Trial Outcomes & Findings for LUX-Lung 8: A Phase III Trial of Afatinib (BIBW 2992) Versus Erlotinib for the Treatment of Squamous Cell Lung Cancer After at Least One Prior Platinum Based Chemotherapy (NCT NCT01523587)

Last Updated: 2019-02-15

Results Overview

Progression Free Survival (PFS) was defined as the time from randomization to disease progression (or death if the patient died before progression) by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize") or worsen ("progress") during treatment. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

795 participants

Primary outcome timeframe

First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).

Results posted on

2019-02-15

Participant Flow

Open-Label Phase-III trial to compare the efficacy of afatinib with erlotinib for the second-line treatment of patients with advanced non-small cell lung cancer, who completed at least 4 cycles of platinum-based doublet chemotherapy. Randomization ratio was 1:1. Stratification was based on race.

Patients screened to ensure that they met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met. Tumor assessments at screening were completed within 21 days and other screening assessments were completed within 28 days, of randomization.

Participant milestones

Participant milestones
Measure	Afatinib Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Overall Study STARTED	398	397
Overall Study Treated	392	395
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	398	397

Reasons for withdrawal

Reasons for withdrawal
Measure	Afatinib Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Overall Study Other than listed	5	5
Overall Study Worsening of underlying cancer disease	19	34
Overall Study Adverse Event	68	52
Overall Study Protocol Violation	5	3
Overall Study Lost to Follow-up	2	2
Overall Study Withdrawal by Subject	28	20
Overall Study Withdrew due to Progressive disease	265	279
Overall Study Randomised but bot treated	6	2

Baseline Characteristics

Randomised set

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Afatinib n=398 Participants Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib n=397 Participants Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.	Total n=795 Participants Total of all reporting groups
Age, Continuous	64.9 Years STANDARD_DEVIATION 8.39 • n=5 Participants • Randomised set	63.4 Years STANDARD_DEVIATION 8.98 • n=7 Participants • Randomised set	64.1 Years STANDARD_DEVIATION 8.72 • n=5 Participants • Randomised set
Sex: Female, Male Female	63 Participants n=5 Participants • Randomised set	66 Participants n=7 Participants • Randomised set	129 Participants n=5 Participants • Randomised set
Sex: Female, Male Male	335 Participants n=5 Participants • Randomised set	331 Participants n=7 Participants • Randomised set	666 Participants n=5 Participants • Randomised set
Race (NIH/OMB) American Indian or Alaska Native	2 Participants n=5 Participants • Randomised set	2 Participants n=7 Participants • Randomised set	4 Participants n=5 Participants • Randomised set
Race (NIH/OMB) Asian	97 Participants n=5 Participants • Randomised set	94 Participants n=7 Participants • Randomised set	191 Participants n=5 Participants • Randomised set
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants • Randomised set	0 Participants n=7 Participants • Randomised set	0 Participants n=5 Participants • Randomised set
Race (NIH/OMB) Black or African American	7 Participants n=5 Participants • Randomised set	8 Participants n=7 Participants • Randomised set	15 Participants n=5 Participants • Randomised set
Race (NIH/OMB) White	288 Participants n=5 Participants • Randomised set	291 Participants n=7 Participants • Randomised set	579 Participants n=5 Participants • Randomised set
Race (NIH/OMB) More than one race	0 Participants n=5 Participants • Randomised set	0 Participants n=7 Participants • Randomised set	0 Participants n=5 Participants • Randomised set
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants • Randomised set	2 Participants n=7 Participants • Randomised set	6 Participants n=5 Participants • Randomised set

PRIMARY outcome

Timeframe: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).

Population: Randomized Set (RS): All patients who were randomized, regardless of whether they received investigational treatment.

Outcome measures

Outcome measures
Measure	Afatinib n=398 Participants Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib n=397 Participants Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Progression-free Survival, Based on Central Independent Review as Determined by Response Evaluation Criteria in Solid Tumours 1.1	2.63 Months Interval 2.0 to 2.86	1.94 Months Interval 1.87 to 2.1

SECONDARY outcome

Timeframe: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).

Population: RS

Overall Survival is defined as the time from randomisation to death. It was a key secondary endpoint.

Outcome measures

Outcome measures
Measure	Afatinib n=398 Participants Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib n=397 Participants Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Overall Survival	7.82 Months Interval 7.19 to 8.71	6.77 Months Interval 5.85 to 7.79

SECONDARY outcome

Timeframe: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).

Population: RS

A patient with a best overall response of Complete Responder (CR) or Partial Responder (PR) was considered to show objective response to study medication. For patients with an objective response, time to objective response was defined as the time from randomization to the first objective response; duration of objective response was defined as the time from the first objective response to progression (or death if the patient died before progression). Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Outcome measures

Outcome measures
Measure	Afatinib n=398 Participants Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib n=397 Participants Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Number of Participants With Objective Response According to RECIST 1.1	22 Participants	11 Participants

SECONDARY outcome

Timeframe: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).

