Trial Outcomes & Findings for Afatinib and Vinorelbine in Tumours Known to Overexpress EGFR and/or HER2 (NCT NCT00906698)

NCT ID: NCT00906698

Last Updated: 2014-06-09

Results Overview

Number of participants with DLT for the determination of the Maximum Tolerated Dose (MTD). 3+3 dose escalation design. MTD based on DLTs during first treatment course. After MTD was determined, additional patients were included at the MTD in an expansion cohort.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 55 participants
• Primary outcome timeframe: 28 days
• Results posted on: 2014-06-09

Participant Flow

Participant milestones

Measure	Afatinib 20mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity	Afatinib 40mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Overall Study STARTED	3	19	6	4	18	5
Overall Study COMPLETED	0	0	0	0	0	0
Overall Study NOT COMPLETED	3	19	6	4	18	5

Reasons for withdrawal

Measure	Afatinib 20mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity	Afatinib 40mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Overall Study Dose-limiting toxicity (DLT)	0	6	0	0	1	0
Overall Study Adverse Event	0	0	2	0	4	1
Overall Study Disease progression	3	12	4	4	12	4
Overall Study Withdrawal by Subject	0	0	0	0	1	0
Overall Study incl. non compliance, lost to follow-up	0	1	0	0	0	0

Baseline Characteristics

Afatinib and Vinorelbine in Tumours Known to Overexpress EGFR and/or HER2

Baseline characteristics by cohort

Measure	Afatinib 20mg With Vinorelbine i.v. n=3 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=19 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. n=6 Participants Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os n=4 Participants Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os n=18 Participants Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os n=5 Participants Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Total n=55 Participants Total of all reporting groups
Age, Continuous	59.7 years STANDARD_DEVIATION 15.3 • n=5 Participants	55.3 years STANDARD_DEVIATION 8.0 • n=7 Participants	61.7 years STANDARD_DEVIATION 5.0 • n=5 Participants	55.3 years STANDARD_DEVIATION 6.2 • n=4 Participants	50.9 years STANDARD_DEVIATION 9.5 • n=21 Participants	51.0 years STANDARD_DEVIATION 8.3 • n=8 Participants	54.4 years STANDARD_DEVIATION 9.0 • n=8 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	11 Participants n=7 Participants	4 Participants n=5 Participants	0 Participants n=4 Participants	11 Participants n=21 Participants	4 Participants n=8 Participants	31 Participants n=8 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	8 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants	7 Participants n=21 Participants	1 Participants n=8 Participants	24 Participants n=8 Participants

PRIMARY outcome

Timeframe: 28 days

Population: Treated Set (TS). TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib.

Number of participants with DLT for the determination of the Maximum Tolerated Dose (MTD). 3+3 dose escalation design. MTD based on DLTs during first treatment course. After MTD was determined, additional patients were included at the MTD in an expansion cohort.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=3 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=19 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. n=6 Participants Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os n=4 Participants Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os n=18 Participants Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os n=5 Participants Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Number of Participants With Dose-limiting Toxicities (DLT) First cycle (N=3;6;6;4;6;5)	0 participants	1 participants	4 participants	0 participants	1 participants	3 participants
Number of Participants With Dose-limiting Toxicities (DLT) Expansion cohort (N=0;13;0;0;12;0)	NA participants no expansion cohort for this arm	7 participants	NA participants no expansion cohort for this arm	NA participants no expansion cohort for this arm	2 participants	NA participants no expansion cohort for this arm

SECONDARY outcome

Timeframe: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.

Population: All patients from the Treated Set (TS).

