Trial Outcomes & Findings for A Multicenter, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-line Treatment of Participants With Unresectable Hepatocellular Carcinoma (NCT NCT01761266)

NCT ID: NCT01761266

Last Updated: 2022-04-05

Results Overview

OS was defined as the duration from the date of randomization until the date of death from any cause. Participants who were lost to follow-up were censored at the last date the participant was known to be alive, and participants who remained alive were censored at the time of data cutoff.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 954 participants
• Primary outcome timeframe: From date of randomization until date of death from any cause (approximately up to 3.8 years)
• Results posted on: 2022-04-05

Participant Flow

Participants took part in the study at 154 investigative sites in Australia, Belgium, Canada, China, France, Germany, Hong Kong, Israel, Italy, Japan, South Korea, Malaysia, Philippines, Poland, Russia, Singapore, Spain, Taiwan, Thailand, United Kingdom, and the United States from 1 March 2013 to 10 March 2021.

A total of 1,492 participants were screened, 954 participants were enrolled and randomized, out of which 951 participants were treated in the study.

Participant milestones

Measure	Lenvatinib Participants received lenvatinib capsules 12 milligram (mg) based on the participant's body weight greater than or equal to (\>=) 60 kilogram (kg) or 8 mg based on the participant's body weight less than (\<) 60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Overall Study STARTED	478	476
Overall Study Treated	476	475
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	478	476

Reasons for withdrawal

Measure	Lenvatinib Participants received lenvatinib capsules 12 milligram (mg) based on the participant's body weight greater than or equal to (\>=) 60 kilogram (kg) or 8 mg based on the participant's body weight less than (\<) 60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Overall Study Death	415	402
Overall Study Lost to Follow-up	8	12
Overall Study Withdrawal by Subject	14	10
Overall Study Sponsor Decision	41	52

Baseline Characteristics

A Multicenter, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-line Treatment of Participants With Unresectable Hepatocellular Carcinoma

Baseline characteristics by cohort

Measure	Lenvatinib n=478 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=476 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Total n=954 Participants Total of all reporting groups
Age, Continuous	61.3 years STANDARD_DEVIATION 11.69 • n=93 Participants	61.2 years STANDARD_DEVIATION 12.01 • n=4 Participants	61.3 years STANDARD_DEVIATION 11.84 • n=27 Participants
Sex: Female, Male Female	73 Participants n=93 Participants	75 Participants n=4 Participants	148 Participants n=27 Participants
Sex: Female, Male Male	405 Participants n=93 Participants	401 Participants n=4 Participants	806 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=93 Participants	11 Participants n=4 Participants	17 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	472 Participants n=93 Participants	465 Participants n=4 Participants	937 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race/Ethnicity, Customized Asian	334 Participants n=93 Participants	326 Participants n=4 Participants	660 Participants n=27 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Race/Ethnicity, Customized Black or African American	7 Participants n=93 Participants	6 Participants n=4 Participants	13 Participants n=27 Participants
Race/Ethnicity, Customized White	135 Participants n=93 Participants	141 Participants n=4 Participants	276 Participants n=27 Participants
Race/Ethnicity, Customized Other	1 Participants n=93 Participants	2 Participants n=4 Participants	3 Participants n=27 Participants

PRIMARY outcome

Timeframe: From date of randomization until date of death from any cause (approximately up to 3.8 years)

Population: The FAS included all participants who were randomized.

OS was defined as the duration from the date of randomization until the date of death from any cause. Participants who were lost to follow-up were censored at the last date the participant was known to be alive, and participants who remained alive were censored at the time of data cutoff.

Outcome measures

Measure	Lenvatinib n=478 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=476 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Overall Survival (OS)	13.6 months 95% Confidence Interval 12.1 • Interval 12.1 to 14.9	12.3 months 95% Confidence Interval 10.4 • Interval 10.4 to 13.9

SECONDARY outcome

Timeframe: From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (approximately up to 3.8 years)

Population: The FAS included all participants who were randomized.

PFS was defined as the time from the date of randomization to the date of first documentation of disease progression based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), or date of death, whichever occurred first. Disease progression was defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.

Outcome measures

Measure	Lenvatinib n=478 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=476 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Progression Free Survival (PFS)	7.4 months 95% Confidence Interval 6.9 • Interval 6.9 to 8.8	3.7 months 95% Confidence Interval 3.6 • Interval 3.6 to 4.6

SECONDARY outcome

Timeframe: The time from the date of randomization to the date of first documentation of disease progression (approximately up to 3.8 years)

Population: The FAS included all participants who were randomized.

TTP was defined as the time from the date of randomization to the date of first documentation of disease progression based on mRECIST. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.

Outcome measures

Measure	Lenvatinib n=478 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=476 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Time to Progression (TTP)	8.9 months 95% Confidence Interval 7.4 • Interval 7.4 to 9.2	3.7 months 95% Confidence Interval 3.6 • Interval 3.6 to 5.4

SECONDARY outcome

Timeframe: From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (approximately up to 3.8 years)

Population: The FAS included all participants who were randomized.

ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) based on mRECIST. CR was defined as disappearance of any intratumoral arterial enhancement in all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of viable (enhancement of arterial phase) target lesions taking as reference to the baseline sum of the diameters of target lesions. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.

Outcome measures

Measure	Lenvatinib n=478 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=476 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Objective Response Rate (ORR)	24.1 percentage of participants 95% Confidence Interval 20.2 • Interval 20.2 to 27.9	9.2 percentage of participants 95% Confidence Interval 6.6 • Interval 6.6 to 11.8

SECONDARY outcome

Timeframe: Baseline up to Off-Treatment Visit (approximately up to 3.8 years)

Population: The FAS included all participants who were randomized.

