Trial Outcomes & Findings for Study to Evaluate Treatment of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain (NCT NCT02039947)

NCT ID: NCT02039947

Last Updated: 2019-05-21

Results Overview

The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 127 participants
• Primary outcome timeframe: From the start of treatment until disease progression or the start of new anti-cancer therapy
• Results posted on: 2019-05-21

Participant Flow

A subject was considered to have completed the study if the subject died during the study treatment or follow-up period or (for subject in Cohort A) had at least 3 years follow-up from the date of first dose of study treatment at the end of the study. All subjects achieved that definition and then the study ended.

Participant milestones

Measure	Cohort A Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort B Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort C Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
Overall Study STARTED	76	16	16	17
Overall Study COMPLETED	76	16	16	17
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study to Evaluate Treatment of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain

Baseline characteristics by cohort

Measure	Cohort A n=76 Participants Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort B n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort C n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=17 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Total n=125 Participants Total of all reporting groups
Age, Continuous	53.2 Years STANDARD_DEVIATION 14.69 • n=93 Participants	55.1 Years STANDARD_DEVIATION 11.05 • n=4 Participants	65.6 Years STANDARD_DEVIATION 10.40 • n=27 Participants	47.5 Years STANDARD_DEVIATION 13.01 • n=483 Participants	54.2 Years STANDARD_DEVIATION 14.29 • n=36 Participants
Sex: Female, Male Female	36 Participants n=93 Participants	6 Participants n=4 Participants	5 Participants n=27 Participants	6 Participants n=483 Participants	53 Participants n=36 Participants
Sex: Female, Male Male	40 Participants n=93 Participants	10 Participants n=4 Participants	11 Participants n=27 Participants	11 Participants n=483 Participants	72 Participants n=36 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) White	76 Participants n=93 Participants	16 Participants n=4 Participants	16 Participants n=27 Participants	17 Participants n=483 Participants	125 Participants n=36 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants

PRIMARY outcome

Timeframe: From the start of treatment until disease progression or the start of new anti-cancer therapy

Population: All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population.

The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response.

Outcome measures

Measure	Cohort A n=76 Participants Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort C Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
Intracranial Response (IR) Rate in Cohort A	45 Number of participants	—	—	—

SECONDARY outcome

Timeframe: Approximately 2 years

Population: All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population

The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response. No hypothesis testing completed for cohort A, B,C and D

Outcome measures

Measure	Cohort A n=16 Participants Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort C n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=17 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
Intracranial Response Rate of Cohorts B, C and D	9 Number of participants	7 Number of participants	10 Number of participants	—

SECONDARY outcome

Timeframe: Approximately 2 years

Population: All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population

Disease Control rate is defined as the percentage of subjects achieving a confirmed intracranial/extracranial/overall CR or PR or SD or Non-CR/Non-PD. This is based on investigator-assessed response. No hypothesis testing completed for cohort A, B,C and D

Outcome measures

Measure	Cohort A n=76 Participants Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort C n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=17 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
Disease Control for Intracranial, Extracranial and Overall Response for Each Cohort Intracranial	59 Number of participants	14 Number of participants	12 Number of participants	15 Number of participants
Disease Control for Intracranial, Extracranial and Overall Response for Each Cohort Extra cranial	60 Number of participants	11 Number of participants	15 Number of participants	11 Number of participants
Disease Control for Intracranial, Extracranial and Overall Response for Each Cohort Overall rate	60 Number of participants	14 Number of participants	12 Number of participants	15 Number of participants

SECONDARY outcome

Timeframe: Approximately 2 years

Population: All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population

Extracranial Response Rate was defined as the percentage of participants with Complete response (CR) or Partial response (PR) at anytime. This is based on investigator-assessed response. No hypothesis testing completed for cohort A,B,C and D

Outcome measures

Measure	Cohort A n=76 Participants Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort C n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=17 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
Extracranial Response Rate (ER) for Each Cohort	42 Number of participants	7 Number of participants	12 Number of participants	7 Number of participants

SECONDARY outcome

Timeframe: Approximately 2 years

Population: All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population

the number of subjects with a confirmed overall Complete response (CR) or Partial response (PR) by investigator assessment using the Response evaluation criteria in solid tumors (RECIST 1.1 criteria). To determine the overall response, all target and non-target lesions will be assessed using modified RECIST 1.1 criteria.