Overall response is defined as complete response, partial response and stable disease and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0). Complete response (CR) and partial response (PR) had to be confirmed by a subsequent tumour assessment at least 28 days after the criteria for CR or PR were first met. To confirm a status of stable disease, the duration of stable disease was to be at least 42 days.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=3 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=19 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. n=6 Participants Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os n=4 Participants Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os n=18 Participants Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os n=5 Participants Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Number of Patients With Best Overall Response Complete response	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants
Number of Patients With Best Overall Response Partial response	0 participants	0 participants	0 participants	0 participants	3 participants	0 participants
Number of Patients With Best Overall Response Stable disease	1 participants	10 participants	5 participants	0 participants	6 participants	5 participants
Number of Patients With Best Overall Response Progressive disease	2 participants	6 participants	0 participants	4 participants	7 participants	0 participants
Number of Patients With Best Overall Response Missing	0 participants	3 participants	1 participants	0 participants	2 participants	0 participants

SECONDARY outcome

Timeframe: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.

Population: All patients from the Treated Set (TS).

OR is defined as confirmed complete response and confirmed partial response (PR) and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0).

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=3 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=19 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. n=6 Participants Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os n=4 Participants Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os n=18 Participants Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os n=5 Participants Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Number of Patients With Objective Response (OR)	0 participants	0 participants	0 participants	0 participants	3 participants	0 participants

SECONDARY outcome

Timeframe: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.

Population: All patients from the Treated Set (TS).

DC is defined as confirmed complete response (CR), partial response (PR) and stable disease (SD) and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0).

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=3 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=19 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. n=6 Participants Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os n=4 Participants Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os n=18 Participants Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os n=5 Participants Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Number of Patients With Disease Control (DC)	1 participants	10 participants	5 participants	0 participants	9 participants	5 participants

SECONDARY outcome

Timeframe: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.

Population: Patients from the Treated Set (TS) with objective response.

The time to OR was the duration from the first treatment to the time when the measurement criteria for first documented confirmed CR and/or PR were met according to RECIST 1.0 criteria.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os n=3 Participants Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Time to Objective Response	—	—	—	—	55 days Interval 55.0 to 343.0	—

SECONDARY outcome

Timeframe: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.

Population: Patients from Treated Set (TS) with Objective Response.

The duration of objective response was measured from the time of first documented confirmed CR or PR to the time of progressive disease or death, whichever occured earlier.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os n=3 Participants Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Duration of Objective Response	—	—	—	—	114 days Interval 113.0 to 151.0	—

SECONDARY outcome

Timeframe: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.

Population: Patients from Treated Set (TS) with disease control.

Duration of disease control was measured from the start of study treatment to the time of progression or death, whichever occured first.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=1 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=10 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. n=5 Participants Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os n=9 Participants Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os n=5 Participants Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Duration of Disease Control	110 days Interval 110.0 to 110.0	167 days Interval 94.0 to 351.0	168 days Interval 81.0 to 202.0	—	162 days Interval 50.0 to 493.0	120 days Interval 54.0 to 230.0

SECONDARY outcome

Timeframe: Screening and every 8 weeks after starting of treatment, up to 44 weeks.

Population: Patients from Treated Set (TS).

Best percentage change in tumour size was the best percentage change in the sum of diameters of target lesions and was calculated as (minimum sum of diameters post baseline - sum of diameters at baseline)/sum of diameters at baseline. Negative values indicate a decrease, positive values an increase.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=3 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=19 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. n=6 Participants Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os n=4 Participants Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os n=18 Participants Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os n=5 Participants Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Best Percentage Change in Tumour Size	-5.65 percentage change in tumour size Standard Error 10.91	-7.51 percentage change in tumour size Standard Error 4.22	-24.10 percentage change in tumour size Standard Error 9.57	25.89 percentage change in tumour size Standard Error 4.55	-1.36 percentage change in tumour size Standard Error 9.62	-10.76 percentage change in tumour size Standard Error 3.47

SECONDARY outcome

Timeframe: From first dose of study medication to the occurrence of progression or death whichever came first, up to 44 months.

Population: All patients treated in the MTD cohorts.

