Trial Outcomes & Findings for A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Trial of Lenvatinib (E7080) in 131I-Refractory Differentiated Thyroid Cancer (DTC) (NCT NCT01321554)

Last Updated: 2023-06-22

Results Overview

PFS was defined as the time from the date of randomization to the date of first documentation of disease progression or death (whichever occurred first), as determined by blinded IIR using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for the double-blind treatment period (Randomization Phase). Disease progression per RECIST v1.1 was defined as at least a 20 percent (%) relative increase and 5 millimeter (mm) absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), recorded since the treatment started or the appearance of 1 or more new lesions.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

392 participants

Primary outcome timeframe

Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years

Results posted on

2023-06-22

Participant Flow

Participants took part in the study at 117 investigative sites in Europe, North America, Asia Pacific, Japan, and Latin America from 17 March 2011 to 19 March 2019.

A total of 612 participants were screened for entry into the study. Of these 612 participants, 220 participants were screening failures and 392 participants were randomly assigned to receive either lenvatinib or placebo in a 2:1 ratio.

Participant milestones

Participant milestones
Measure	Randomization Phase: Lenvatinib 24 mg Participants received lenvatinib 24 milligram (mg), hard capsule, orally, once daily, until documentation of disease progression (confirmed by Investigator-Initiated Research \[IIR\]), development of unacceptable toxicity, or withdrawal of consent.	Randomization Phase: Placebo Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	OOL, Treatment Period: Lenvatinib 24 mg Participants received lenvatinib 24 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib. OOL refers to Optional Open-Label.	OOL, Treatment Period: Lenvatinib 20 mg Participants received lenvatinib 20 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.
Randomization Phase STARTED	261	131	0	0
Randomization Phase COMPLETED	261	131	0	0
Randomization Phase NOT COMPLETED	0	0	0	0
OOL Lenvatinib Treatment Period STARTED	0	0	85	30
OOL Lenvatinib Treatment Period COMPLETED	0	0	85	30
OOL Lenvatinib Treatment Period NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Trial of Lenvatinib (E7080) in 131I-Refractory Differentiated Thyroid Cancer (DTC)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Randomization Phase: Lenvatinib 24 mg n=261 Participants Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Randomization Phase: Placebo n=131 Participants Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Total n=392 Participants Total of all reporting groups
Age, Continuous	62.1 years STANDARD_DEVIATION 10.57 • n=5 Participants	61.5 years STANDARD_DEVIATION 10.09 • n=7 Participants	61.9 years STANDARD_DEVIATION 10.40 • n=5 Participants
Sex: Female, Male Female	136 Participants n=5 Participants	56 Participants n=7 Participants	192 Participants n=5 Participants
Sex: Female, Male Male	125 Participants n=5 Participants	75 Participants n=7 Participants	200 Participants n=5 Participants

PRIMARY outcome

Timeframe: Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years

Population: The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.

Outcome measures

Outcome measures
Measure	Randomization Phase: Lenvatinib 24 mg n=261 Participants Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Randomization Phase: Placebo n=131 Participants Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
Progression Free Survival (PFS)	18.3 months Interval 15.1 to The upper limit of the 95% confidence interval was not estimable because an insufficient number of participants reached the event at the final assessment time point.	3.6 months Interval 2.2 to 3.7

SECONDARY outcome

Timeframe: Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years

Population: The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.

ORR, defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by blinded IIR using RECIST 1.1 for target lesions and assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans (for double blind treatment period i.e. Randomization Phase). CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR = CR + PR.

Outcome measures

Outcome measures
Measure	Randomization Phase: Lenvatinib 24 mg n=261 Participants Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Randomization Phase: Placebo n=131 Participants Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
Overall Response Rate (ORR)	64.8 percentage of participants Interval 59.0 to 70.5	1.5 percentage of participants Interval 0.0 to 3.6

SECONDARY outcome

Timeframe: Date of randomization until date of death from any cause, assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years

Population: The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.

Overall survival measured from the date of randomization until date of death from any cause. Overall survival is adjusted with rank preserving structural failure time.