Outcome measures

Measure	Cohort A n=76 Participants Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort C n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=17 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
Overall Response (OR) for Each Cohort	45 Number of participants	9 Number of participants	7 Number of participants	11 Number of participants

SECONDARY outcome

Timeframe: From first documented evidence of CR or PR until time of first documented intracranial, extracranial, or overall disease progression

Population: All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population

Duration of intracranial, extracranial and overall response, are defined as the time from first documented evidence of CR or PR until time of first documented intracranial, extracranial, or overall disease progression. No hypothesis testing completed for cohort A,B,C and D

Outcome measures

Measure	Cohort A n=76 Participants Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort C n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=17 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
Duration of Intracranial, Extracranial and Overall Response for Each Cohort Duration of intracranial	6.5 Month Interval 4.9 to 8.6	7.3 Month Interval 3.6 to 12.6	8.3 Month Interval 1.3 to 15.0	4.5 Month Interval 2.8 to 5.9
Duration of Intracranial, Extracranial and Overall Response for Each Cohort Duration of extracranial	10.2 Month Interval 5.8 to Upper Limit not reachable.	NA Month Lower and upper Limit not reachable.	4.9 Month Interval 3.0 to 22.4	5.9 Month Interval 1.8 to Upper Limit not reachable.
Duration of Intracranial, Extracranial and Overall Response for Each Cohort Duration of Overall Response	6.2 Month Interval 4.9 to 8.3	12.5 Month Interval 5.3 to Upper Limit not reachable.	6.6 Month Interval 1.3 to 16.3	4.5 Month Interval 2.8 to 11.2

SECONDARY outcome

Timeframe: From the first dose to the earliest date of disease progression or death

Population: All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population

PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. No hypothesis testing completed for cohort A,B,C and D

Outcome measures

Measure	Cohort A n=76 Participants Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort C n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=17 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
Progression-free Survival (PFS) for Each Cohort Based on Investigator Assessment	5.7 Month Interval 5.3 to 7.3	7.2 Month Interval 4.7 to 14.6	3.7 Month Interval 1.7 to 6.5	5.5 Month Interval 3.7 to 11.6

SECONDARY outcome

Timeframe: From the first dose to death

Population: All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population

Overall survival (OS) is defined as the time from the first dose until death due to any cause. No hypothesis testing completed for cohort A,B,C and D

Outcome measures

Measure	Cohort A n=76 Participants Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort C n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=16 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=17 Participants Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
Overall Survival (OS) for Each Cohort	10.8 Month Interval 8.7 to 17.9	24.3 Month Interval 7.9 to NA - Not reachable	10.1 Month Interval 4.6 to 17.6	11.5 Month Interval 6.8 to 22.4