PFS was defined as the time from the first dose of study medication to the occurrence of tumour progression or death, whichever came first. It was assessed according to RECIST 1.0. Median time results from unstratified Kaplan-Meier estimates.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=19 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=18 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Progression-free Survival (PFS)	14.6 weeks Interval 7.1 to 31.9	15.9 weeks Interval 7.4 to 23.7	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing

Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=14 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=8 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State	892 ng*h/mL Geometric Coefficient of Variation 87.3	683 ng*h/mL Geometric Coefficient of Variation 375.0	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing

Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=12 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=18 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Area Under the Concentration-time Curve of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State	512 ng*h/mL Geometric Coefficient of Variation 41.4	655 ng*h/mL Geometric Coefficient of Variation 26.0	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing

Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=14 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=8 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State	62.0 ng/mL Geometric Coefficient of Variation 97.9	42.7 ng/mL Geometric Coefficient of Variation 425	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing

Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=12 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=18 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Maximum Measured Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25 mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State	822 ng/mL Geometric Coefficient of Variation 56.2	941 ng/mL Geometric Coefficient of Variation 55.1	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing

Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=14 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=8 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State	3.16 hours Interval 2.0 to 6.0	2.00 hours Interval 1.0 to 4.03	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing

Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=12 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=18 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State	0.166 hours Interval 0.15 to 0.167	0.167 hours Interval 0.15 to 0.233	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h,, 7h and 24h after dosing

Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=9 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=8 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State	872 ng*h/mL Geometric Coefficient of Variation 39.8	1070 ng*h/mL Geometric Coefficient of Variation 33.8	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing

Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=15 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=25 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Area Under the Concentration-time Curve of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State	258 ng*h/mL Geometric Coefficient of Variation 79.8	334 ng*h/mL Geometric Coefficient of Variation 70.9	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing

Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=10 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=9 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 Per os Vinorelbine at Steady State	55.1 ng/mL Geometric Coefficient of Variation 35.6	67.2 ng/mL Geometric Coefficient of Variation 29.4	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing

Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=15 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=25 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Maximum Measured Concentration of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 in Presence and Absence of Afatinib at Steady State	52.8 ng/mL Geometric Coefficient of Variation 80.8	65.0 ng/mL Geometric Coefficient of Variation 63.9	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing

Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=10 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=9 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State	3.54 hours Interval 2.0 to 5.03	3.00 hours Interval 1.0 to 6.0	—	—	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing

Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.

Outcome measures

Measure	Afatinib 20mg With Vinorelbine i.v. n=15 Participants Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine i.v. n=25 Participants Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.	Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.
Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Administrations of 60mg/m^2 Vinorelbine Per os in Presence and Absence of Afatinib at Steady State	1.50 hours Interval 1.0 to 6.0	1.50 hours Interval 0.917 to 3.17	—	—	—	—

Adverse Events

Afatinib 20mg With Vinorelbine i.v.

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Afatinib 40mg With Vinorelbine i.v.

Serious events: 11 serious events

Other events: 19 other events

Deaths: 0 deaths

Afatinib 50mg With Vinorelbine i.v.

Serious events: 4 serious events

Other events: 6 other events

Deaths: 0 deaths

Afatinib 20mg With Vinorelbine Per os

Serious events: 2 serious events

Other events: 4 other events

Deaths: 0 deaths

Afatinib 40mg With Vinorelbine Per os

Serious events: 13 serious events

Other events: 18 other events

Deaths: 0 deaths

Afatinib 50mg With Vinorelbine Per os

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Measure	Afatinib 20mg With Vinorelbine i.v. n=3 participants at risk Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 40mg With Vinorelbine i.v. n=19 participants at risk Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 50mg With Vinorelbine i.v. n=6 participants at risk Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 20mg With Vinorelbine Per os n=4 participants at risk Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 40mg With Vinorelbine Per os n=18 participants at risk Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 50mg With Vinorelbine Per os n=5 participants at risk Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .
Blood and lymphatic system disorders Anaemia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 3/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Neutropenia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Ear and labyrinth disorders Vertigo	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Diarrhoea	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	15.8% 3/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Nausea	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Stomatitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Vomiting	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Asthenia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Chest pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders General physical health deterioration	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Mucosal inflammation	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Hepatobiliary disorders Hepatocellular injury	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Biliary tract infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Bronchitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Lung infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Pneumonia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Injury, poisoning and procedural complications Fall	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Injury, poisoning and procedural complications Pneumothorax traumatic	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Lipase increased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Weight decreased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Dehydration	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Mobility decreased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to meninges	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Aphasia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Convulsion	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Hemianopia homonymous	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Intracranial pressure increased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Paraesthesia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Psychiatric disorders Depression	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Renal and urinary disorders Renal failure	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	15.8% 3/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Vascular disorders Orthostatic hypotension	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.