Outcome measures

Outcome measures
Measure	Randomization Phase: Lenvatinib 24 mg n=261 Participants Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Randomization Phase: Placebo n=131 Participants Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
Overall Survival (OS)	NA months Interval 22.0 to The median OS was not yet reached for either the lenvatinib or the placebo arm (including crossover participants) at data cutoff date.	NA months Interval 14.3 to The median OS was not yet reached for either the lenvatinib or the placebo arm (including crossover participants) at data cutoff date.

SECONDARY outcome

Timeframe: Cycle 1 Days 1 and 15: 0-10 hours postdose; Cycle 2 Day 1: 0-12 hour postdose

Population: The PK analysis set included all the participants who received at least one dose of study drug and had evaluable PK data.

Outcome measures

Outcome measures
Measure	Randomization Phase: Lenvatinib 24 mg n=260 Participants Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Randomization Phase: Placebo Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
Pharmacokinetic (PK) Profile of Lenvatinib: Area Under the Plasma Concentration Curve	3490 nanogramhour per milliliter (ngh/mL) Interval 1410.0 to 10700.0	—

Adverse Events

Randomization Phase: Lenvatinib 24 mg

Serious events: 171 serious events

Other events: 259 other events

Deaths: 161 deaths

Randomization Phase: Placebo

Serious events: 31 serious events

Other events: 118 other events

Deaths: 13 deaths

OOL, Treatment Period: Lenvatinib 24 mg

Serious events: 62 serious events

Other events: 84 other events

Deaths: 62 deaths

OOL, Treatment Period: Lenvatinib 20 mg

Serious events: 16 serious events

Other events: 29 other events

Deaths: 15 deaths

Serious adverse events

Other adverse events

Additional Information

Eisai Medical Information

Eisai, Inc.

Phone: 1-888-274-2378

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Randomization Phase: Lenvatinib 24 mg n=261 participants at risk Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Randomization Phase: Placebo n=131 participants at risk Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	OOL, Treatment Period: Lenvatinib 24 mg n=85 participants at risk Participants received lenvatinib 24 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.	OOL, Treatment Period: Lenvatinib 20 mg n=30 participants at risk Participants received lenvatinib 20 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.
Vascular disorders Aneurysm ruptured	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Cardiac disorders Right ventricular hypertrophy	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Skin and subcutaneous tissue disorders Angioedema	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Cardiac disorders Sinus tachycardia	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.76% 1/131 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Eye disorders Retinal vein thrombosis	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Musculoskeletal and connective tissue disorders Arthralgia	1.1% 3/261 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.76% 1/131 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Abdominal pain upper	0.77% 2/261 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Colitis	0.77% 2/261 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
General disorders Asthenia	1.1% 3/261 • Number of events 4 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	2.4% 2/85 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Cardiac disorders Atrial fibrillation	1.5% 4/261 • Number of events 6 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.5% 3/85 • Number of events 4 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Cardiac disorders Atrial flutter	0.77% 2/261 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Musculoskeletal and connective tissue disorders Back pain	1.1% 3/261 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.5% 3/85 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Colitis ischaemic	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.76% 1/131 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Constipation	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.76% 1/131 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	6.7% 2/30 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Diarrhoea	0.77% 2/261 • Number of events 4 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Investigations Blood uric acid increased	0.77% 2/261 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.76% 1/131 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Functional gastrointestinal disorder	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Infections and infestations Bronchitis	0.77% 2/261 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Intestinal obstruction	0.77% 2/261 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Nausea	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.76% 1/131 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Cardiac disorders Cardiac arrest	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Cardiac disorders Cardiac failure	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Oesophageal stenosis	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.76% 1/131 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Nervous system disorders Cauda equina syndrome	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Infections and infestations Cellulitis	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Pneumatosis intestinalis	0.77% 2/261 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Nervous system disorders Cerebrovascular accident	0.77% 2/261 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.5% 3/85 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
General disorders Chest pain	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Stomatitis	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Vomiting	1.9% 5/261 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Hepatobiliary disorders Cholecystitis acute	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Hepatobiliary disorders Cholelithiasis	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Abdominal pain	1.1% 3/261 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	4.7% 4/85 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Blood and lymphatic system disorders Anaemia	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Infections and infestations Abscess intestinal	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Blood and lymphatic system disorders Neutropenia	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Blood and lymphatic system disorders Thrombocytopenia	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Cardiac disorders Acute myocardial infarction	1.9% 5/261 • Number of events 7 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.2% 1/85 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Cardiac disorders Angina pectoris	0.38% 1/261 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.76% 1/131 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.

