Trial Outcomes & Findings for E7050 in Combination With Sorafenib Versus Sorafenib Alone as First Line Therapy in Participants With Hepatocellular Carcinoma (NCT NCT01271504)

NCT ID: NCT01271504

Last Updated: 2021-05-12

Results Overview

DLTs were defined as clinically significant adverse events (AEs) (non-hematological, hematological and other events) occurring less than or equal to (\<=) 28 days after commencing study treatment and considered to be at least possibly or probably related to study drug by the Investigator. Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v.4.0).

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 102 participants
• Primary outcome timeframe: Cycle 1 (Cycle length is 28 days)
• Results posted on: 2021-05-12

Participant Flow

Participants took part in the study at 23 investigative sites in Belgium, Italy, Spain, the Ukraine, the United Kingdom and the United States from 19 July 2011 to 23 June 2015.

A total of 102 participants were enrolled and randomized in this study, out of which, 15 participants were enrolled in Phase 1b of study, of which 14 received study drug, and 87 participants were enrolled in Phase 2 of study, of which 84 participants received the study drug.

Participant milestones

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Participants received golvatinib 200 milligram (mg), tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of progressive disease (PD), unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 Days).	Phase 2: Sorafenib 400 mg Participants received sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 Days).
Overall Study STARTED	7	8	44	43
Overall Study Treated	7	7	42	42
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	7	8	44	43

Reasons for withdrawal

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg Participants received golvatinib 200 milligram (mg), tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of progressive disease (PD), unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 Days).	Phase 2: Sorafenib 400 mg Participants received sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 Days).
Overall Study Death	7	6	32	32
Overall Study Lost to Follow-up	0	1	3	1
Overall Study Protocol Violation	0	0	0	2
Overall Study Administrative Reasons	0	0	6	5
Overall Study Withdrawal by Subject	0	0	1	3
Overall Study Other	0	1	2	0

Baseline Characteristics

E7050 in Combination With Sorafenib Versus Sorafenib Alone as First Line Therapy in Participants With Hepatocellular Carcinoma

Baseline characteristics by cohort

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 Days).	Phase 2: Sorafenib 400 mg n=42 Participants Participants received sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 Days).	Total n=98 Participants Total of all reporting groups
Age, Continuous	52.9 years STANDARD_DEVIATION 15.68 • n=5 Participants	68.1 years STANDARD_DEVIATION 9.56 • n=7 Participants	63.2 years STANDARD_DEVIATION 9.31 • n=5 Participants	65.8 years STANDARD_DEVIATION 8.02 • n=4 Participants	63.9 years STANDARD_DEVIATION 9.82 • n=21 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	2 Participants n=7 Participants	10 Participants n=5 Participants	12 Participants n=4 Participants	25 Participants n=21 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	5 Participants n=7 Participants	32 Participants n=5 Participants	30 Participants n=4 Participants	73 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants	8 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants n=5 Participants	5 Participants n=7 Participants	36 Participants n=5 Participants	36 Participants n=4 Participants	84 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	5 Participants n=5 Participants	1 Participants n=4 Participants	6 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants	1 Participants n=4 Participants	5 Participants n=21 Participants
Race (NIH/OMB) White	7 Participants n=5 Participants	5 Participants n=7 Participants	37 Participants n=5 Participants	37 Participants n=4 Participants	86 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants	4 Participants n=21 Participants

PRIMARY outcome

Timeframe: Cycle 1 (Cycle length is 28 days)

Population: Safety analysis set included all participants enrolled and randomized into the Phase 1b of this study, except those who dropped out of the study prior to receiving any study drug, or were without any safety assessment after first dose of study drug.

DLTs were defined as clinically significant adverse events (AEs) (non-hematological, hematological and other events) occurring less than or equal to (<=) 28 days after commencing study treatment and considered to be at least possibly or probably related to study drug by the Investigator. Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v.4.0).