Other adverse events

Measure	Afatinib 20mg With Vinorelbine i.v. n=3 participants at risk Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 40mg With Vinorelbine i.v. n=19 participants at risk Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 50mg With Vinorelbine i.v. n=6 participants at risk Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 20mg With Vinorelbine Per os n=4 participants at risk Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 40mg With Vinorelbine Per os n=18 participants at risk Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .	Afatinib 50mg With Vinorelbine Per os n=5 participants at risk Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity .
Investigations Blood creatinine increased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Blood phosphorus decreased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Eastern Cooperative Oncology Group performance status worsened	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Weight decreased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	21.1% 4/19 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 3/6 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 2/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations White blood cell count increased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Cell death	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Decreased appetite	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	68.4% 13/19 • First administration of trial medication until 28 days after last administration of trial medication.	66.7% 4/6 • First administration of trial medication until 28 days after last administration of trial medication.	75.0% 3/4 • First administration of trial medication until 28 days after last administration of trial medication.	55.6% 10/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Dehydration	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	15.8% 3/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hyperproteinaemia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hypoalbuminaemia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Anaemia	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	47.4% 9/19 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 3/6 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 2/4 • First administration of trial medication until 28 days after last administration of trial medication.	44.4% 8/18 • First administration of trial medication until 28 days after last administration of trial medication.	100.0% 5/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Leukocytosis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Leukopenia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Lymph node pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Lymphadenopathy	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Lymphopenia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 3/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Neutropenia	66.7% 2/3 • First administration of trial medication until 28 days after last administration of trial medication.	63.2% 12/19 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 3/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	44.4% 8/18 • First administration of trial medication until 28 days after last administration of trial medication.	80.0% 4/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Thrombocytosis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Cardiac disorders Atrioventricular block	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Ear and labyrinth disorders Ear disorder	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Ear and labyrinth disorders Hypoacusis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Ear and labyrinth disorders Tinnitus	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Ear and labyrinth disorders Vertigo	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Eye disorders Blepharitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Eye disorders Conjunctivitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Eye disorders Dry eye	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Eye disorders Exophthalmos	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Eye disorders Eyelid ptosis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Eye disorders Lacrimation increased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Eye disorders Ocular icterus	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Eye disorders Photopsia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Eye disorders Visual acuity reduced	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Abdominal pain	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	15.8% 3/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	27.8% 5/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Abdominal pain upper	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	26.3% 5/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Anal haemorrhage	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Anorectal discomfort	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Aphthous stomatitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	21.1% 4/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Ascites	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Chapped lips	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Cheilitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Colitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Constipation	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	36.8% 7/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 2/4 • First administration of trial medication until 28 days after last administration of trial medication.	38.9% 7/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Diarrhoea	100.0% 3/3 • First administration of trial medication until 28 days after last administration of trial medication.	100.0% 19/19 • First administration of trial medication until 28 days after last administration of trial medication.	100.0% 6/6 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 2/4 • First administration of trial medication until 28 days after last administration of trial medication.	94.4% 17/18 • First administration of trial medication until 28 days after last administration of trial medication.	100.0% 5/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Dry mouth	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Dyspepsia	66.7% 2/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 3/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Dysphagia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	21.1% 4/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Gastritis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Gastrointestinal toxicity	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Gastrooesophageal reflux disease	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	22.2% 4/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Gingival bleeding	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Gingival pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Glossodynia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Haemorrhoids	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	15.8% 3/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Melaena	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Nausea	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	63.2% 12/19 • First administration of trial medication until 28 days after last administration of trial medication.	83.3% 5/6 • First administration of trial medication until 28 days after last administration of trial medication.	75.0% 3/4 • First administration of trial medication until 28 days after last administration of trial medication.	61.1% 11/18 • First administration of trial medication until 28 days after last administration of trial medication.	80.0% 4/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Odynophagia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Oesophagitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Oral disorder	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Pancreatitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Portal hypertensive gastropathy	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Proctalgia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Salivary hypersecretion	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Stomatitis	66.7% 2/3 • First administration of trial medication until 28 days after last administration of trial medication.	36.8% 7/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	38.9% 7/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Tongue ulceration	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Vomiting	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	42.1% 8/19 • First administration of trial medication until 28 days after last administration of trial medication.	