Trial Outcomes & Findings for BIBW 2992 and BSC Versus Placebo and BSC in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib (LUX-LUNG 1) (NCT NCT00656136)

NCT ID: NCT00656136

Last Updated: 2016-07-26

Results Overview

Overall survival was the duration from the date of randomization to the date of death. Patients who were alive were censored at the last contact date prior to the database lock. For the primary analysis 11 patients were lost to follow-up and were censored at the last contact date when they were known to be still alive. Primary analysis data cut-off date was 08 July 2010. For the final analysis 13 patients were lost to follow-up and were censored at the last contact date when they were known to be still alive. Final analysis data cut-off date was 04 October 2013.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 585 participants
• Primary outcome timeframe: From randomization until death or the last patient out date, an average of 12 months
• Results posted on: 2016-07-26

Participant Flow

Two-arm, randomised (2:1 ratio), double-blind , placebo-controlled, multi-centre trial. 585 patients were randomised. All patients randomized received at least one dose of study medication.

Participant milestones

Measure	Placebo Plus Best Supportive Care (BSC) Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.	Afatinib 50 mg/Day Plus Best Supportive Care (BSC) Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus Best Supportive Care (BSC) or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).
Overall Study STARTED	195	390
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	195	390

Reasons for withdrawal

Measure	Placebo Plus Best Supportive Care (BSC) Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.	Afatinib 50 mg/Day Plus Best Supportive Care (BSC) Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus Best Supportive Care (BSC) or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).
Overall Study Progressive disease	177	322
Overall Study Other Adverse Event	5	51
Overall Study Protocol Violation	2	3
Overall Study Patient refused to take study medication	7	10
Overall Study Unknown and others	4	4

Baseline Characteristics

BIBW 2992 and BSC Versus Placebo and BSC in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib (LUX-LUNG 1)

Baseline characteristics by cohort

Measure	Placebo Plus Best Supportive Care (BSC) n=195 Participants Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.	Afatinib 50 mg/Day Plus Best Supportive Care (BSC) n=390 Participants Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus BSC or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).	Total n=585 Participants Total of all reporting groups
Age, Continuous	59 years STANDARD_DEVIATION 10.4 • n=5 Participants	58 years STANDARD_DEVIATION 10.8 • n=7 Participants	58 years STANDARD_DEVIATION 10.6 • n=5 Participants
Sex: Female, Male Female	117 Participants n=5 Participants	231 Participants n=7 Participants	348 Participants n=5 Participants
Sex: Female, Male Male	78 Participants n=5 Participants	159 Participants n=7 Participants	237 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	72 Number of participants n=5 Participants	121 Number of participants n=7 Participants	193 Number of participants n=5 Participants
Race/Ethnicity, Customized Eastern Asian	110 Number of participants n=5 Participants	227 Number of participants n=7 Participants	337 Number of participants n=5 Participants
Race/Ethnicity, Customized Other Asian	12 Number of participants n=5 Participants	38 Number of participants n=7 Participants	50 Number of participants n=5 Participants
Race/Ethnicity, Customized Other	1 Number of participants n=5 Participants	4 Number of participants n=7 Participants	5 Number of participants n=5 Participants
Baseline Eastern Cooperative Oncology Group (ECOG) performance score ECOG score = 0	53 Number of participants n=5 Participants	92 Number of participants n=7 Participants	145 Number of participants n=5 Participants
Baseline Eastern Cooperative Oncology Group (ECOG) performance score ECOG score = 1	127 Number of participants n=5 Participants	268 Number of participants n=7 Participants	395 Number of participants n=5 Participants
Baseline Eastern Cooperative Oncology Group (ECOG) performance score ECOG score = 2	15 Number of participants n=5 Participants	30 Number of participants n=7 Participants	45 Number of participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization until death or the last patient out date, an average of 12 months

Population: Randomized set was all patients who were randomized and for this study all of these patients received at least one dose of study medication.

Overall survival was the duration from the date of randomization to the date of death. Patients who were alive were censored at the last contact date prior to the database lock.

For the primary analysis 11 patients were lost to follow-up and were censored at the last contact date when they were known to be still alive. Primary analysis data cut-off date was 08 July 2010.

For the final analysis 13 patients were lost to follow-up and were censored at the last contact date when they were known to be still alive. Final analysis data cut-off date was 04 October 2013.

Outcome measures

Measure	Placebo Plus Best Supportive Care (BSC) n=195 Participants Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.	Afatinib 50 mg/Day Plus Best Supportive Care (BSC) n=390 Participants Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus BSC or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).
Overall Survival Primary analysis (358 deaths)	11.96 Months Interval 10.15 to 14.26	10.78 Months Interval 9.95 to 11.99
Overall Survival Final analysis (526 deaths)	11.73 Months Interval 10.05 to 14.06	10.87 Months Interval 9.95 to 12.25

SECONDARY outcome

Timeframe: From randomization to disease progression, death or the data cutoff on 07 July 2010, an average of 3.3 months

Population: Randomized set was all patients who were randomized and for this study all of these patients received at least one dose of study medication.

