Trial Outcomes & Findings for Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma (HCC) Who Have Been Treated With One Prior Therapy (NCT NCT01755767)

Last Updated: 2021-04-06

Results Overview

Overall survival (OS) is defined as the time from randomization to the date of death. The rate of OS (percentage of participants still alive) was determined only in the tivantinib 120 mg BID cohort.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

383 participants

Primary outcome timeframe

within 36 months

Results posted on

2021-04-06

Participant Flow

A total of 383 participants who met all inclusion criteria and no exclusion criteria were randomized to treatment. One participant in the tivantinib 120 mg BID cohort was randomized but did not receive treatment.

Eligible participants were randomly assigned on a 2:1 basis to either tivantinib or placebo. Initially, the tivantinib dosage of 240 mg was selected on the basis of efficacy and tolerability established in Phase 1 and Phase 2 studies.

Participant milestones

Participant milestones
Measure	Tivantinib 240 mg BID Cohort Participants who received tivantinib 240 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg.	Placebo Matching 240 mg BID Cohort Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.	Tivantinib 120 mg BID Cohort Participants who received tivantinib 120 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).	Placebo Matching 120 mg BID Cohort Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.
Overall Study STARTED	28	15	226	114
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	28	15	226	114

Reasons for withdrawal

Reasons for withdrawal
Measure	Tivantinib 240 mg BID Cohort Participants who received tivantinib 240 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg.	Placebo Matching 240 mg BID Cohort Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.	Tivantinib 120 mg BID Cohort Participants who received tivantinib 120 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).	Placebo Matching 120 mg BID Cohort Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.
Overall Study Progressive Disease	8	7	91	43
Overall Study Clinical Disease Progression	4	2	29	20
Overall Study Radiographic Disease Progression	9	4	44	27
Overall Study Adverse Event	6	0	28	11
Overall Study Death	1	2	15	4
Overall Study Subject Decision	0	0	10	3
Overall Study Withdrawal by Subject	0	0	2	1
Overall Study Other	0	0	2	3
Overall Study Ongoing Treatment as of 06 Jan 2017	0	0	5	2

Baseline Characteristics

Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma (HCC) Who Have Been Treated With One Prior Therapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tivantinib 240 mg BID Cohort n=28 Participants Participants who received tivantinib 240 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg.	Placebo Matching 240 mg BID Cohort n=15 Participants Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.	Tivantinib 120 mg BID Cohort n=225 Participants Participants who received tivantinib 120 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).	Placebo Matching 120 mg BID Cohort n=114 Participants Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.	Total n=382 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	11 Participants n=5 Participants	5 Participants n=7 Participants	98 Participants n=5 Participants	50 Participants n=4 Participants	164 Participants n=21 Participants
Age, Categorical >=65 years	17 Participants n=5 Participants	10 Participants n=7 Participants	127 Participants n=5 Participants	64 Participants n=4 Participants	218 Participants n=21 Participants
Age, Continuous	66.6 years STANDARD_DEVIATION 9.3 • n=5 Participants	64.9 years STANDARD_DEVIATION 7.4 • n=7 Participants	65.6 years STANDARD_DEVIATION 10.2 • n=5 Participants	64.7 years STANDARD_DEVIATION 10.2 • n=4 Participants	64.8 years STANDARD_DEVIATION 7.8 • n=21 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	0 Participants n=7 Participants	27 Participants n=5 Participants	7 Participants n=4 Participants	38 Participants n=21 Participants
Sex: Female, Male Male	24 Participants n=5 Participants	15 Participants n=7 Participants	198 Participants n=5 Participants	107 Participants n=4 Participants	344 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	8 Participants n=5 Participants	7 Participants n=4 Participants	16 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	11 Participants n=5 Participants	1 Participants n=4 Participants	12 Participants n=21 Participants
Race (NIH/OMB) White	27 Participants n=5 Participants	15 Participants n=7 Participants	161 Participants n=5 Participants	86 Participants n=4 Participants	289 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	43 Participants n=5 Participants	20 Participants n=4 Participants	63 Participants n=21 Participants

PRIMARY outcome

Timeframe: within 36 months

Population: Overall survival was assessed in the Intent-to-Treat Analysis Set.