Adverse Events

Cohort A

Serious events: 26 serious events

Other events: 74 other events

Deaths: 54 deaths

Cohort B

Serious events: 5 serious events

Other events: 16 other events

Deaths: 10 deaths

Cohort C

Serious events: 4 serious events

Other events: 16 other events

Deaths: 15 deaths

Cohort D

Serious events: 9 serious events

Other events: 17 other events

Deaths: 13 deaths

Total

Serious events: 44 serious events

Other events: 123 other events

Deaths: 92 deaths

Serious adverse events

Measure	Cohort A n=76 participants at risk Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort B n=16 participants at risk Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort C n=16 participants at risk Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=17 participants at risk Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Total n=125 participants at risk Total
Cardiac disorders Atrial fibrillation	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Cardiac disorders Cardiac failure	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Cardiac disorders Cardio-respiratory arrest	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Cardiac disorders Cardiomyopathy	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Cardiac disorders Myocardial ischaemia	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Cardiac disorders Myocarditis	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Cardiac disorders Pericardial effusion	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Cardiac disorders Tachyarrhythmia	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Detachment of retinal pigment epithelium	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Macular detachment	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Vision blurred	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Abdominal pain	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Constipation	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Diarrhoea	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Intestinal perforation	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Melaena	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Nausea	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Pancreatitis	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Vomiting	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Chills	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Fatigue	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
General disorders General physical health deterioration	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Malaise	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Pyrexia	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	7.2% 9/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Erysipelas	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Escherichia infection	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Lung infection	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Pneumonia	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Pneumonia pneumococcal	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Staphylococcal infection	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Injury, poisoning and procedural complications Fall	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Injury, poisoning and procedural complications Hip fracture	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Injury, poisoning and procedural complications Overdose	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Ejection fraction decreased	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	4.0% 5/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Transaminases increased	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Troponin T increased	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Metabolism and nutrition disorders Dehydration	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Intracranial tumour haemorrhage	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Aphasia	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Cerebrovascular accident	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Epilepsy	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Headache	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Presyncope	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Seizure	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Somnolence	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Status epilepticus	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Syncope	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Psychiatric disorders Confusional state	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Renal and urinary disorders Acute kidney injury	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Renal and urinary disorders Renal failure	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Vascular disorders Hypotension	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Vascular disorders Pelvic venous thrombosis	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description