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)	1 Participants	2 Participants

PRIMARY outcome

Timeframe: Day -7: 0-72 hours post-dose

Population: Pharmacokinetic (PK) analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=6 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day -7	1330 nanograms per milliliter (ng/mL) Standard Deviation 858	2320 nanograms per milliliter (ng/mL) Standard Deviation 2720

PRIMARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=6 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	1820 ng/mL Standard Deviation 750	2820 ng/mL Standard Deviation 3170

PRIMARY outcome

Timeframe: Cycle 1 Day 28: 0-24 hours post-dose

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters. Here, overall number analyzed "N" were the participants who were evaluable for the outcome measure.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=4 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	2140 ng/mL Standard Deviation 757	4570 ng/mL Standard Deviation 3610

PRIMARY outcome

Timeframe: Day -7: 0-72 hours post-dose

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=6 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day -7	2 hour Interval 1.03 to 24.3	2.38 hour Interval 1.0 to 4.0

PRIMARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=6 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	3 hour Interval 2.0 to 23.8	3.53 hour Interval 2.0 to 24.0

PRIMARY outcome

Timeframe: Cycle 1 Day 28: 0-24 hours post-dose

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters. Here, overall number analyzed "N" were the participants who were evaluable for the outcome measure.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=4 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	2.98 hour Interval 1.08 to 4.03	5.01 hour Interval 0.833 to 23.5

PRIMARY outcome

Timeframe: Day -7: 0-72 hours post-dose

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=6 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day -7	30400 nanogram*hour per milliliter(ng*h/mL) Standard Deviation 18900	47200 nanogram*hour per milliliter(ng*h/mL) Standard Deviation 37500

PRIMARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=6 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1	24000 ng*h/mL Standard Deviation 14300	36800 ng*h/mL Standard Deviation 38000

PRIMARY outcome

Timeframe: Cycle 1 Day 28: 0-24 hours post-dose (Cycle length is 28 days)

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters. Here, overall number analyzed "N" were the participants who were evaluable for the outcome measure.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=4 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1	35300 ng*h/mL Standard Deviation 16700	68700 ng*h/mL Standard Deviation 72500

PRIMARY outcome

Timeframe: Day -7: 0-72 hours post-dose

Population: PK analysis set was defined as all participants in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=6 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 1b: t1/2: Terminal Elimination Half-life for Golvatinib When Administered in Combination With Sorafenib at Day -7	38.1 hour Standard Deviation 6.82	35.9 hour Standard Deviation 11.7

PRIMARY outcome

Timeframe: From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Population: Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	42 Participants	40 Participants
Phase 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	20 Participants	17 Participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Population: Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug. Here, overall number analyzed included are those participants who were evaluable for this outcome measure.

AE severity was graded using CTCAE version 4.0, where Grade 1 = mild, Grade 2 = moderate, Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death related to the AE. All AEs graded as 4 or 5 were considered to be serious. Higher grade indicates more severe condition.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=40 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Number of Participants With AEs by Severity Grades Any AE: Grade 5	8 Participants	2 Participants
Phase 2: Number of Participants With AEs by Severity Grades Any AE: Grade 1	0 Participants	2 Participants
Phase 2: Number of Participants With AEs by Severity Grades Any AE: Grade 2	4 Participants	6 Participants
Phase 2: Number of Participants With AEs by Severity Grades Any AE: Grade 3	24 Participants	25 Participants
Phase 2: Number of Participants With AEs by Severity Grades Any AE: Grade 4	6 Participants	5 Participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Population: Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.

Number of participants are reported with AEs related to Vital signs including body temperature, respiratory rate, heart rate, height, and weight.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Number of Participants With Adverse Events Related to Vital Signs	2 Participants	0 Participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Population: Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Number of Participants With Clinically Significant Change From Baseline in Blood Pressure Including Systolic and Diastolic Blood Pressures	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Population: Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.

Number of participants with worst shifts post baseline in ECOG-PS levels were reported. ECOG has 6 levels (0-5). Level 0 is the best status (fully active, able to carry on all pre-disease performance without restriction); Level 1 is mildly restricted (Restricted in physically strenuous activity but ambulatory ad able to carry out work of a light or sedentary nature, e.g. light house work, office work); Level 2 is more restricted (Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours); Level 3 is restricted (Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours); Level 4 is highly restricted (completely disabled; cannot carry on any selfcare; totally confined to bed or chair); and Level 5 is death (dead).