The EORTC QLQ-C30 included 30 questions comprising 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social) and 9 symptom scales (fatigue, pain, nausea/vomiting, dyspnoea, appetite loss, insomnia, constipation, diarrhea and financial difficulties) and a single global health and QOL status score. Most questions used a 4-point scale (1=Not at all to 4=Very much); 2 questions used a 7-point scale (1= Very poor to 7=Excellent). All domain scores were calculated as an average of item scores and transformed to 0 to 100 score range. A high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/quality of life (QoL) represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problem. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.

Outcome measures

Measure	Lenvatinib n=478 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=476 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Time to Clinically Meaningful Worsening of Health Related Quality of Life (HRQoL) Assessed Using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)	1.7 months 95% Confidence Interval 1.05 • Interval 1.05 to 1.84	1.8 months 95% Confidence Interval 1.05 • Interval 1.05 to 1.84

SECONDARY outcome

Timeframe: Baseline up to Off-Treatment Visit (approximately up to 3.8 years)

Population: The FAS included all participants who were randomized.

The EORTC QLQ-HCC-18 was an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30. EORTC QLQ-HCC 18 questionnaire included 8 symptom scales such as fatigue, jaundice, body image, nutrition, pain, fever, sex life and abdominal swelling. Each individual item ranges from 1 to 4, where 1 = "not at all" and 4 = "very much." All domain scores were calculated as an average of item scores and transformed to 0 to 100 score range. A high score for a functional scale represented a high/healthy level of functioning, a high score for the global health status/quality of life (QoL) represented a high QoL, but a high score for a symptom scale/item represented a high level of symptomatology/problem. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.

Outcome measures

Measure	Lenvatinib n=478 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=476 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Time to Clinically Meaningful Worsening of HRQoL Assessed Using - EORTC QLQ- Hepatocellular Carcinoma Domain (HCC 18) Fatigue	1.9 months 95% Confidence Interval 1.81 • Interval 1.81 to 1.97	1.8 months 95% Confidence Interval 1.74 • Interval 1.74 to 1.87
Time to Clinically Meaningful Worsening of HRQoL Assessed Using - EORTC QLQ- Hepatocellular Carcinoma Domain (HCC 18) Pain	2.7 months 95% Confidence Interval 1.97 • Interval 1.97 to 2.83	2.8 months 95% Confidence Interval 2.73 • Interval 2.73 to 3.72
Time to Clinically Meaningful Worsening of HRQoL Assessed Using - EORTC QLQ- Hepatocellular Carcinoma Domain (HCC 18) Sex Life	7.4 months 95% Confidence Interval 5.46 • Interval 5.46 to 9.17	6.7 months 95% Confidence Interval 4.60 • Interval 4.6 to 13.78
Time to Clinically Meaningful Worsening of HRQoL Assessed Using - EORTC QLQ- Hepatocellular Carcinoma Domain (HCC 18) Abdominal swelling	7.4 months 95% Confidence Interval 5.52 • Interval 5.52 to 9.24	7.4 months 95% Confidence Interval 5.46 • Interval 5.46 to 10.13
Time to Clinically Meaningful Worsening of HRQoL Assessed Using - EORTC QLQ- Hepatocellular Carcinoma Domain (HCC 18) Jaundice	4.6 months 95% Confidence Interval 3.72 • Interval 3.72 to 5.52	3.7 months 95% Confidence Interval 2.86 • Interval 2.86 to 4.73
Time to Clinically Meaningful Worsening of HRQoL Assessed Using - EORTC QLQ- Hepatocellular Carcinoma Domain (HCC 18) Body Image	2.8 months 95% Confidence Interval 2.73 • Interval 2.73 to 3.68	1.9 months 95% Confidence Interval 1.84 • Interval 1.84 to 2.73
Time to Clinically Meaningful Worsening of HRQoL Assessed Using - EORTC QLQ- Hepatocellular Carcinoma Domain (HCC 18) Nutrition	4.1 months 95% Confidence Interval 3.68 • Interval 3.68 to 5.52	2.8 months 95% Confidence Interval 2.04 • Interval 2.04 to 3.06
Time to Clinically Meaningful Worsening of HRQoL Assessed Using - EORTC QLQ- Hepatocellular Carcinoma Domain (HCC 18) Fever	5.5 months 95% Confidence Interval 4.57 • Interval 4.57 to 6.51	3.7 months 95% Confidence Interval 2.99 • Interval 2.99 to 5.52

SECONDARY outcome

Timeframe: Baseline up to Off-Treatment Visit (approximately up to 3.8 years)

Population: The FAS included all participants who were randomized.

The EuroQol five dimension health questionnaire (EQ-5D-3L) assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 3-15 with "3" corresponding to no problems and "15" corresponding to severe problems in the 5 dimensions. EQ-5D-3L also included an EQ visual analogue scale (VAS) that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score was weighted with a range of -0.594 (worst) to 1.0 (best). EQ-5D-3L also included an EQ health utilities index (HUI) where 1.00 indicated perfect health while a score of 0.00 indicated death. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.

Outcome measures

Measure	Lenvatinib n=478 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=476 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Time to Clinically Meaningful Worsening of HRQoL Assessed Using EuroQol Five Dimension Health Questionnaire (EQ-5D-3L) HUI	2.8 months 95% Confidence Interval 1.97 • Interval 1.97 to 3.52	1.9 months 95% Confidence Interval 1.84 • Interval 1.84 to 2.66
Time to Clinically Meaningful Worsening of HRQoL Assessed Using EuroQol Five Dimension Health Questionnaire (EQ-5D-3L) VAS	2.8 months 95% Confidence Interval 2.17 • Interval 2.17 to 3.65	1.9 months 95% Confidence Interval 1.84 • Interval 1.84 to 2.33

SECONDARY outcome

Timeframe: Cycle 1 Day 1, Cycle 2 Day 1: pre-dose, 0.5-4 and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 2-12 hours post-dose (cycle length= 28 days)

Population: The pharmacokinetic (PK) analysis set included all participants who had received at least 1 dose of lenvatinib and had at least 1 quantifiable lenvatinib concentration.