Other adverse events

Measure	Cohort A n=76 participants at risk Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.	Cohort B n=16 participants at risk Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort C n=16 participants at risk Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Cohort D n=17 participants at risk Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity	Total n=125 participants at risk Total
Vascular disorders Peripheral venous disease	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Papule	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Rash erythematous	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Skin lesion	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Skin mass	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Skin striae	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Vascular disorders Deep vein thrombosis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Vascular disorders Flushing	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Vascular disorders Hot flush	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Rash generalised	6.6% 5/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	4.0% 5/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Rash maculo-papular	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Seborrhoeic dermatitis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Vascular disorders Hypertension	7.9% 6/76 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	9.6% 12/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Pruritus	6.6% 5/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	7.2% 9/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Pruritus generalised	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Rash	11.8% 9/76 • every 12 weeks until death up to 4 years AE additional description	43.8% 7/16 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	17.6% 22/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Skin exfoliation	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Skin fissures	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Vascular disorders Hypotension	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Vascular disorders Lymphoedema	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Skin hyperplasia	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Blood and lymphatic system disorders Anaemia	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	4.8% 6/125 • every 12 weeks until death up to 4 years AE additional description
Blood and lymphatic system disorders Lymphopenia	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Blood and lymphatic system disorders Neutropenia	14.5% 11/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	11.2% 14/125 • every 12 weeks until death up to 4 years AE additional description
Blood and lymphatic system disorders Thrombocytopenia	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	5.6% 7/125 • every 12 weeks until death up to 4 years AE additional description
Cardiac disorders Cyanosis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Ear and labyrinth disorders Ear pain	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Ear and labyrinth disorders Hypoacusis	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Ear and labyrinth disorders Vertigo	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Asthenopia	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Cataract	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Conjunctival irritation	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Diplopia	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Dry eye	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Eye pain	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Eye pruritus	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Eyelid oedema	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Lacrimation increased	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Posterior capsule opacification	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Punctate keratitis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Retinopathy	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Vision blurred	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	4.8% 6/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Visual acuity reduced	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Visual impairment	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Vitreous detachment	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Eye disorders Vitreous floaters	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Abdominal distension	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Abdominal pain	10.5% 8/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	29.4% 5/17 • every 12 weeks until death up to 4 years AE additional description	11.2% 14/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Abdominal pain lower	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Abdominal pain upper	6.6% 5/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	5.6% 7/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Constipation	10.5% 8/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	25.0% 4/16 • every 12 weeks until death up to 4 years AE additional description	35.3% 6/17 • every 12 weeks until death up to 4 years AE additional description	15.2% 19/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Diarrhoea	31.6% 24/76 • every 12 weeks until death up to 4 years AE additional description	50.0% 8/16 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	41.2% 7/17 • every 12 weeks until death up to 4 years AE additional description	33.6% 42/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Dry mouth	6.6% 5/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	8.8% 11/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Dyspepsia	6.6% 5/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	6.4% 8/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Faecalith	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Faeces soft	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Gastrointestinal disorder	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Gastrooesophageal reflux disease	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Gingival bleeding	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Nausea	31.6% 24/76 • every 12 weeks until death up to 4 years AE additional description	43.8% 7/16 • every 12 weeks until death up to 4 years AE additional description	25.0% 4/16 • every 12 weeks until death up to 4 years AE additional description	35.3% 6/17 • every 12 weeks until death up to 4 years AE additional description	32.8% 41/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Rectal haemorrhage	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Retching	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Stomatitis	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	4.8% 6/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Tongue discolouration	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Gastrointestinal disorders Vomiting	31.6% 24/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	35.3% 6/17 • every 12 weeks until death up to 4 years AE additional description	27.2% 34/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Asthenia	36.8% 28/76 • every 12 weeks until death up to 4 years AE additional description	31.2% 5/16 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	29.4% 5/17 • every 12 weeks until death up to 4 years AE additional description	32.8% 41/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Chest pain	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Chills	23.7% 18/76 • every 12 weeks until death up to 4 years AE additional description	37.5% 6/16 • every 12 weeks until death up to 4 years AE additional description	43.8% 7/16 • every 12 weeks until death up to 4 years AE additional description	35.3% 6/17 • every 12 weeks until death up to 4 years AE additional description	29.6% 37/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Face oedema	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Fatigue	9.2% 7/76 • every 12 weeks until death up to 4 years AE additional description	25.0% 4/16 • every 12 weeks until death up to 4 years AE additional description	50.0% 8/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	17.6% 22/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Gait disturbance	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