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Number of Participants With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG PS Level change from 0 to 1	7 Participants	4 Participants
Phase 2: Number of Participants With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG PS Level change from 0 to 2	3 Participants	7 Participants
Phase 2: Number of Participants With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG PS Level change from 0 to 3	3 Participants	0 Participants
Phase 2: Number of Participants With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG PS Level change from 1 to 2	4 Participants	6 Participants
Phase 2: Number of Participants With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG PS Level change from 0 to 4	0 Participants	1 Participants
Phase 2: Number of Participants With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ECOG PS Level change from 1 to 3	0 Participants	5 Participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Population: Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Population: Safety analysis set included all participants enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Number of Participants With Markedly Abnormal Change From Baseline in Electrocardiograms (ECGs) Parameters	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From the date of randomization until the date of PD (up to approximately 3 years 11 months)

Population: Modified Intent-to-Treat (MITT) set included all participants randomized in the applicable study arm, except a participant who dropped out of such arm prior to receiving any comparator or investigative drug. Here 'N' (Overall number of participants analyzed) signifies participants with events (PD).

TTP was defined as the time from the date of randomization until the date of PD of such participants disease based on independent assessments according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. PD was defined as at least a 20% increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. TTP was estimated and analyzed using Kaplan-Meier (K-M) method.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=31 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=36 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Time to Progression (TTP)	10.29 weeks Interval 8.57 to 17.14	16.00 weeks Interval 8.57 to 23.29

SECONDARY outcome

Timeframe: From the date of randomization until the earlier of the following two events: the date of PD or the date of death (Up to approximately 3 years 11 months)

Population: MITT analysis set included all participants randomized in the applicable study arm, except a participant who dropped out of such arm prior to receiving any comparator or investigative drug. Here 'N' (Overall number of participants analyzed) signifies participants with events (PD or/and death).

PFS was defined as the time from the date of randomization of a participant until (1) the date of first documented progression (2) the date of such participant's death due to any cause based on independent assessments according to RECIST v. 1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using KM method.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=32 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=37 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Progression Free Survival (PFS)	10.29 weeks Interval 8.14 to 17.14	15.57 weeks Interval 8.57 to 23.14

SECONDARY outcome

Timeframe: At 12 weeks

Population: MITT analysis set included all participants randomized in the applicable study arm, except a participant who dropped out of such arm prior to receiving any comparator or investigative drug. Here 'N' (Overall number of participants analyzed) signifies participants with events (PD or/and death).

The PFS rate at week 12 was defined as the percentage of participants who were still alive without disease progression at 12 weeks from the date of randomization. PFS was defined as the time from the date of randomization of a participant until (1) the date of first documented progression (2) the date of such participant's death due to any cause based on independent assessments according to RECIST v. 1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=32 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=37 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Percentage of Participants With PFS at Week 12	47.4 percentage of participants	57.5 percentage of participants

SECONDARY outcome

Timeframe: From the date of randomization until the date of death (Up to approximately 3 years 11 months)

Population: MITT analysis set included all participants randomized in the applicable study arm, except a participant who dropped out of such arm prior to receiving any comparator or investigative drug.

OS was defined as the time from the date of randomization until the date of death. Participants were censored at the date of last known alive. OS was analyzed using K-M method.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Overall Survival (OS)	27.86 weeks Interval 20.86 to 67.71	37.71 weeks Interval 23.29 to 57.0

SECONDARY outcome

Timeframe: From the date of randomization until disease progression or death (Up to approximately 3 years 11 months)

Population: MITT analysis set included all participants randomized in the applicable study arm, except a participant who dropped out of such arm prior to receiving any comparator or investigative drug.