AUC was assessed on Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 1 Day 15. Summarized data for all time points was reported. As planned, data for this secondary endpoint was collected and analyzed up to the primary completion date.

Outcome measures

Measure	Lenvatinib n=150 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=318 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib	1969.6 nanogram*hour per milliliter (ng*h/mL) Standard Deviation 743.0	2120.9 nanogram*hour per milliliter (ng*h/mL) Standard Deviation 685.6

OTHER_PRE_SPECIFIED outcome

Timeframe: From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (approximately up to 3.8 years)

Population: The FAS included all participants who were randomized.

DCR was defined as the percentage of participants with a best overall response of CR or PR, or stable disease (SD). Best overall response of SD must have been >=7 weeks after randomization. CR was defined as disappearance of any intratumoral arterial enhancement in all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of viable (enhancement of arterial phase) target lesions taking as reference the baseline sum of the diameters of target lesions. SD was when a case does not qualify for either PR or PD and was new non-target lesions. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. As planned, data for this pre-specified endpoint was collected and analyzed up to the primary completion date.

Outcome measures

Measure	Lenvatinib n=478 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=476 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Disease Control Rate (DCR)	75.5 percentage of participants 95% Confidence Interval 71.7 • Interval 71.7 to 79.4	60.5 percentage of participants 95% Confidence Interval 56.1 • Interval 56.1 to 64.9

OTHER_PRE_SPECIFIED outcome

Timeframe: From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (approximately up to 3.8 years)

Population: The FAS included all participants who were randomized.

CBR was defined as the percentage of participants with a best overall response of CR or PR or durable SD (duration of SD >=23 weeks after randomization). For participants whose best overall response (BOR) was SD, the duration of SD was defined as the time from the date of randomization to the first documented PD or death, whichever occurred first. CR was defined as disappearance of any intratumoral arterial enhancement in all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of viable (enhancement of arterial phase) target lesions taking as reference the baseline sum of the diameters of target lesions. SD was when a case does not qualify for either PR or PD. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. As planned, data for this pre-specified endpoint was collected and analyzed up to the primary completion date.

Outcome measures

Measure	Lenvatinib n=478 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=476 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Clinical Benefit Rate (CBR)	59.0 percentage of participants 95% Confidence Interval 54.6 • Interval 54.6 to 63.4	38.4 percentage of participants 95% Confidence Interval 34.1 • Interval 34.1 to 42.8

OTHER_PRE_SPECIFIED outcome

Timeframe: Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 7 Day 1, Cycle 8 Day 1, Cycle 9 Day 1 and at the Off-Treatment Visit (approximately up to 3.8 years)

Population: The pharmacodynamics (PD) analysis set included all participants who received at least 1 dose of study drug and had evaluable PD data. Here "n" was participants who were evaluable for the outcome measure at given time points.

The serum biomarkers analysed were angiopoietin-2 (ANG2), fibroblast growth factor 19 (FGF19), fibroblast growth factor 21 (FGF21), fibroblast growth factor 23 (FGF23) and vascular endothelial growth factor (VEGF) as blood serum biomarkers, and protein induced by vitamin K absence or antagonist-II (PIVKA-II) as a blood tumor marker in serum. As planned, data for this pre-specified endpoint was collected and analyzed up to the primary completion date.