General disorders General physical health deterioration	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Ill-defined disorder	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Influenza like illness	6.6% 5/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	6.4% 8/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Mucosal inflammation	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Oedema peripheral	14.5% 11/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	14.4% 18/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Pain	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Pyrexia	59.2% 45/76 • every 12 weeks until death up to 4 years AE additional description	43.8% 7/16 • every 12 weeks until death up to 4 years AE additional description	50.0% 8/16 • every 12 weeks until death up to 4 years AE additional description	47.1% 8/17 • every 12 weeks until death up to 4 years AE additional description	54.4% 68/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Temperature regulation disorder	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Thirst	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
General disorders Xerosis	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Hepatobiliary disorders Hepatocellular injury	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Angular cheilitis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Bronchitis	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	4.0% 5/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Cellulitis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Folliculitis	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	23.5% 4/17 • every 12 weeks until death up to 4 years AE additional description	8.0% 10/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Fungal skin infection	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Herpes zoster	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Influenza	9.2% 7/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	5.6% 7/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Laryngitis	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Lower respiratory tract infection	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Lung infection	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Nasopharyngitis	9.2% 7/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	8.8% 11/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Onychomycosis	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Oral candidiasis	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Oral herpes	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Paronychia	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Pharyngitis streptococcal	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Pneumonia	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Postoperative wound infection	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Pulpitis dental	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Rash pustular	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Respiratory tract infection	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Rhinitis	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	4.8% 6/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Sialoadenitis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Skin infection	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Tonsillitis	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Tooth infection	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Upper respiratory tract infection	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Infections and infestations Urinary tract infection	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	4.8% 6/125 • every 12 weeks until death up to 4 years AE additional description
Injury, poisoning and procedural complications Animal bite	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Injury, poisoning and procedural complications Contusion	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Injury, poisoning and procedural complications Fall	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Injury, poisoning and procedural complications Ligament sprain	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Injury, poisoning and procedural complications Muscle strain	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Injury, poisoning and procedural complications Procedural pain	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Alanine aminotransferase increased	11.8% 9/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	12.0% 15/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Amylase increased	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Aspartate aminotransferase increased	15.8% 12/76 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	16.0% 20/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Blood alkaline phosphatase increased	7.9% 6/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	9.6% 12/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Blood cholesterol increased	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Blood creatine phosphokinase increased	9.2% 7/76 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	8.0% 10/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Blood creatinine increased	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Blood lactate dehydrogenase increased	7.9% 6/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	6.4% 8/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Blood phosphorus decreased	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Blood potassium decreased	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Blood pressure increased	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Blood sodium increased	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Investigations C-reactive protein increased	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	4.0% 5/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Ejection fraction decreased	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	5.6% 7/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Electrocardiogram QT prolonged	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Gamma-glutamyltransferase increased	9.2% 7/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	23.5% 4/17 • every 12 weeks until death up to 4 years AE additional description	10.4% 13/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Lipase increased	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Neutrophil count decreased	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	4.8% 6/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Neutrophil count increased	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Platelet count decreased	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Weight decreased	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	9.6% 12/125 • every 12 weeks until death up to 4 years AE additional description
Investigations Weight increased	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	4.8% 6/125 • every 12 weeks until death up to 4 years AE additional description
Investigations White blood cell count decreased	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Metabolism and nutrition disorders Decreased appetite	11.8% 9/76 • every 12 weeks until death up to 4 years AE additional description	25.0% 4/16 • every 12 weeks until death up to 4 years AE additional description	43.8% 7/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	18.4% 23/125 • every 12 weeks until death up to 4 years AE additional description
Metabolism and nutrition disorders Dehydration	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Metabolism and nutrition disorders Diabetes mellitus	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Metabolism and nutrition disorders Gout	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Metabolism and nutrition disorders Hyperglycaemia	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Metabolism and nutrition disorders Hypocalcaemia	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	4.0% 5/125 • every 12 weeks until death up to 4 years AE additional description
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Metabolism and nutrition disorders Hypomagnesaemia	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Metabolism and nutrition disorders Hyponatraemia	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	4.0% 5/125 • every 12 weeks until death up to 4 years AE additional description