66.7% 4/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	72.2% 13/18 • First administration of trial medication until 28 days after last administration of trial medication.	60.0% 3/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Asthenia	66.7% 2/3 • First administration of trial medication until 28 days after last administration of trial medication.	100.0% 19/19 • First administration of trial medication until 28 days after last administration of trial medication.	100.0% 6/6 • First administration of trial medication until 28 days after last administration of trial medication.	100.0% 4/4 • First administration of trial medication until 28 days after last administration of trial medication.	77.8% 14/18 • First administration of trial medication until 28 days after last administration of trial medication.	100.0% 5/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Catheter site pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Chest pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Chills	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Facial pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Fatigue	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Feeling cold	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders General physical health deterioration	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Hyperthermia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Inflammation	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Mucosal discolouration	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Mucosal inflammation	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	42.1% 8/19 • First administration of trial medication until 28 days after last administration of trial medication.	66.7% 4/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 6/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Oedema peripheral	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	15.8% 3/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Puncture site pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Pyrexia	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	52.6% 10/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 2/4 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 6/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Ulcer	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Xerosis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Hepatobiliary disorders Cholestasis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	15.8% 3/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Hepatobiliary disorders Hepatocellular injury	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	31.6% 6/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Hepatobiliary disorders Jaundice cholestatic	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Bronchitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Cystitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Device related infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Ear infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Escherichia infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Escherichia urinary tract infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Folliculitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	36.8% 7/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	38.9% 7/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Fungal infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Fungal oesophagitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Fungal paronychia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Furuncle	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Gastroenteritis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Genital infection fungal	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Gingivitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Herpes virus infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Hordeolum	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Lymphangitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Nasopharyngitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	15.8% 3/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Oesophageal candidiasis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Oral fungal infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Oral herpes	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Otitis externa	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Paronychia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	26.3% 5/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	27.8% 5/18 • First administration of trial medication until 28 days after last administration of trial medication.	60.0% 3/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Pharyngitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Proteus infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Pulpitis dental	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Puncture site abscess	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Rash pustular	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Rhinitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	31.6% 6/19 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 3/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	22.2% 4/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Sinusitis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Staphylococcal infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Tinea pedis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Tooth abscess	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Upper respiratory fungal infection	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Urinary tract infection	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	21.1% 4/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Urinary tract infection bacterial	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Urinary tract infection enterococcal	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Injury, poisoning and procedural complications Burn oesophageal	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Injury, poisoning and procedural complications Fall	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Amylase increased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Aspartate aminotransferase increased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Blood bilirubin increased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Blood creatine phosphokinase increased	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hypocalcaemia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hypoglycaemia	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hypomagnesaemia	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	26.3% 5/19 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 3/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	27.8% 5/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	21.1% 4/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	22.2% 4/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Hypercreatinaemia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	26.3% 5/19 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 3/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	22.2% 4/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	15.8% 3/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 3/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Myalgia	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Osteonecrosis of jaw	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Pain in jaw	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Sarcopenia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Haemangioma of bone	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Aphonia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Balance disorder	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Burning sensation	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Cerebral microhaemorrhage	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Cervical root pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Dysaesthesia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Dysgeusia	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	21.1% 4/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Epilepsy	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Headache	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Hydrocephalus	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Hyperaesthesia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Neuralgia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Neuropathy peripheral	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Paraesthesia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	21.1% 4/19 • First administration of trial medication until 28 days after last administration of trial medication.	83.3% 5/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	27.8% 5/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Sciatica	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Sensory loss	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Somnolence	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Syncope	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Toxic neuropathy	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Tremor	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Psychiatric disorders Anxiety	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 2/4 • First administration of trial medication until 28 days after last administration of trial medication.	22.2% 4/18 • First administration of trial medication until 28 days after last administration of trial medication.	60.0% 3/5 • First administration of trial medication until 28 days after last administration of trial medication.