Outcome measures

Measure	Lenvatinib n=66 Participants Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=48 Participants Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Percent Change From Baseline in Serum Biomarker ANG 2: Cycle 1 Day 15	-28.1 percent change Standard Deviation 15.94 • Interval 15.94 to	8.9 percent change Standard Deviation 23.96 • Interval 23.96 to
Percent Change From Baseline in Serum Biomarker ANG 2: Cycle 7 Day 1	-41.4 percent change Standard Deviation 21.20 • Interval 21.2 to	1.0 percent change Standard Deviation 32.83 • Interval 32.83 to
Percent Change From Baseline in Serum Biomarker ANG 2: Cycle 8 Day 1	-40.2 percent change Standard Deviation 25.33 • Interval 25.33 to	-6.7 percent change Standard Deviation 31.26 • Interval 31.26 to
Percent Change From Baseline in Serum Biomarker ANG 2: Cycle 9 Day 1	-39.6 percent change Standard Deviation 14.04 • Interval 14.04 to	-1.1 percent change Standard Deviation 29.68 • Interval 29.68 to
Percent Change From Baseline in Serum Biomarker FGF19: Cycle 7 Day 1	64.4 percent change Standard Deviation 101.97 • Interval 101.97 to	-5.9 percent change Standard Deviation 57.39 • Interval 57.39 to
Percent Change From Baseline in Serum Biomarker FGF19: Cycle 8 Day 1	95.8 percent change Standard Deviation 135.31 • Interval 135.31 to	53.9 percent change Standard Deviation 113.79 • Interval 113.79 to
Percent Change From Baseline in Serum Biomarker FGF19: Cycle 9 Day 1	159.3 percent change Standard Deviation 202.00 • Interval 202.0 to	56.6 percent change Standard Deviation 109.46 • Interval 109.46 to
Percent Change From Baseline in Serum Biomarker FGF19: Off-Treatment	140.1 percent change Standard Deviation 270.73 • Interval 270.73 to	9.0 percent change Standard Deviation 64.17 • Interval 64.17 to
Percent Change From Baseline in Serum Biomarker FGF 21: Cycle 1 Day 15	22.0 percent change Standard Deviation 75.22 • Interval 75.22 to	4.0 percent change Standard Deviation 43.14 • Interval 43.14 to
Percent Change From Baseline in Serum Biomarker FGF 21: Cycle 2 Day 1	15.7 percent change Standard Deviation 77.44 • Interval 77.44 to	18.6 percent change Standard Deviation 57.18 • Interval 57.18 to
Percent Change From Baseline in Serum Biomarker FGF 21: Cycle 4 Day 1	42.9 percent change Standard Deviation 145.43 • Interval 145.43 to	32.8 percent change Standard Deviation 70.63 • Interval 70.63 to
Percent Change From Baseline in Serum Biomarker FGF 21: Cycle 5 Day 1	41.0 percent change Standard Deviation 95.97 • Interval 95.97 to	31.1 percent change Standard Deviation 43.15 • Interval 43.15 to
Percent Change From Baseline in Serum Biomarker FGF 21: Cycle 6 Day 1	52.6 percent change Standard Deviation 168.22 • Interval 168.22 to	23.2 percent change Standard Deviation 40.90 • Interval 40.9 to
Percent Change From Baseline in Serum Biomarker FGF 21: Cycle 7 Day 1	63.4 percent change Standard Deviation 128.34 • Interval 128.34 to	23.7 percent change Standard Deviation 53.84 • Interval 53.84 to
Percent Change From Baseline in Serum Biomarker FGF 21 : Cycle 8 Day1	38.3 percent change Standard Deviation 115.53 • Interval 115.53 to	17.0 percent change Standard Deviation 68.51 • Interval 68.51 to
Percent Change From Baseline in Serum Biomarker FGF 21: Cycle 9 Day1	59.1 percent change Standard Deviation 108.39 • Interval 108.39 to	68.9 percent change Standard Deviation 103.55 • Interval 103.55 to
Percent Change From Baseline in Serum Biomarker FGF 23: Cycle 2 Day 1	20.9 percent change Standard Deviation 56.91 • Interval 56.91 to	-6.2 percent change Standard Deviation 48.18 • Interval 48.18 to
Percent Change From Baseline in Serum Biomarker FGF 23: Cycle 6 Day 1	26.3 percent change Standard Deviation 54.57 • Interval 54.57 to	-10.6 percent change Standard Deviation 46.15 • Interval 46.15 to
Percent Change From Baseline in Serum Biomarker FGF 23: Off-Treatment	17.8 percent change Standard Deviation 73.59 • Interval 73.59 to	14.2 percent change Standard Deviation 47.11 • Interval 47.11 to
Percent Change From Baseline in Serum Biomarker PIVKA-II: Cycle 1 Day 15	80.0 percent change Standard Deviation 171.41 • Interval 171.41 to	166.9 percent change Standard Deviation 256.04 • Interval 256.04 to
Percent Change From Baseline in Serum Biomarker PIVKA-II: Cycle 3 Day 1	252.4 percent change Standard Deviation 611.40 • Interval 611.4 to	218.7 percent change Standard Deviation 281.45 • Interval 281.45 to
Percent Change From Baseline in Serum Biomarker PIVKA-II: Cycle 5 Day 1	628.2 percent change Standard Deviation 1752.64 • Interval 1752.64 to	369.5 percent change Standard Deviation 766.59 • Interval 766.59 to
Percent Change From Baseline in Serum Biomarker PIVKA-II: Cycle 6 Day 1	648.7 percent change Standard Deviation 2746.41 • Interval 2746.41 to	415.7 percent change Standard Deviation 554.27 • Interval 554.27 to
Percent Change From Baseline in Serum Biomarker PIVKA-II: Cycle 7 Day 1	184.8 percent change Standard Deviation 352.75 • Interval 352.75 to	703.6 percent change Standard Deviation 1226.58 • Interval 1226.58 to
Percent Change From Baseline in Serum Biomarker PIVKA-II: Cycle 8 Day 1	277.8 percent change Standard Deviation 481.53 • Interval 481.53 to	724.0 percent change Standard Deviation 1257.87 • Interval 1257.87 to
Percent Change From Baseline in Serum Biomarker PIVKA-II: Off-Treatment	809.3 percent change Standard Deviation 1827.42 • Interval 1827.42 to	272.5 percent change Standard Deviation 489.60 • Interval 489.6 to
Percent Change From Baseline in Serum Biomarker VEGF: Cycle 1 Day 15	157.5 percent change Standard Deviation 300.21 • Interval 300.21 to	97.4 percent change Standard Deviation 118.43 • Interval 118.43 to
Percent Change From Baseline in Serum Biomarker VEGF: Cycle 4 Day 1	113.4 percent change Standard Deviation 231.19 • Interval 231.19 to	76.1 percent change Standard Deviation 111.20 • Interval 111.2 to
Percent Change From Baseline in Serum Biomarker VEGF: Cycle 5 Day 1	132.4 percent change Standard Deviation 249.59 • Interval 249.59 to	116.2 percent change Standard Deviation 215.57 • Interval 215.57 to
