)	2 / 7 (28.57%)
occurrences all number	2	32	2	2
Skin ulcer
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
Renal and urinary disorders
Chromaturia
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Pollakiuria
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Dysuria
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Proteinuria
subjects affected / exposed	4 / 15 (26.67%)	27 / 133 (20.30%)	1 / 68 (1.47%)	1 / 7 (14.29%)
occurrences all number	9	79	1	5
Endocrine disorders
Hypothyroidism
subjects affected / exposed	4 / 15 (26.67%)	33 / 133 (24.81%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	8	40	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 15 (13.33%)	7 / 133 (5.26%)	1 / 68 (1.47%)	0 / 7 (0.00%)
occurrences all number	4	9	1	0
Arthropathy
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Back pain
subjects affected / exposed	4 / 15 (26.67%)	11 / 133 (8.27%)	11 / 68 (16.18%)	1 / 7 (14.29%)
occurrences all number	7	12	13	1
Flank pain
subjects affected / exposed	4 / 15 (26.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	8	0	0	0
Bone pain
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Muscle spasms
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Muscular weakness
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
Musculoskeletal chest pain
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
Musculoskeletal pain
subjects affected / exposed	2 / 15 (13.33%)	8 / 133 (6.02%)	4 / 68 (5.88%)	0 / 7 (0.00%)
occurrences all number	2	9	6	0
Musculoskeletal discomfort
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Myalgia
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Neck pain
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Pain in extremity
subjects affected / exposed	2 / 15 (13.33%)	7 / 133 (5.26%)	1 / 68 (1.47%)	0 / 7 (0.00%)
occurrences all number	5	8	2	0
Infections and infestations
Bronchitis
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
Cystitis
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
Nasopharyngitis
subjects affected / exposed	0 / 15 (0.00%)	9 / 133 (6.77%)	8 / 68 (11.76%)	1 / 7 (14.29%)
occurrences all number	0	12	9	1
Pneumonia
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	6 / 15 (40.00%)	62 / 133 (46.62%)	14 / 68 (20.59%)	5 / 7 (71.43%)
occurrences all number	12	138	26	8
Dehydration
alternative assessment type: Systematic
subjects affected / exposed	0 / 15 (0.00%)	9 / 133 (6.77%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	10	0	0
Hypercalcaemia
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
Hyperkalaemia
subjects affected / exposed	0 / 15 (0.00%)	9 / 133 (6.77%)	2 / 68 (2.94%)	1 / 7 (14.29%)
occurrences all number	0	10	5	3
Hypoalbuminaemia
subjects affected / exposed	4 / 15 (26.67%)	8 / 133 (6.02%)	1 / 68 (1.47%)	2 / 7 (28.57%)
occurrences all number	4	9	2	2
Hypocalcaemia
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
Hypokalaemia
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	2
Hyponatraemia
subjects affected / exposed	1 / 15 (6.67%)	8 / 133 (6.02%)	3 / 68 (4.41%)	3 / 7 (42.86%)
occurrences all number	1	10	4	4
Hypophosphataemia
subjects affected / exposed	1 / 15 (6.67%)	0 / 133 (0.00%)	0 / 68 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0

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Were there any global substantial amendments to the protocol? Yes

04 Apr 2011

- Inclusion criterion was revised to remove “subjects must have received at least 4 weeks of prior therapy”. - Inclusion criterion was revised to allow enrollment of subjects with mild and clinically irrelevant ascites (i.e., Child-Pugh score of 2). - Exclusion criterion was removed to allow enrollment of subjects with prior history of liver transplant. - Exclusion criterion was revised to be consistent with inclusion criterion to allow enrollment of subjects with mild and clinically irrelevant ascites (i.e., Child-Pugh score of 2). - Exclusion criterion was revised to clarify that subjects with invasion to 1st or 2nd branch of portal vein are allowed. - Exclusion criterion was revised to allow enrollment of subjects whose ulcer is completely healed confirmed by endoscopy prior to study treatment. - One DLT criterion was added ”Compliance with taking the drug through the end of Cycle 1 is <75% because of treatment-related toxicity, regarded as a DLT by both investigator and sponsor”. – “Management of Axitinib-Related Adverse Events” section was revised to emphasize that “Subjects should continue study treatment unless they experience intolerable AEs or if the subject is no longer benefiting from the treatment. In case of drug-related AEs, toxicity should be managed by introducing medication or dose reduction if necessary”. – “SAE” section was revised; added the definition and reporting requirement of potential cases of drug-induced liver injury.

11 Jun 2012

- “AE Follow-up” was clarified when follow-up of an AE by the investigator was required, to reflect current regulatory guidance. - Language about active reporting period was clarified and added necessity to report all SAEs post-active reporting period, to reflect current regulatory requirement. - Definition of AE was updated, including addition of medication error, and clarified that drug abuse and drug dependency are to be considered AEs, to reflect current regulatory requirement. - The definition of persistent or significant disability/incapacity in the context of SAE criteria was clarified to indicate that it includes substantial disruption of the ability to conduct normal life functions. - Clarification of the criteria for laboratory abnormalities that required further evaluation in the context of potential cases of drug-induced liver injury. The recommended list of repeated laboratory tests was updated to include prothrombin time. – “Causality Assessment” was clarified that generally the facts (evidence) or arguments to suggest a causal relationship were to be provided by the investigator.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Secondary: Concentration of Soluble Proteins at Baseline in Randomized Portion

Secondary: Concentration of Soluble Proteins at Baseline in Randomized Portion

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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