Overall survival (OS) is defined as the time from randomization to the date of death. The rate of OS (percentage of participants still alive) was determined only in the tivantinib 120 mg BID cohort.

Outcome measures

Outcome measures
Measure	Tivantinib 120 mg BID Cohort n=226 Participants Participants who received tivantinib 120 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).	Placebo Matching 120 mg BID Cohort n=114 Participants Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.
Median Overall Survival (OS) Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy	8.4 months Interval 6.8 to 10.0	9.1 months Interval 7.3 to 10.4

PRIMARY outcome

Timeframe: within 36 months

Population: Overall survival was assessed in the Intent-to-Treat Analysis Set.

Overall survival (OS) is defined as the time from randomization to the date of death. The rate of OS (percentage of participants still alive) was determined only in the tivantinib 120 mg BID cohort.

Outcome measures

Outcome measures
Measure	Tivantinib 120 mg BID Cohort n=226 Participants Participants who received tivantinib 120 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).	Placebo Matching 120 mg BID Cohort n=114 Participants Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.
Overall Survival (OS) Rate At Different Time Points Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Overall survival at 3 months	86.6 percentage of participants still alive Interval 81.4 to 90.5	85.9 percentage of participants still alive Interval 78.0 to 91.1
Overall Survival (OS) Rate At Different Time Points Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Overall survival at 6 months	61.2 percentage of participants still alive Interval 54.5 to 67.2	70.8 percentage of participants still alive Interval 61.5 to 78.3
Overall Survival (OS) Rate At Different Time Points Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Overall survival at 9 months	46.9 percentage of participants still alive Interval 40.2 to 53.3	50.5 percentage of participants still alive Interval 40.9 to 59.2
Overall Survival (OS) Rate At Different Time Points Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Overall survival at 12 months	36.6 percentage of participants still alive Interval 30.3 to 42.9	38.0 percentage of participants still alive Interval 29.1 to 46.9
Overall Survival (OS) Rate At Different Time Points Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Overall survival at 18 months	25.1 percentage of participants still alive Interval 19.4 to 31.2	21.9 percentage of participants still alive Interval 14.3 to 30.5
Overall Survival (OS) Rate At Different Time Points Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Overall survival at 24 months	16.2 percentage of participants still alive Interval 11.0 to 22.3	12.2 percentage of participants still alive Interval 5.9 to 20.8

SECONDARY outcome

Timeframe: within 10 months

Population: PFS was assessed in the Intent-to-Treat Analysis Set.

Progression-free survival (PFS) is defined as the time from the date of randomization to the date of the first radiographic disease progression or death due to any cause. The rate of PFS (percentage of participants still alive without disease progression) was determined only in the tivantinib 120 mg BID cohort.

Outcome measures

Outcome measures
Measure	Tivantinib 120 mg BID Cohort n=226 Participants Participants who received tivantinib 120 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).	Placebo Matching 120 mg BID Cohort n=114 Participants Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.
Progression-free Survival Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy (ITT Population)	2.1 months Interval 1.9 to 3.0	2.0 months Interval 1.9 to 3.6

SECONDARY outcome

Timeframe: Baseline to 30 days after last dose, up to approximately 4 years

Population: TEAEs were assessed in the Safety Analysis Set.

Treatment-emergent adverse events (TEAEs) are reported for the tivantinib 120 mg BID cohort group.

Outcome measures

Outcome measures
Measure	Tivantinib 120 mg BID Cohort n=225 Participants Participants who received tivantinib 120 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).	Placebo Matching 120 mg BID Cohort n=114 Participants Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Any TEAEs	214 Participants	108 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Gastrointestinal Disorders	159 Participants	84 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy General Disorders & Administration Site Conditions	146 Participants	75 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Musculoskeletal and Connective Tissue Disorders	75 Participants	34 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Respiratory, Thoracic, and Mediastinal Disorders	70 Participants	32 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Metabolism and Nutrition Disorders	65 Participants	30 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Blood and Lymphatic System Disorders	64 Participants	27 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Nervous System Disorders	60 Participants	27 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Infections and Infestations	58 Participants	33 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Skin and Subcutaneous Tissue Disorders	57 Participants	38 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Investigations	55 Participants	36 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Cardiac Disorders	52 Participants	13 Participants

SECONDARY outcome

Timeframe: Baseline to 30 days after last dose, up to approximately 4 years

Population: TEAEs were assessed in the Safety Analysis Set.