Percent Change From Baseline in Serum Biomarker VEGF: Cycle 7 Day 1	133.1 percent change Standard Deviation 383.43 • Interval 383.43 to	96.9 percent change Standard Deviation 173.77 • Interval 173.77 to
Percent Change From Baseline in Serum Biomarker VEGF: Cycle 8 Day 1	148.7 percent change Standard Deviation 349.58 • Interval 349.58 to	181.1 percent change Standard Deviation 399.67 • Interval 399.67 to
Percent Change From Baseline in Serum Biomarker VEGF: Off-Treatment	127.1 percent change Standard Deviation 266.64 • Interval 266.64 to	147.8 percent change Standard Deviation 304.31 • Interval 304.31 to
Percent Change From Baseline in Serum Biomarker ANG 2: Cycle 2 Day 1	-28.8 percent change Standard Deviation 16.53 • Interval 16.53 to	-0.9 percent change Standard Deviation 24.06 • Interval 24.06 to
Percent Change From Baseline in Serum Biomarker ANG 2: Cycle 3 Day 1	-32.2 percent change Standard Deviation 23.23 • Interval 23.23 to	0.5 percent change Standard Deviation 26.62 • Interval 26.62 to
Percent Change From Baseline in Serum Biomarker ANG 2: Cycle 4 Day 1	-35.6 percent change Standard Deviation 22.91 • Interval 22.91 to	-4.5 percent change Standard Deviation 20.05 • Interval 20.05 to
Percent Change From Baseline in Serum Biomarker ANG 2: Cycle 5 Day 1	-38.9 percent change Standard Deviation 19.83 • Interval 19.83 to	7.0 percent change Standard Deviation 23.25 • Interval 23.25 to
Percent Change From Baseline in Serum Biomarker ANG 2: Cycle 6 Day 1	-36.7 percent change Standard Deviation 23.59 • Interval 23.59 to	-3.6 percent change Standard Deviation 24.82 • Interval 24.82 to
Percent Change From Baseline in Serum Biomarker ANG 2: Off-Treatment	11.7 percent change Standard Deviation 99.13 • Interval 99.13 to	16.8 percent change Standard Deviation 27.88 • Interval 27.88 to
Percent Change From Baseline in Serum Biomarker FGF19: Cycle 1 Day 15	75.0 percent change Standard Deviation 155.01 • Interval 155.01 to	1.3 percent change Standard Deviation 83.65 • Interval 83.65 to
Percent Change From Baseline in Serum Biomarker FGF19: Cycle 2 Day 1	66.5 percent change Standard Deviation 134.26 • Interval 134.26 to	36.6 percent change Standard Deviation 119.65 • Interval 119.65 to
Percent Change From Baseline in Serum Biomarker FGF19: Cycle 3 Day 1	86.9 percent change Standard Deviation 123.85 • Interval 123.85 to	22.8 percent change Standard Deviation 70.58 • Interval 70.58 to
Percent Change From Baseline in Serum Biomarker FGF19: Cycle 4 Day 1	208.1 percent change Standard Deviation 602.11 • Interval 602.11 to	46.8 percent change Standard Deviation 214.14 • Interval 214.14 to
Percent Change From Baseline in Serum Biomarker FGF19: Cycle 5 Day 1	152.8 percent change Standard Deviation 228.37 • Interval 228.37 to	-1.0 percent change Standard Deviation 40.36 • Interval 40.36 to
Percent Change From Baseline in Serum Biomarker FGF19: Cycle 6 Day 1	119.8 percent change Standard Deviation 203.81 • Interval 203.81 to	26.9 percent change Standard Deviation 67.13 • Interval 67.13 to
Percent Change From Baseline in Serum Biomarker FGF 21: Cycle 3 Day 1	38.3 percent change Standard Deviation 38.3 • Interval 38.3 to	49.4 percent change Standard Deviation 76.43 • Interval 76.43 to
Percent Change From Baseline in Serum Biomarker FGF 21: Off-Treatment	141.4 percent change Standard Deviation 340.51 • Interval 340.51 to	104.9 percent change Standard Deviation 183.28 • Interval 183.28 to
Percent Change From Baseline in Serum Biomarker FGF 23: Cycle 1 Day15	23.9 percent change Standard Deviation 49.01 • Interval 49.01 to	-16.3 percent change Standard Deviation 36.14 • Interval 36.14 to
Percent Change From Baseline in Serum Biomarker FGF 23: Cycle 3 Day 1	25.5 percent change Standard Deviation 45.27 • Interval 45.27 to	17.3 percent change Standard Deviation 75.25 • Interval 75.25 to
Percent Change From Baseline in Serum Biomarker FGF 23: Cycle 4 Day 1	29.5 percent change Standard Deviation 48.38 • Interval 48.38 to	14.2 percent change Standard Deviation 49.29 • Interval 49.29 to
Percent Change From Baseline in Serum Biomarker FGF 23: Cycle 5 Day 1	29.6 percent change Standard Deviation 63.69 • Interval 63.69 to	1.0 percent change Standard Deviation 47.28 • Interval 47.28 to
Percent Change From Baseline in Serum Biomarker FGF 23: Cycle 7 Day 1	31.5 percent change Standard Deviation 57.44 • Interval 57.44 to	0.7 percent change Standard Deviation 46.95 • Interval 46.95 to
Percent Change From Baseline in Serum Biomarker FGF 23: Cycle 8 Day 1	38.1 percent change Standard Deviation 67.35 • Interval 67.35 to	2.8 percent change Standard Deviation 43.84 • Interval 43.84 to
Percent Change From Baseline in Serum Biomarker FGF 23: Cycle 9 Day 1	23.2 percent change Standard Deviation 62.58 • Interval 62.58 to	0.5 percent change Standard Deviation 38.74 • Interval 38.74 to
Percent Change From Baseline in Serum Biomarker PIVKA-II: Cycle 2 Day 1	169.7 percent change Standard Deviation 329.33 • Interval 329.33 to	243.8 percent change Standard Deviation 416.82 • Interval 416.82 to
Percent Change From Baseline in Serum Biomarker PIVKA-II: Cycle 4 Day 1	371.7 percent change Standard Deviation 812.45 • Interval 812.45 to	196.2 percent change Standard Deviation 348.80 • Interval 348.8 to
Percent Change From Baseline in Serum Biomarker PIVKA-II: Cycle 9 Day 1	318.8 percent change Standard Deviation 577.21 • Interval 577.21 to	859.1 percent change Standard Deviation 1492.93 • Interval 1492.93 to
Percent Change From Baseline in Serum Biomarker VEGF: Cycle 2 Day 1	128.9 percent change Standard Deviation 333.85 • Interval 333.85 to	94.0 percent change Standard Deviation 180.80 • Interval 180.8 to
Percent Change From Baseline in Serum Biomarker VEGF: Cycle 3 Day 1	97.7 percent change Standard Deviation 162.39 • Interval 162.39 to	66.0 percent change Standard Deviation 124.58 • Interval 124.58 to
Percent Change From Baseline in Serum Biomarker VEGF: Cycle 6 Day 1	113.1 percent change Standard Deviation 219.36 • Interval 219.36 to	130.9 percent change Standard Deviation 341.12 • Interval 341.12 to
Percent Change From Baseline in Serum Biomarker VEGF: Cycle 9 Day 1	129.6 percent change Standard Deviation 215.05 • Interval 215.05 to	135.6 percent change Standard Deviation 267.61 • Interval 267.61 to