PFS is defined as time from randomisation to disease progression or death whichever occurs first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST 1.0).

Outcome measures

Measure	Placebo Plus Best Supportive Care (BSC) n=195 Participants Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.	Afatinib 50 mg/Day Plus Best Supportive Care (BSC) n=390 Participants Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus BSC or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).
Progression-free Survival (PFS)	1.08 Months Interval 0.95 to 1.68	3.29 Months Interval 2.79 to 4.4

SECONDARY outcome

Timeframe: From randomization to disease progression, death or the data cutoff on 07 July 2010, an average of 3.3 months

Population: Randomized set was all patients who were randomized and for this study all of these patients received at least one dose of study medication.

OR is defined as complete response (CR) and partial response (PR). Assessed by central independent review according to RECIST 1.0.

Outcome measures

Measure	Placebo Plus Best Supportive Care (BSC) n=195 Participants Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.	Afatinib 50 mg/Day Plus Best Supportive Care (BSC) n=390 Participants Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus BSC or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).
Objective Response Rate (OR)	0.5 Percentage of patients with OR Interval 0.0 to 2.8	7.4 Percentage of patients with OR Interval 5.0 to 10.5

Adverse Events

Placebo

Serious events: 36 serious events

Other events: 167 other events

Deaths: 0 deaths

Afatinib 50 mg/Day

Serious events: 136 serious events

Other events: 383 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=195 participants at risk Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.	Afatinib 50 mg/Day n=390 participants at risk Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus BSC or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).
Nervous system disorders Dizziness	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.77% 3/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Blood and lymphatic system disorders Lymphadenopathy	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Blood and lymphatic system disorders Neutropenia	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Cardiac disorders Acute left ventricular failure	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Cardiac disorders Atrial fibrillation	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Cardiac disorders Cardiac failure	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Cardiac disorders Cardiac tamponade	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Cardiac disorders Cardio-respiratory arrest	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Cardiac disorders Myocardial infarction	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Cardiac disorders Pericardial effusion	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Cardiac disorders Sick sinus syndrome	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Cardiac disorders Supraventricular tachycardia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Cardiac disorders Tachycardia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Eye disorders Blindness	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Eye disorders Diplopia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Eye disorders Eye movement disorder	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Eye disorders Vision blurred	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Abdominal discomfort	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Abdominal pain	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Ascites	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Diarrhoea	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	4.6% 18/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Dysphagia	1.5% 3/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Haematemesis	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Ileus	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Nausea	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	1.0% 4/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Pancreatitis	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	1.0% 4/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Proctalgia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Stomatitis	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.77% 3/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Vomiting	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	1.3% 5/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Asthenia	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Chest discomfort	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Chest pain	1.0% 2/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Condition aggravated	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Death	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.77% 3/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Extravasation	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Face oedema	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Fatigue	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.77% 3/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders General physical health deterioration	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Hernia	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Malaise	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Medical device complication	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Multi-organ failure	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Oedema peripheral	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Pain	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Pyrexia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	1.8% 7/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Sudden cardiac death	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Sudden death	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Hepatobiliary disorders Acute hepatic failure	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Hepatobiliary disorders Hepatitis acute	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Atypical pneumonia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Bacteraemia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Candida infection	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Cellulitis	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Device related infection	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Gastroenteritis	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Gastroenteritis viral	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Lower respiratory tract infection fungal	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Lung infection	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	1.0% 4/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Paronychia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Peritonitis bacterial	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Pneumonia	2.1% 4/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	2.6% 10/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Sepsis	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Septic shock	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	1.3% 5/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Soft tissue infection	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Upper respiratory tract infection	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Wound infection	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Injury, poisoning and procedural complications Fall	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Injury, poisoning and procedural complications Head injury	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Injury, poisoning and procedural complications Multiple fractures	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Injury, poisoning and procedural complications Thoracic vertebral fracture	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Investigations Blood creatinine increased	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	1.0% 4/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Investigations Blood culture positive	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Investigations Blood potassium increased	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Investigations Electrocardiogram T wave inversion	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Investigations Oxygen saturation decreased	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Investigations Prostatic specific antigen increased	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.77% 3/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Metabolism and nutrition disorders Dehydration	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	2.1% 8/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Metabolism and nutrition disorders Hypocalcaemia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	1.3% 5/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Metabolism and nutrition disorders Hyponatraemia	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Musculoskeletal and connective tissue disorders Back pain	1.0% 2/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Musculoskeletal and connective tissue disorders Bone pain	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Musculoskeletal and connective tissue disorders Flank pain	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Musculoskeletal and connective tissue disorders Muscular weakness	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.77% 3/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Musculoskeletal and connective tissue disorders Pain in extremity	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Musculoskeletal and connective tissue disorders Pathological fracture	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cervix carcinoma	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma metastatic	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant ascites	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	3.6% 7/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	4.1% 16/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant pleural effusion	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	1.5% 3/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	2.8% 11/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to meninges	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic pain	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Altered state of consciousness	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Brain mass	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Brain oedema	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Cerebral haemorrhage	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Cerebral infarction	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Cerebrovascular accident	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Convulsion	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Dysarthria	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Embolic cerebral infarction	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Headache	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Hemiparesis	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Hydrocephalus	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Intracranial pressure increased	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Ischaemic stroke	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Paraesthesia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Paraplegia	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Partial seizures	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Spinal cord compression	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Tremor	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders VIIth nerve paralysis	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Psychiatric disorders Delirium	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Renal and urinary disorders Acute prerenal failure	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Renal and urinary disorders Oliguria	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Renal and urinary disorders Renal colic	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Renal and urinary disorders Renal failure	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Renal and urinary disorders Renal failure acute	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	1.8% 7/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Renal and urinary disorders Renal impairment	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Reproductive system and breast disorders Pelvic pain	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Cough	1.5% 3/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.1% 4/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	2.1% 8/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Dyspnoea at rest	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Haemothorax	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.00% 0/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Hydropneumothorax	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Pleural effusion	3.6% 7/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	3.6% 14/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	1.3% 5/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.0% 2/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	2.3% 9/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Skin and subcutaneous tissue disorders Dermatitis allergic	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Skin and subcutaneous tissue disorders Rash	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Skin and subcutaneous tissue disorders Stevens-Johnson syndrome	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Vascular disorders Deep vein thrombosis	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	1.3% 5/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Vascular disorders Hypertensive crisis	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.26% 1/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Vascular disorders Hypotension	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Vascular disorders Thrombosis	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	0.51% 2/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.