Overall response rate was defined as percentage of participants with best confirmed response (CR) or partial response (PR) assessed by investigator per RECIST v1.1. A confirmatory scan was required after no less than 4 weeks and no later than 8 weeks, starting on the date that the response was first recorded. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<)10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Outcome measures

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=42 Participants Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).
Phase 2: Percentage of Participants With Overall Response	4.8 percentage of participant Interval 0.0 to 11.2	4.8 percentage of participant Interval -1.7 to 11.2

Adverse Events

Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg

Serious events: 4 serious events

Other events: 7 other events

Deaths: 7 deaths

Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg

Serious events: 3 serious events

Other events: 6 other events

Deaths: 6 deaths

Phase 2: Golvatinib 200 mg + Sorafenib 400 mg

Serious events: 20 serious events

Other events: 40 other events

Deaths: 32 deaths

Phase 2: Sorafenib 400 mg

Serious events: 17 serious events

Other events: 40 other events

Deaths: 32 deaths

Serious adverse events

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 participants at risk Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=7 participants at risk Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 days).	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg n=42 participants at risk Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 days).	Phase 2: Sorafenib 400 mg n=42 participants at risk Participants received sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 days).
Nervous system disorders Ischaemic Stroke	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Hepatic Encephalopathy	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Abdominal Pain	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Nausea	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Vomiting	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Gastroenteritis	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Transaminases Increased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Metabolic Encephalopathy	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Psychiatric disorders Confusional State	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Nephropathy Toxic	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Acute Respiratory Failure	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Pleural Effusion	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Dermatitis Acneiform	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Dermatitis Psoriasiform	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Blood and lymphatic system disorders Anaemia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Blood and lymphatic system disorders Febrile Neutropenia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Cardiac disorders Cardiac Arrest	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Abdominal Distension	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Constipation	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Diverticular Perforation	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Dysphagia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Gastric Ulcer	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Haematemesis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Haematochezia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Oesophageal Varices Haemorrhage	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Pancreatitis Acute	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Upper Gastrointestinal Haemorrhage	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders General Physical Health Deterioration	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Non-Cardiac Chest Pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Oedema Peripheral	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Hepatic Failure	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Liver Disorder	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Cellulitis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Escherichia Urinary Tract Infection	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Infected Skin Ulcer	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Infective Exacerbation Of Chronic Obstructive Airways Disease	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Klebsiella Infection	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Liver Abscess	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Pneumonia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Scrotal Abscess	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Sepsis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Septic Shock	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Urinary Tract Infection	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Injury, poisoning and procedural complications Spinal Compression Fracture	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hypoalbuminaemia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma Gastric	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant Neoplasm Progression	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Ataxia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Renal Impairment	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Palmar-Plantar Erythrodysaesthesia Syndrome	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Aneurysm Ruptured	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Hypertensive Crisis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Hypotension	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Renal Failure	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Other adverse events