Psychiatric disorders Depression	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Psychiatric disorders Hallucination, visual	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Psychiatric disorders Insomnia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 2/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Psychiatric disorders Sleep disorder	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Renal and urinary disorders Bladder discomfort	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Renal and urinary disorders Dysuria	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Renal and urinary disorders Micturition disorder	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Renal and urinary disorders Pollakiuria	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Renal and urinary disorders Proteinuria	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Renal and urinary disorders Renal failure	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Renal and urinary disorders Urinary incontinence	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Reproductive system and breast disorders Breast mass	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Reproductive system and breast disorders Breast pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Reproductive system and breast disorders Genital lesion	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Reproductive system and breast disorders Genital tract inflammation	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Reproductive system and breast disorders Scrotal oedema	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Reproductive system and breast disorders Vaginal haemorrhage	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Reproductive system and breast disorders Vulvovaginal burning sensation	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Reproductive system and breast disorders Vulvovaginal dryness	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Reproductive system and breast disorders Vulvovaginal pruritus	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Bronchial hyperreactivity	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	47.4% 9/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	22.2% 4/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Dysphonia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	26.3% 5/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Dyspnoea	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	47.4% 9/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	38.9% 7/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	31.6% 6/19 • First administration of trial medication until 28 days after last administration of trial medication.	66.7% 4/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	22.2% 4/18 • First administration of trial medication until 28 days after last administration of trial medication.	40.0% 2/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Hiccups	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Increased bronchial secretion	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Nasal dryness	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Nasal polyps	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Pharyngeal erythema	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	22.2% 4/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Upper respiratory tract inflammation	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Acne	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Actinic keratosis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Dermatitis acneiform	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	21.1% 4/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	21.1% 4/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	22.2% 4/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Eczema	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Eczema asteatotic	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Erythema	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	21.1% 4/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Hair colour changes	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Hair texture abnormal	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Nail dystrophy	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Nail pigmentation	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Nail pitting	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Nail toxicity	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Night sweats	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	25.0% 1/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Onychoclasis	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	10.5% 2/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Palmar erythema	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Pemphigoid	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Petechiae	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	15.8% 3/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Rash	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	36.8% 7/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	50.0% 9/18 • First administration of trial medication until 28 days after last administration of trial medication.	60.0% 3/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Rash macular	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Rash papular	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Rash pruritic	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Skin fissures	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	15.8% 3/19 • First administration of trial medication until 28 days after last administration of trial medication.	33.3% 2/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 3/18 • First administration of trial medication until 28 days after last administration of trial medication.	60.0% 3/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Skin irritation	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Skin lesion	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Skin toxicity	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Subcutaneous nodule	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Xeroderma	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	11.1% 2/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Vascular disorders Deep vein thrombosis	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Vascular disorders Hypotension	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	16.7% 1/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	5.6% 1/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Vascular disorders Intermittent claudication	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	20.0% 1/5 • First administration of trial medication until 28 days after last administration of trial medication.
Vascular disorders Lymphoedema	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Vascular disorders Orthostatic hypotension	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Vascular disorders Pallor	0.00% 0/3 • First administration of trial medication until 28 days after last administration of trial medication.	5.3% 1/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.
Vascular disorders Thrombophlebitis superficial	33.3% 1/3 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/19 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/6 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/4 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/18 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/5 • First administration of trial medication until 28 days after last administration of trial medication.

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
• Publication restrictions are in place

Restriction type: OTHER