Other adverse events

Measure	Placebo n=195 participants at risk Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.	Afatinib 50 mg/Day n=390 participants at risk Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus BSC or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).
Blood and lymphatic system disorders Anaemia	1.5% 3/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	5.9% 23/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Abdominal pain upper	4.1% 8/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	6.4% 25/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Constipation	12.3% 24/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	11.0% 43/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Diarrhoea	9.2% 18/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	85.6% 334/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Mouth ulceration	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	13.1% 51/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Nausea	20.0% 39/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	23.1% 90/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Stomatitis	1.0% 2/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	21.0% 82/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Gastrointestinal disorders Vomiting	12.8% 25/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	19.2% 75/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Asthenia	8.2% 16/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	9.2% 36/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Chest pain	5.6% 11/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	6.9% 27/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Fatigue	11.8% 23/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	18.5% 72/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Mucosal inflammation	1.0% 2/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	24.4% 95/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
General disorders Pyrexia	3.6% 7/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	9.2% 36/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Folliculitis	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	6.4% 25/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Infections and infestations Paronychia	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	33.6% 131/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Investigations Weight decreased	1.0% 2/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	9.5% 37/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Metabolism and nutrition disorders Decreased appetite	11.3% 22/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	30.3% 118/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Metabolism and nutrition disorders Hypokalaemia	2.1% 4/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	7.4% 29/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Musculoskeletal and connective tissue disorders Back pain	11.3% 22/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	7.4% 29/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Musculoskeletal and connective tissue disorders Muscle spasms	1.5% 3/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	5.1% 20/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Musculoskeletal and connective tissue disorders Pain in extremity	2.1% 4/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	6.9% 27/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Dizziness	3.1% 6/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	5.1% 20/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Dysgeusia	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	5.6% 22/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Nervous system disorders Headache	4.6% 9/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	5.4% 21/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Psychiatric disorders Insomnia	5.1% 10/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	4.4% 17/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Cough	18.5% 36/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	13.8% 54/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Dyspnoea	11.3% 22/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	13.8% 54/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	18.7% 73/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Productive cough	6.7% 13/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	2.3% 9/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	1.0% 2/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	10.8% 42/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Skin and subcutaneous tissue disorders Acne	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	6.9% 27/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Skin and subcutaneous tissue disorders Dermatitis acneiform	0.51% 1/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	7.2% 28/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Skin and subcutaneous tissue disorders Dry skin	7.2% 14/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	15.9% 62/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	7.7% 30/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Skin and subcutaneous tissue disorders Pruritus	5.6% 11/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	18.7% 73/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Skin and subcutaneous tissue disorders Rash	11.8% 23/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	63.6% 248/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.
Skin and subcutaneous tissue disorders Skin fissures	0.00% 0/195 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.	8.2% 32/390 • From the date of first drug intake up to 28 days after the last drug intake for on-treatment adverse events or the last patient out date on 4 October 2013.

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim

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