Measure	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg n=7 participants at risk Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 days).	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg n=7 participants at risk Participants received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 days).	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg n=42 participants at risk Participants received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 days).	Phase 2: Sorafenib 400 mg n=42 participants at risk Participants received sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 days).
General disorders Malaise	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Reproductive system and breast disorders Vaginal Haemorrhage	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Reproductive system and breast disorders Vaginal Polyp	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Reproductive system and breast disorders Vulvovaginal Discomfort	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Dysphonia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	11.9% 5/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Dyspnoea	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	16.7% 7/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	9.5% 4/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Hiccups	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Paranasal sinus hypersecretion	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Throat tightness	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Rash maculo-papular	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Dermatitis acneiform	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Dermatitis psoriasiform	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Dry skin	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Night sweats	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Rash generalised	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Skin irritation	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Urticaria	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Deep vein thrombosis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Hot flush	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Orthostatic hypotension	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	9.5% 4/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Lethargy	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Blister	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	9.5% 4/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Pain of skin	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	9.5% 4/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Abdominal distension	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Psychiatric disorders Depression	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Dysuria	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Haemorrhoids	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Hyperkeratosis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Pollakiuria	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Transaminases increased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Psychiatric disorders Confusional state	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Gastric ulcer	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Haematoma	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hyperlipasaemia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Liver disorder	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Plantar erythema	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Protein urine present	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Renal failure acute	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Skin exfoliation	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Skin ulcer	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Abdominal hernia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Acid fast bacilli infection	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Acidosis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Cardiac disorders Angina pectoris	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Aphonia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Arteriosclerosis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Arthropathy	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Axillary mass	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Bacterial test positive	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Balance disorder	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Blood albumin decreased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Blood potassium increased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Blood urine present	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Body temperature increased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Breath sounds abnormal	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Cardiac disorders Cardiac failure	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Cellulitis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Cholangitis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Injury, poisoning and procedural complications Contusion	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Cystitis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Decubitus ulcer	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Psychiatric disorders Depressed mood	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Dermatitis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Diabetic ulcer	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Ear and labyrinth disorders Ear pruritus	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Early satiety	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Enterocolitis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Reproductive system and breast disorders Erectile dysfunction	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Ear and labyrinth disorders External ear inflammation	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Face oedema	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Facial pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Faecal incontinence	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Faeces soft	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Flushing	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Food poisoning	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Gastric hypomotility	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Gastritis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Gastrointestinal pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Reproductive system and breast disorders Genital lesion	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Globulins increased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Glossitis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Gout	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Groin pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Haematuria	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Hepatic cirrhosis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Hepatic function abnormal	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Hepatic pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Hepatotoxicity	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Endocrine disorders Hyperthyroidism	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hyperuricaemia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Hypothermia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Endocrine disorders Hypothyroidism	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Inflammation	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Influenza	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Influenza like illness	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Injection site haematoma	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Jaundice	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Joint swelling	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Lip blister	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Liver tenderness	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Localised infection	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Localised oedema	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Malabsorption	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Malnutrition	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Melaena	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Mental impairment	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Metabolic acidosis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Monoparesis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Musculoskeletal discomfort	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Myositis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Nasal dryness	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Nephrolithiasis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Reproductive system and breast disorders Nipple pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Oxygen saturation decreased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Pallor	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Paraneoplastic syndrome	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Polyuria	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Portal vein thrombosis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Productive cough	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Reproductive system and breast disorders Prostatic obstruction	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Rash erythematous	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Renal failure	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Retching	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Serum ferritin increased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Cardiac disorders Sinus tachycardia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Sinusitis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Skin fissures	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Skin toxicity	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Somnolence	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Spinal pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Injury, poisoning and procedural complications Subcutaneous haematoma	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Syncope	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Tenosynovitis stenosans	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Reproductive system and breast disorders Testicular pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Reproductive system and breast disorders Testicular swelling	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Thirst	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Thyroxine increased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Tooth abscess	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Toothache	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Urine analysis abnormal	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Varices oesophageal	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Vascular insufficiency	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Viral diarrhoea	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Vulvovaginal candidiasis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Injury, poisoning and procedural complications Wound	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Xerosis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Eye disorders Eye pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Pyrexia	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 6/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Weight Decreased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Musculoskeletal Chest Pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	11.9% 5/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Erythema	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hyperkalaemia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	57.1% 4/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Hypotension	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Respiratory, thoracic and mediastinal disorders Dyspnoea Exertional	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Abdominal Pain Lower	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Chest Pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Injury, poisoning and procedural complications