Other adverse events
Measure	Randomization Phase: Lenvatinib 24 mg n=261 participants at risk Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	Randomization Phase: Placebo n=131 participants at risk Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.	OOL, Treatment Period: Lenvatinib 24 mg n=85 participants at risk Participants received lenvatinib 24 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.	OOL, Treatment Period: Lenvatinib 20 mg n=30 participants at risk Participants received lenvatinib 20 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.
General disorders Pyrexia	15.7% 41/261 • Number of events 58 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	11.5% 15/131 • Number of events 17 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	11.8% 10/85 • Number of events 20 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	16.7% 5/30 • Number of events 8 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	16.5% 43/261 • Number of events 86 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.5% 2/131 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.6% 9/85 • Number of events 13 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	13.3% 4/30 • Number of events 4 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Respiratory, thoracic and mediastinal disorders Dyspnoea	18.0% 47/261 • Number of events 65 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	16.0% 21/131 • Number of events 29 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	18.8% 16/85 • Number of events 26 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	16.7% 5/30 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Infections and infestations Nasopharyngitis	10.7% 28/261 • Number of events 54 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	6.1% 8/131 • Number of events 8 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	7.1% 6/85 • Number of events 7 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	20.0% 6/30 • Number of events 6 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Blood and lymphatic system disorders Lymphopenia	7.7% 20/261 • Number of events 60 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.5% 2/131 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Reproductive system and breast disorders Pelvic pain	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.0% 3/30 • Number of events 4 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Investigations Platelet count decreased	6.5% 17/261 • Number of events 108 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	2.4% 2/85 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	16.7% 5/30 • Number of events 7 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Skin and subcutaneous tissue disorders Dermatitis acneiform	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	4.7% 4/85 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	6.7% 2/30 • Number of events 4 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Endocrine disorders Hypothyroidism	5.4% 14/261 • Number of events 26 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	8.2% 7/85 • Number of events 7 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	6.7% 2/30 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Investigations Aspartate aminotransferase increased	6.5% 17/261 • Number of events 30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.5% 2/131 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	7.1% 6/85 • Number of events 7 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Investigations Blood thyroid stimulating hormone increased	6.9% 18/261 • Number of events 20 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	5.9% 5/85 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Vascular disorders Hypotension	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	9.4% 8/85 • Number of events 12 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	13.3% 4/30 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Blood and lymphatic system disorders Anaemia	11.9% 31/261 • Number of events 60 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	4.6% 6/131 • Number of events 13 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	8.2% 7/85 • Number of events 11 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.0% 3/30 • Number of events 11 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Oral pain	10.0% 26/261 • Number of events 44 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.76% 1/131 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	5.9% 5/85 • Number of events 9 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Infections and infestations Urinary tract infection	11.5% 30/261 • Number of events 54 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	5.3% 7/131 • Number of events 9 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	7.1% 6/85 • Number of events 8 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.0% 3/30 • Number of events 4 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Cheilitis	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	5.9% 5/85 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Toothache	6.9% 18/261 • Number of events 22 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.8% 5/131 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	8.2% 7/85 • Number of events 8 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	6.7% 2/30 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
General disorders General physical health deterioration	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	7.1% 6/85 • Number of events 7 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Metabolism and nutrition disorders Hyperglycaemia	5.7% 15/261 • Number of events 22 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	4.6% 6/131 • Number of events 7 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	5.9% 5/85 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Psychiatric disorders Anxiety	5.7% 15/261 • Number of events 16 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.8% 5/131 • Number of events 6 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	5.9% 5/85 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Investigations Alanine aminotransferase increased	8.0% 21/261 • Number of events 33 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	9.4% 8/85 • Number of events 9 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	6.7% 2/30 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Musculoskeletal and connective