Adverse Events

Lenvatinib

Serious events: 209 serious events

Other events: 469 other events

Deaths: 415 deaths

Sorafenib

Serious events: 149 serious events

Other events: 469 other events

Deaths: 402 deaths

Serious adverse events

Measure	Lenvatinib n=476 participants at risk Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=475 participants at risk Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Infections and infestations Urinary tract infection	0.42% 2/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Appendiceal abscess	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Bacteraemia	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Biliary tract infection	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Dengue fever	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Diverticulitis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Liver injury	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Pneumonia	1.1% 5/476 • Number of events 5 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.1% 5/475 • Number of events 7 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Cellulitis	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Gastroenteritis	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Liver abscess	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Lung infection	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.21% 1/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Blood and lymphatic system disorders Anaemia vitamin B12 deficiency	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Cardiac disorders Cardiopulmonary failure	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Cardiac disorders Acute myocardial infarction	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Cardiac disorders Atrial flutter	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Cardiac disorders Heart valve stenosis	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Ear and labyrinth disorders Hypoacusis	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Ear and labyrinth disorders Vertigo	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Eye disorders Cataract	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Ascites	2.5% 12/476 • Number of events 15 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	2.5% 12/475 • Number of events 15 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Diarrhoea	1.7% 8/476 • Number of events 8 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Oesophageal varices haemorrhage	1.5% 7/476 • Number of events 8 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.1% 5/475 • Number of events 7 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Abdominal pain	1.3% 6/476 • Number of events 7 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	2.3% 11/475 • Number of events 11 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Vomiting	1.3% 6/476 • Number of events 6 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	1.3% 6/476 • Number of events 7 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 5 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Duodenal ulcer haemorrhage	0.63% 3/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Abdominal pain upper	0.42% 2/476 • Number of events 8 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Duodenal ulcer	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Gastric ulcer	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Umbilical hernia	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Abdominal distension	0.21% 1/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Abdominal pain lower	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Dyspepsia	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Gastric haemorrhage	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.63% 3/475 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Intestinal haemorrhage	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Pancreatitis acute	0.21% 1/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Varices oesophageal	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Colitis	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Enterocolitis	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Food poisoning	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Gastric perforation	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Gastric ulcer haemorrhage	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Haematochezia	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Peritoneal haemorrhage	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Jaundice cholestatic	1.5% 7/476 • Number of events 7 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.84% 4/475 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Portal vein thrombosis	0.84% 4/476 • Number of events 6 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Cholangitis	0.63% 3/476 • Number of events 6 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Hepatic cirrhosis	0.63% 3/476 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Bile duct obstruction	0.42% 2/476 • Number of events 7 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Bile duct stone	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Cholecystitis	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Acute hepatic failure	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Biliary dilatation	0.21% 1/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Cholecystitis acute	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Chronic hepatic failure	0.21% 1/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Haemobilia	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Hepatic function abnormal	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.1% 5/475 • Number of events 6 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Hepatic pain	0.21% 1/476 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Hepatorenal syndrome	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Hydrocholecystis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Hyperbilirubinaemia	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Jaundice	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.84% 4/475 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Escherichia sepsis	0.21% 1/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Gastrointestinal viral infection	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Groin abscess	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Infection	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Infectious pleural effusion	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Lung abscess	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Perihepatic abscess	0.21% 1/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Periodontitis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Pleural infection	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Postoperative abscess	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Pulmonary tuberculosis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Scrotal infection	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Septic shock	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Tuberculosis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Urinary tract infection enterococcal	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Urosepsis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Acute sinusitis	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Aspergillus infection	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Bronchitis	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Device related infection	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Diabetic foot infection	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Lower respiratory tract infection	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Ophthalmic herpes simplex	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Perineal abscess	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Pneumonia escherichia	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Upper respiratory tract infection	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Injury, poisoning and procedural complications Fall	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Injury, poisoning and procedural complications Intentional overdose	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Injury, poisoning and procedural complications Spinal compression fracture	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Injury, poisoning and procedural complications Thoracic vertebral fracture	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Injury, poisoning and procedural complications Foreign body	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Injury, poisoning and procedural complications Spinal fracture	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Injury, poisoning and procedural complications Subarachnoid haemorrhage	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Injury, poisoning and procedural complications Traumatic haematoma	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Blood bilirubin increased	1.5% 7/476 • Number of events 8 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Aspartate aminotransferase increased	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Alanine aminotransferase increased	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Blood pressure decreased	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Clostridium test positive	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Hepatic enzyme increased	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Neutrophil count decreased	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Weight decreased	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Haemoglobin decreased	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Platelet count decreased	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 5 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Decreased appetite	2.3% 11/476 • Number of events 12 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Hyponatraemia	0.63% 3/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Dehydration	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Hyperkalaemia	0.42% 2/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Cachexia	0.21% 1/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Diabetes mellitus	