Treatment-emergent adverse events (TEAEs) are reported for the tivantinib 240 mg BID cohort group.

Outcome measures

Outcome measures
Measure	Tivantinib 120 mg BID Cohort n=28 Participants Participants who received tivantinib 120 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).	Placebo Matching 120 mg BID Cohort n=15 Participants Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Any TEAEs	28 Participants	14 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Blood and Lymphatic System Disorders	20 Participants	4 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Gastrointestinal Disorders	20 Participants	12 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy General Disorders & Administration Site Conditions	19 Participants	9 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Investigations	11 Participants	8 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Respiratory, Thoracic, and Mediastinal Disorders	8 Participants	4 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Infections and Infestations	7 Participants	3 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Skin and Subcutaneous Tissue Disorders	7 Participants	3 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Cardiac Disorders	7 Participants	0 Participants
Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy Metabolism and Nutrition Disorders	6 Participants	5 Participants

Adverse Events

Tivantinib 240 mg BID Cohort

Serious events: 17 serious events

Other events: 17 other events

Deaths: 28 deaths

Placebo Matching 240 mg BID Cohort

Serious events: 10 serious events

Other events: 10 other events

Deaths: 14 deaths

Tivantinib 120 mg BID Cohort

Serious events: 103 serious events

Other events: 214 other events

Deaths: 180 deaths

Placebo Matching 120 mg BID Cohort

Serious events: 51 serious events

Other events: 108 other events

Deaths: 94 deaths

Serious adverse events

Other adverse events

Additional Information

Contact for Clinical Trial Information

Daiichi Sankyo

Phone: 908-992-6400

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Tivantinib 240 mg BID Cohort n=28 participants at risk Participants who received tivantinib 240 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg.	Placebo Matching 240 mg BID Cohort n=15 participants at risk Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.	Tivantinib 120 mg BID Cohort n=225 participants at risk Participants who received tivantinib 120 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).	Placebo Matching 120 mg BID Cohort n=114 participants at risk Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.
Blood and lymphatic system disorders Anaemia	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	1.8% 4/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	2.6% 3/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Blood and lymphatic system disorders Febrile neutropenia	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.89% 2/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Blood and lymphatic system disorders Leukopenia	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.89% 2/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Blood and lymphatic system disorders Neutropenia	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	1.3% 3/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Cardiac disorders Acute coronary syndrome	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Cardiac disorders Acute myocardial infarction	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Cardiac disorders Atrial fibrillation	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Cardiac disorders Atrioventricular block complete	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Cardiac disorders Bradycardia	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Cardiac disorders Cardiac arrest	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.89% 2/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Cardiac disorders Cardiac failure	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.89% 2/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Cardiac disorders Myocardial infarction	7.1% 2/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.89% 2/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Abdominal hernia	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Abdominal pain	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.89% 2/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	3.5% 4/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Ascites	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.3% 2/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	3.1% 7/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	2.6% 3/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Constipation	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Diarrhoea	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.89% 2/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Duodenal ulcer	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Duodenal ulcer haemorrhage	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Gastric haemorrhage	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	1.8% 2/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Gastrointestinal haemorrhage	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	3.6% 8/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	1.8% 2/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Haematemesis	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Haemorrhoidal haemorrhage	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Intra-abdominal haemorrhage	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Melaena	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Oesophageal haemorrhage	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Oesophageal varices haemorrhage	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.3% 2/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	2.7% 6/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	2.6% 3/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Peritoneal haemorrhage	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.89% 2/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.89% 2/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Retroperitoneal haemorrhage	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Subileus	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	1.3% 3/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Varices oesophageal	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Vomiting	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
General disorders Asthenia	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
General disorders Chest pain	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
General disorders Device malfunction	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
General disorders Disease progression	7.1% 2/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
General disorders Fatigue	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	1.8% 2/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.