tissue disorders Neck pain	8.8% 23/261 • Number of events 33 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	11.5% 15/131 • Number of events 19 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	7.1% 6/85 • Number of events 8 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Investigations Electrocardiogram QT prolonged	10.3% 27/261 • Number of events 53 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.5% 2/131 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.6% 9/85 • Number of events 26 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Blood and lymphatic system disorders Thrombocytopenia	9.6% 25/261 • Number of events 83 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	2.3% 3/131 • Number of events 4 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	8.2% 7/85 • Number of events 84 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Metabolism and nutrition disorders Hypocalcaemia	14.6% 38/261 • Number of events 74 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	12.9% 11/85 • Number of events 23 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.0% 3/30 • Number of events 6 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Haemorrhoids	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	7.1% 6/85 • Number of events 6 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Infections and infestations Pneumonia	0.00% 0/261 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	7.1% 6/85 • Number of events 11 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Skin and subcutaneous tissue disorders Alopecia	13.0% 34/261 • Number of events 39 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	5.3% 7/131 • Number of events 7 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.6% 9/85 • Number of events 14 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	20.0% 6/30 • Number of events 8 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Glossodynia	6.9% 18/261 • Number of events 32 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/131 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.6% 9/85 • Number of events 12 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	0.00% 0/30 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Musculoskeletal and connective tissue disorders Muscle spasms	8.4% 22/261 • Number of events 31 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.8% 5/131 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	12.9% 11/85 • Number of events 15 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	16.7% 5/30 • Number of events 13 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	12.3% 32/261 • Number of events 40 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	9.9% 13/131 • Number of events 14 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	12.9% 11/85 • Number of events 14 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.0% 3/30 • Number of events 5 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Abdominal pain upper	17.6% 46/261 • Number of events 85 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	8.4% 11/131 • Number of events 11 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	12.9% 11/85 • Number of events 13 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	30.0% 9/30 • Number of events 11 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Dry mouth	17.6% 46/261 • Number of events 58 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	8.4% 11/131 • Number of events 13 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	12.9% 11/85 • Number of events 12 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 1 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Respiratory, thoracic and mediastinal disorders Haemoptysis	4.6% 12/261 • Number of events 17 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	9.2% 12/131 • Number of events 14 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.6% 9/85 • Number of events 10 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.0% 3/30 • Number of events 4 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Nervous system disorders Dysgeusia	18.4% 48/261 • Number of events 70 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.1% 4/131 • Number of events 4 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	11.8% 10/85 • Number of events 13 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	20.0% 6/30 • Number of events 9 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Musculoskeletal and connective tissue disorders Myalgia	19.5% 51/261 • Number of events 95 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	4.6% 6/131 • Number of events 9 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	14.1% 12/85 • Number of events 16 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	30.0% 9/30 • Number of events 16 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Skin and subcutaneous tissue disorders Dry skin	12.3% 32/261 • Number of events 35 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	6.1% 8/131 • Number of events 8 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	11.8% 10/85 • Number of events 11 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	6.7% 2/30 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Gastrointestinal disorders Dyspepsia	14.6% 38/261 • Number of events 66 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	4.6% 6/131 • Number of events 6 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	12.9% 11/85 • Number of events 14 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	10.0% 3/30 • Number of events 10 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Metabolism and nutrition disorders Hypoalbuminaemia	10.3% 27/261 • Number of events 50 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	1.5% 2/131 • Number of events 2 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	14.1% 12/85 • Number of events 17 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	3.3% 1/30 • Number of events 3 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
Nervous system disorders Dizziness	17.2% 45/261 • Number of events 77 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	9.9% 13/131 • Number of events 14 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	17.6% 15/85 • Number of events 19 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.	26.7% 8/30 • Number of events 12 • For each participant, from the first dose till 30 days after the last dose up to approximately 8 years Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.