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Hypercalcaemia	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Hypoalbuminaemia	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Hypocalcaemia	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Hypoglycaemia	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Hypomagnesaemia	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Hypoproteinaemia	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Muscular weakness	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Pathological fracture	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.1% 5/475 • Number of events 5 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Bone pain	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Flank pain	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Neck pain	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Pain in extremity	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Spinal column stenosis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	2.3% 11/476 • Number of events 12 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	2.9% 14/475 • Number of events 14 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour haemorrhage	0.63% 3/476 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.63% 3/475 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Liver carcinoma ruptured	0.42% 2/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.42% 2/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to spine	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Infected neoplasm	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Intracranial tumour haemorrhage	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Meningioma	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour necrosis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour rupture	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant ascites	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant pleural effusion	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Plasma cell myeloma	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Hepatic encephalopathy	4.4% 21/476 • Number of events 35 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.63% 3/475 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Cerebral haemorrhage	0.63% 3/476 • Number of events 5 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Coma hepatic	0.63% 3/476 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Cerebral infarction	0.42% 2/476 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Cerebrovascular accident	0.42% 2/476 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Headache	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Seizure	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Spinal cord compression	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Diplegia	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Disturbance in attention	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Dizziness	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Facial paralysis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Paralysis recurrent laryngeal nerve	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Posterior reversible encephalopathy syndrome	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Syncope	0.21% 1/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Transient ischaemic attack	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Basal ganglia haemorrhage	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Encephalopathy	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Ischaemic stroke	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Loss of consciousness	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Thrombotic cerebral infarction	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Psychiatric disorders Major depression	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Renal and urinary disorders Acute kidney injury	0.63% 3/476 • Number of events 5 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Renal and urinary disorders Proteinuria	0.84% 4/476 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Renal and urinary disorders Renal failure	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Renal and urinary disorders Renal impairment	0.42% 2/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Renal and urinary disorders Haematuria	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Renal and urinary disorders IgA nephropathy	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Renal and urinary disorders Renal tubular necrosis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Reproductive system and breast disorders Pelvic pain	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.1% 5/476 • Number of events 6 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.84% 4/476 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.63% 3/476 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.63% 3/476 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.63% 3/475 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Hepatopulmonary syndrome	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.21% 1/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Hiccups	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Necrotising bronchiolitis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Non-cardiogenic pulmonary oedema	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Pulmonary infarction	0.21% 1/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Skin and subcutaneous tissue disorders Intertrigo	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Skin and subcutaneous tissue disorders Seborrhoeic dermatitis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Skin and subcutaneous tissue disorders Drug eruption	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Skin and subcutaneous tissue disorders Erythema multiforme	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.63% 3/475 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Skin and subcutaneous tissue disorders Psoriasis	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Vascular disorders Aortic dissection	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Vascular disorders Circulatory collapse	0.21% 1/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Vascular disorders Deep vein thrombosis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Vascular disorders Thrombophlebitis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Vascular disorders Hypotension	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Vascular disorders Shock	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Vascular disorders Thrombophlebitis superficial	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Cardiac disorders Coronary artery disease	0.21% 1/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Blood and lymphatic system disorders Anaemia	0.21% 1/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.3% 6/475 • Number of events 12 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Blood and lymphatic system disorders Bone marrow failure	0.21% 1/476 • Number of events 5 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Cardiac disorders Myocardial infarction	0.84% 4/476 • Number of events 5 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Cardiac disorders Atrial fibrillation	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Nausea	0.63% 3/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Haemorrhoids	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Asthenia	1.5% 7/476 • Number of events 7 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Pyrexia	1.5% 7/476 • Number of events 8 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.1% 5/475 • Number of events 6 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders General physical health deterioration	1.1% 5/476 • Number of events 5 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.63% 3/475 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Oedema peripheral	0.63% 3/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Fatigue	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Multiple organ dysfunction syndrome	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Death	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Generalised oedema	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Organ failure	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Peripheral swelling	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Sudden death	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Hepatic failure	2.9% 14/476 • Number of events 22 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.7% 8/475 • Number of events 11 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Sepsis	1.5% 7/476 • Number of events 11 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.63% 3/475 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Peritonitis bacterial	0.42% 2/476 • Number of events 3 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Salmonellosis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Injury, poisoning and procedural complications Accidental overdose	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Injury, poisoning and procedural complications Pneumothorax traumatic	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Back pain	0.42% 2/476 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.1% 5/475 • Number of events 5 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.84% 4/476 • Number of events 4 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Psychiatric disorders Confusional state	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.42% 2/475 • Number of events 2 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Psychiatric disorders Suicide attempt	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Cardiac disorders Cardiac failure	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Hepatobiliary disorders Cholelithiasis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Mantle cell lymphoma	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to adrenals	0.00% 0/476 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.21% 1/475 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.21% 1/476 • Number of events 1 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	0.00% 0/475 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.