Eye Contusion	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Fungal Skin Infection	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Gastroenteritis Viral	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Generalised Oedema	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Hepatitis C Virus Test Positive	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Keratoacanthoma	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Liver Palpable Subcostal	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Oral candidiasis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Blood and lymphatic system disorders Leukopenia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Vomiting	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	71.4% 5/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	33.3% 14/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	16.7% 7/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Diarrhoea	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	85.7% 6/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	61.9% 26/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	52.4% 22/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Nausea	85.7% 6/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	71.4% 5/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	35.7% 15/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 12/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Fatigue	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	57.1% 4/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	31.0% 13/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 12/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Aspartate Aminotransferase Increased	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	71.4% 5/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	26.2% 11/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	31.0% 13/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Asthenia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 12/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 12/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Palmar-Plantar Erythrodysaesthesia Syndrome	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	35.7% 15/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	21.4% 9/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Rash	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	31.0% 13/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	21.4% 9/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Abdominal Pain	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	71.4% 5/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	19.0% 8/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	16.7% 7/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Blood Alkaline Phosphatase Increased	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	57.1% 4/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 6/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	26.2% 11/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Vascular disorders Hypertension	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	19.0% 8/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	21.4% 9/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Alanine Aminotransferase Increased	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	57.1% 4/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	16.7% 7/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	19.0% 8/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Abdominal Pain Upper	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	19.0% 8/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	11.9% 5/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Ascites	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	19.0% 8/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	11.9% 5/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Constipation	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	16.7% 7/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	11.9% 5/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Headache	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	19.0% 8/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	9.5% 4/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Pruritus	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	21.4% 9/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Blood and lymphatic system disorders Anaemia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 6/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Hepatobiliary disorders Hyperbilirubinaemia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	57.1% 4/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	11.9% 5/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 6/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Skin and subcutaneous tissue disorders Alopecia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	19.0% 8/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Blood and lymphatic system disorders Thrombocytopenia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	9.5% 4/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	9.5% 4/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Blood and lymphatic system disorders Neutropenia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Blood and lymphatic system disorders Anaemia Macrocytic	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Blood and lymphatic system disorders Lymphadenopathy	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Blood and lymphatic system disorders Lymphopenia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Dry Mouth	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Gastrooesophageal Reflux Disease	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Abdominal Discomfort	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Anal Fissure	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Anorectal Discomfort	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Dyspepsia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	11.9% 5/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Dysphagia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Flatulence	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Hypoaesthesia Oral	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Stomatitis	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 6/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	9.5% 4/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Gastrointestinal disorders Leukopenia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Eye disorders Dry Eye	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Nasopharyngitis	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Eye disorders Vision Blurred	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Oedema Peripheral	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	11.9% 5/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Mucosal Inflammation	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Pain	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Chills	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Oedema	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
General disorders Vessel Puncture Site Bruise	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Blood Thyroid Stimulating Hormone Increased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Immune system disorders Drug Hypersensitivity	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Urinary Tract Infection	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 6/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Bronchitis	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Oesophageal Candidiasis	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Pneumonia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Infections and infestations Upper Respiratory Tract Infection	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Injury, poisoning and procedural complications Fall	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Blood Creatinine Increased	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Blood Bilirubin Increased	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	11.9% 5/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Lipase Increased	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	16.7% 7/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Ammonia Increased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Amylase Increased	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	9.5% 4/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Blood Lactate Dehydrogenase Increased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Heart Rate Increased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Investigations Platelet Count Decreased	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hypoalbuminaemia	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	57.1% 4/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hypocalcaemia	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	57.1% 4/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hypokalaemia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	57.1% 4/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Decreased Appetite	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	31.0% 13/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	35.7% 15/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hypomagnesaemia	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hyponatraemia	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hyperglycaemia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hypophosphataemia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	9.5% 4/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Dehydration	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Fluid Overload	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hypermagnesaemia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders Hypervolaemia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Metabolism and nutrition disorders hypoproteinaemia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Back Pain	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	16.7% 7/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Neck Pain	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Muscular Weakness	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Muscle Spasms	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Pain In Extremity	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	11.9% 5/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Bone Pain	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Bursitis	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Paraesthesia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Dizziness	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Dementia	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Dysgeusia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	9.5% 4/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Hepatic Encephalopathy	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	7.1% 3/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Memory Impairment	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Neuropathy Peripheral	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Nervous system disorders Restless Legs Syndrome	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Psychiatric disorders Anxiety	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	42.9% 3/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Psychiatric disorders Agitation	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Psychiatric disorders Insomnia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	11.9% 5/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Proteinuria	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	28.6% 2/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	4.8% 2/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Nocturia	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Renal Failure Chronic	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)
Renal and urinary disorders Urinary Incontinence	0.00% 0/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	14.3% 1/7 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	0.00% 0/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)	2.4% 1/42 • From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Additional Information

Eisai Medical Information

Eisai Inc.

Phone: 1-888-274-2378

Email: esi_oncmedinfo@eisai.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place