Other adverse events
Measure	Tivantinib 240 mg BID Cohort n=28 participants at risk Participants who received tivantinib 240 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg.	Placebo Matching 240 mg BID Cohort n=15 participants at risk Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.	Tivantinib 120 mg BID Cohort n=225 participants at risk Participants who received tivantinib 120 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).	Placebo Matching 120 mg BID Cohort n=114 participants at risk Participants who received matching placebo tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food.
Blood and lymphatic system disorders Anaemia	39.3% 11/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.3% 2/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	18.7% 42/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	14.9% 17/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Blood and lymphatic system disorders Neutropenia	53.6% 15/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.3% 2/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	12.4% 28/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	4.4% 5/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Cardiac disorders Bradycardia	10.7% 3/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.8% 31/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Cardiac disorders Sinus bradycardia	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	5.3% 12/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	2.6% 3/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Abdominal distension	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	4.9% 11/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	7.0% 8/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Abdominal pain	10.7% 3/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.3% 2/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	20.9% 47/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	28.1% 32/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Abdominal pain upper	10.7% 3/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	11.6% 26/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.2% 15/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Ascites	21.4% 6/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	46.7% 7/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	20.4% 46/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	21.1% 24/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Constipation	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	12.9% 29/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	12.3% 14/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Diarrhoea	14.3% 4/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.3% 2/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	22.2% 50/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	14.9% 17/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Dyspepsia	7.1% 2/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	5.3% 12/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	7.0% 8/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Nausea	14.3% 4/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	22.2% 50/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	11.4% 13/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Vomiting	7.1% 2/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	11.6% 26/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	11.4% 13/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
General disorders Asthenia	28.6% 8/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.3% 2/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	21.3% 48/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	21.9% 25/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
General disorders Fatigue	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	26.7% 4/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	25.8% 58/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	27.2% 31/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
General disorders General physical health deterioration	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 15/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	4.4% 5/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
General disorders Oedema peripheral	25.0% 7/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	24.0% 54/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	16.7% 19/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
General disorders Pyrexia	21.4% 6/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	12.4% 28/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.2% 15/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Infections and infestations Nasopharyngitis	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	4.0% 9/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.1% 7/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Investigations Alanine aminotransferase increased	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.3% 2/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	3.6% 8/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.1% 7/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Investigations Aspartate aminotransferase increased	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	20.0% 3/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.2% 14/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	8.8% 10/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Investigations Blood bilirubin increased	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	5.3% 12/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	5.3% 6/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Metabolism and nutrition disorders Decreased appetite	7.1% 2/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	20.0% 3/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	16.0% 36/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	18.4% 21/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.3% 2/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	8.4% 19/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	3.5% 4/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Back pain	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	8.4% 19/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	12.3% 14/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	3.6% 8/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	7.0% 8/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Nervous system disorders Dizziness	3.6% 1/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	7.1% 16/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	2.6% 3/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Nervous system disorders Headache	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	5.8% 13/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	2.6% 3/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Cough	17.9% 5/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	14.2% 32/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	10.5% 12/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.1% 2/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.3% 2/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	9.8% 22/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	5.3% 6/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Pruritus	7.1% 2/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	13.3% 2/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	10.7% 24/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	18.4% 21/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Skin and subcutaneous tissue disorders Rash	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	4.0% 9/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	5.3% 6/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Vascular disorders Hypertension	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	8.4% 19/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	4.4% 5/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Blood and lymphatic system disorders Leukopenia	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	1.8% 4/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Blood and lymphatic system disorders Thrombocytopenia	10.7% 3/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	2.2% 5/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	4.4% 5/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Cardiac disorders Myocardial infarction	7.1% 2/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.89% 2/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.88% 1/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Dry mouth	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	1.8% 4/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	2.6% 3/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Gastric haemorrhage	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	1.8% 2/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Haematemesis	7.1% 2/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.44% 1/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	1.8% 2/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.
Gastrointestinal disorders Haemorrhage ascites	0.00% 0/28 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	6.7% 1/15 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/225 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.	0.00% 0/114 • Adverse events (AEs) were collected from baseline to 30 days after the last dose up to approximately 4 years. Treatment-emergent AEs (TEAEs) were defined as those AEs that occurred, having been absent before the study, or worsen in severity after the initiation of study treatment administration and started no later than 30 days after the end of treatment.