Other adverse events

Measure	Lenvatinib n=476 participants at risk Participants received lenvatinib capsules 12 mg based on the participant's body weight \>=60 kg or 8 mg based on the participant's body weight \<60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.	Sorafenib n=475 participants at risk Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Gastrointestinal disorders Ascites	13.2% 63/476 • Number of events 82 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	8.2% 39/475 • Number of events 54 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Constipation	16.0% 76/476 • Number of events 95 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	10.9% 52/475 • Number of events 62 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Diarrhoea	39.1% 186/476 • Number of events 406 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	46.9% 223/475 • Number of events 448 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Dyspepsia	6.5% 31/476 • Number of events 40 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	3.8% 18/475 • Number of events 20 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Nausea	18.9% 90/476 • Number of events 131 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	14.9% 71/475 • Number of events 94 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Stomatitis	9.5% 45/476 • Number of events 67 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	11.8% 56/475 • Number of events 76 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Vomiting	15.8% 75/476 • Number of events 110 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	7.8% 37/475 • Number of events 65 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Alanine aminotransferase increased	11.1% 53/476 • Number of events 86 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	10.7% 51/475 • Number of events 108 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Aspartate aminotransferase increased	13.4% 64/476 • Number of events 128 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	16.8% 80/475 • Number of events 173 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Blood alkaline phosphatase increased	6.7% 32/476 • Number of events 59 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	6.1% 29/475 • Number of events 40 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Blood bilirubin increased	14.1% 67/476 • Number of events 141 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	13.3% 63/475 • Number of events 128 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Electrocardiogram QT prolonged	6.9% 33/476 • Number of events 59 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	5.1% 24/475 • Number of events 62 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Gamma-glutamyltransferase increased	7.8% 37/476 • Number of events 60 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	5.7% 27/475 • Number of events 41 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Neutrophil count decreased	8.6% 41/476 • Number of events 101 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	2.7% 13/475 • Number of events 21 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Platelet count decreased	18.3% 87/476 • Number of events 260 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	12.4% 59/475 • Number of events 127 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations Weight decreased	31.3% 149/476 • Number of events 290 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	22.7% 108/475 • Number of events 182 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Investigations White blood cell count decreased	9.9% 47/476 • Number of events 115 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	5.3% 25/475 • Number of events 55 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Decreased appetite	34.0% 162/476 • Number of events 269 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	26.5% 126/475 • Number of events 165 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Hypoalbuminaemia	9.0% 43/476 • Number of events 88 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	8.0% 38/475 • Number of events 56 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Arthralgia	8.8% 42/476 • Number of events 52 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	4.2% 20/475 • Number of events 31 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Back pain	10.1% 48/476 • Number of events 55 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	5.9% 28/475 • Number of events 30 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	9.9% 47/476 • Number of events 56 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	5.3% 25/475 • Number of events 30 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Musculoskeletal and connective tissue disorders Pain in extremity	8.0% 38/476 • Number of events 59 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	3.8% 18/475 • Number of events 32 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Headache	9.5% 45/476 • Number of events 57 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	8.2% 39/475 • Number of events 48 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Psychiatric disorders Insomnia	6.9% 33/476 • Number of events 38 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	5.9% 28/475 • Number of events 34 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Renal and urinary disorders Proteinuria	24.6% 117/476 • Number of events 363 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	11.6% 55/475 • Number of events 125 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Cough	9.5% 45/476 • Number of events 54 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	7.8% 37/475 • Number of events 46 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Dysphonia	23.7% 113/476 • Number of events 134 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	12.0% 57/475 • Number of events 69 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Epistaxis	7.4% 35/476 • Number of events 35 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	3.2% 15/475 • Number of events 17 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Skin and subcutaneous tissue disorders Pruritus	7.1% 34/476 • Number of events 41 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	7.4% 35/475 • Number of events 46 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Skin and subcutaneous tissue disorders Rash	9.7% 46/476 • Number of events 59 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	16.2% 77/475 • Number of events 105 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Vascular disorders Hypertension	42.0% 200/476 • Number of events 419 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	30.9% 147/475 • Number of events 269 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Blood and lymphatic system disorders Anaemia	7.4% 35/476 • Number of events 55 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	9.1% 43/475 • Number of events 104 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Blood and lymphatic system disorders Thrombocytopenia	6.9% 33/476 • Number of events 81 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	5.9% 28/475 • Number of events 90 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Endocrine disorders Hypothyroidism	17.0% 81/476 • Number of events 104 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.7% 8/475 • Number of events 9 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Abdominal distension	8.2% 39/476 • Number of events 57 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	5.1% 24/475 • Number of events 27 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Abdominal pain	17.2% 82/476 • Number of events 136 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	17.5% 83/475 • Number of events 111 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Abdominal pain upper	12.2% 58/476 • Number of events 82 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	8.6% 41/475 • Number of events 59 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Asthenia	11.1% 53/476 • Number of events 122 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	10.1% 48/475 • Number of events 84 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Fatigue	29.6% 141/476 • Number of events 226 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	25.3% 120/475 • Number of events 170 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Oedema peripheral	14.1% 67/476 • Number of events 107 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	6.9% 33/475 • Number of events 45 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
General disorders Pyrexia	13.2% 63/476 • Number of events 79 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	12.8% 61/475 • Number of events 74 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Skin and subcutaneous tissue disorders Alopecia	3.2% 15/476 • Number of events 16 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	25.3% 120/475 • Number of events 140 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	26.9% 128/476 • Number of events 236 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	51.8% 246/475 • Number of events 614 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Gastrointestinal disorders Dry mouth	6.7% 32/476 • Number of events 38 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.7% 8/475 • Number of events 8 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Dizziness	6.1% 29/476 • Number of events 33 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	3.4% 16/475 • Number of events 22 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.5% 31/476 • Number of events 39 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	3.6% 17/475 • Number of events 19 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Metabolism and nutrition disorders Hypokalaemia	1.9% 9/476 • Number of events 14 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	5.5% 26/475 • Number of events 52 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Nervous system disorders Hepatic encephalopathy	5.0% 24/476 • Number of events 37 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.3% 6/475 • Number of events 6 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Renal and urinary disorders Haematuria	5.3% 25/476 • Number of events 34 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	1.9% 9/475 • Number of events 11 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.
Infections and infestations Upper respiratory tract infection	4.8% 23/476 • Number of events 26 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.	5.3% 25/475 • Number of events 33 • All treatment-emergent adverse events were collected from first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 8 years) The safety analysis set included all participants who received at least 1 dose of study drug. All-cause mortality was reported for all participants randomized.

Additional Information

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• Principal investigator is a sponsor employee
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