Metabolism and nutrition disorders Hypophosphataemia	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Arthralgia	19.7% 15/76 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	35.3% 6/17 • every 12 weeks until death up to 4 years AE additional description	20.8% 26/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Back pain	14.5% 11/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	13.6% 17/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Flank pain	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Joint range of motion decreased	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Muscle spasms	9.2% 7/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	25.0% 4/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	9.6% 12/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Muscular weakness	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	7.2% 9/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Musculoskeletal pain	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	4.0% 5/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Myalgia	17.1% 13/76 • every 12 weeks until death up to 4 years AE additional description	31.2% 5/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	35.3% 6/17 • every 12 weeks until death up to 4 years AE additional description	20.8% 26/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Neck pain	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	4.0% 5/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Pain in extremity	10.5% 8/76 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	12.8% 16/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Rhabdomyolysis	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Synovial cyst	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Musculoskeletal and connective tissue disorders Tendonitis	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lipoma	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Papilloma	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Seborrhoeic keratosis	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Amnesia	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Aphasia	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Aphonia	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Cerebellar syndrome	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Dizziness	6.6% 5/76 • every 12 weeks until death up to 4 years AE additional description	31.2% 5/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	10.4% 13/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Dysarthria	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Dysgeusia	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Haemorrhage intracranial	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Headache	36.8% 28/76 • every 12 weeks until death up to 4 years AE additional description	31.2% 5/16 • every 12 weeks until death up to 4 years AE additional description	37.5% 6/16 • every 12 weeks until death up to 4 years AE additional description	47.1% 8/17 • every 12 weeks until death up to 4 years AE additional description	37.6% 47/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Hemianopia	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Motor dysfunction	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Neuropathy peripheral	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Paraesthesia	6.6% 5/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	6.4% 8/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Paresis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Partial seizures	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Peripheral motor neuropathy	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Presyncope	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Restless legs syndrome	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Seizure	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	7.2% 9/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Syncope	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Temporal lobe epilepsy	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Tongue paralysis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Tonic clonic movements	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Tremor	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Nervous system disorders Visual field defect	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Psychiatric disorders Affective disorder	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Psychiatric disorders Agitation	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Psychiatric disorders Anxiety	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Psychiatric disorders Apathy	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Psychiatric disorders Confusional state	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Psychiatric disorders Delirium	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Psychiatric disorders Depression	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Psychiatric disorders Insomnia	7.9% 6/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	6.4% 8/125 • every 12 weeks until death up to 4 years AE additional description
Psychiatric disorders Sleep disorder	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Renal and urinary disorders Dysuria	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Renal and urinary disorders Nocturia	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Renal and urinary disorders Pollakiuria	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Renal and urinary disorders Urinary incontinence	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Reproductive system and breast disorders Metrorrhagia	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Reproductive system and breast disorders Prostatomegaly	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Respiratory, thoracic and mediastinal disorders Cough	13.2% 10/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	12.8% 16/125 • every 12 weeks until death up to 4 years AE additional description
Respiratory, thoracic and mediastinal disorders Dry throat	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.6% 5/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	4.8% 6/125 • every 12 weeks until death up to 4 years AE additional description
Respiratory, thoracic and mediastinal disorders Epistaxis	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	6.4% 8/125 • every 12 weeks until death up to 4 years AE additional description
Respiratory, thoracic and mediastinal disorders Nasal congestion	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Respiratory, thoracic and mediastinal disorders Productive cough	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Acne	6.6% 5/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	4.8% 6/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Actinic elastosis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Actinic keratosis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Alopecia	9.2% 7/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	11.8% 2/17 • every 12 weeks until death up to 4 years AE additional description	8.0% 10/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Aquagenic wrinkling of palms	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Dermatitis acneiform	3.9% 3/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	6.4% 8/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Dry skin	9.2% 7/76 • every 12 weeks until death up to 4 years AE additional description	12.5% 2/16 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	17.6% 3/17 • every 12 weeks until death up to 4 years AE additional description	12.0% 15/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Ecchymosis	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Eczema	2.6% 2/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	2.4% 3/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Erythema	6.6% 5/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	25.0% 4/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	8.0% 10/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Erythema multiforme	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Generalised erythema	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Hyperhidrosis	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	4.8% 6/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Hyperkeratosis	9.2% 7/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	6.4% 8/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Intertrigo	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	4.0% 5/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Nail disorder	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Night sweats	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Onycholysis	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Pain of skin	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	5.9% 1/17 • every 12 weeks until death up to 4 years AE additional description	1.6% 2/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Palmar erythema	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	1.3% 1/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	18.8% 3/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Palmoplantar keratoderma	0.00% 0/76 • every 12 weeks until death up to 4 years AE additional description	6.2% 1/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	0.80% 1/125 • every 12 weeks until death up to 4 years AE additional description
Skin and subcutaneous tissue disorders Panniculitis	5.3% 4/76 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/16 • every 12 weeks until death up to 4 years AE additional description	0.00% 0/17 • every 12 weeks until death up to 4 years AE additional description	3.2% 4/125 • every 12 weeks until death up to 4 years AE additional description

Additional Information

Study Director

Novartis Pharmaceutical

Phone: 862-778-8300

Email: novartis.email@novartis.com

Results disclosure agreements

• Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety
• Publication restrictions are in place

Restriction type: OTHER