Population: RS

Disease control was assessed based on Independent Radiologic Review (IRR) and investigator assessment. A patient with a best overall response of CR, PR, or Stable Disease (SD) was considered to have disease control. Patients with no baseline target lesions who had no evidence of disease progression in their non-target lesions and had no new lesions were considered to have disease control. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Outcome measures

Outcome measures
Measure	Afatinib n=398 Participants Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib n=397 Participants Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Number of Participants With Disease Control According to RECIST 1.1	201 Participants	157 Participants

SECONDARY outcome

Timeframe: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days).

Population: Patients from the randomised set with tumour assessments are considered for the analysis of this endpoint.

Maximum percentage decrease from baseline in the sum of target lesion diameters following independent review. The change in the size (i.e. the sum of diameters (SOD)) of target lesions from baseline was derived. Tumour shrinkage for each patient was measured (based on Independent Radiologic Review (IRR)) as the minimum SOD of target lesions after randomisation. A negative percentage indicates decrease from baseline; positive numbers indicate an increase of tumour size. The mean maximum decrease from baseline of +5 and +9.4 reflect an average increase in tumour size. Post-baseline mean is adjusted for baseline sum of diameters and race.

Outcome measures

Outcome measures
Measure	Afatinib n=307 Participants Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib n=311 Participants Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Tumour Shrinkage	78.8 Millimeter (mm) Standard Error 1.26	80.0 Millimeter (mm) Standard Error 1.24

SECONDARY outcome

Timeframe: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).

Population: RS

Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the european organization for research and treatment of cancer (eortc) quality of life questionnaire (QLQ-C30) questionnaire and its lung cancer specific supplementary module EORTC QLQ-LC13 and the EQ-5D health status self-assessment questionnaire. The questionnaires were assessed at the first visit of each treatment course, at end of treatment (EOT) and follow up prior to clinical assessment. The results displayed show number of patients with improvement in the relevant criteria. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: The number of patients that were improved: Change in cough; dyspnoea and pain scores over time.

Outcome measures

Outcome measures
Measure	Afatinib n=398 Participants Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib n=397 Participants Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire Improved Cough	147 Participants	120 Participants
Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire Improved Dyspnoea	174 Participants	150 Participants
Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire Improved Pain Related	138 Participants	134 Participants
Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire Improved Global Health Status	121 Participants	96 Participants

SECONDARY outcome

Timeframe: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).

Population: RS

Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: Time to deterioration.

Outcome measures

Outcome measures
Measure	Afatinib n=398 Participants Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib n=397 Participants Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. Time to Deterioration - Coughing	4.53 Months Interval 2.86 to 4.93	3.65 Months Interval 2.79 to 4.66
Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. Time to Deterioration - Dyspnoea	2.63 Months Interval 1.97 to 2.86	1.91 Months Interval 1.87 to 2.33
Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. Time to Deterioration - Pain	2.50 Months Interval 2.0 to 2.79	2.37 Months Interval 1.91 to 2.76

SECONDARY outcome

Timeframe: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days).

Population: RS

Health related quality of life (HRQoL) was measured with the following multi dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of change in score over time, adjusted for baseline score and race. Questionnaires have items relating to Cough, Dyspnoea and Pain. Overall Scores are transformed to a standardised scale of 0 to 100 with the larger value indicating a worse outcome. A change of (+/-) 10 points is considered to be relevant. The change in cough, dyspnea and pain will be assessed using a mixed effects growth curve model with the average profile over time for each endpoint described by a piecewise linear model (presented as post baseline in data table). Post-baseline mean is adjusted for baseline and race.

Outcome measures

Outcome measures
Measure	Afatinib n=398 Participants Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib n=397 Participants Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Change in Score Over Time in Coughing,Dyspnoea and Pain Coughing	15.8 Units on a scale Standard Error 2.40	19.3 Units on a scale Standard Error 2.37
Change in Score Over Time in Coughing,Dyspnoea and Pain Dyspnoea	11.4 Units on a scale Standard Error 1.83	14.9 Units on a scale Standard Error 1.85
Change in Score Over Time in Coughing,Dyspnoea and Pain Pain	10.3 Units on a scale Standard Error 2.13	13.1 Units on a scale Standard Error 2.17

Adverse Events

Afatinib

Serious events: 174 serious events

Other events: 383 other events

Deaths: 77 deaths

Erlotinib

Serious events: 175 serious events

Other events: 371 other events

Deaths: 71 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim, Call Centre

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Afatinib n=392 participants at risk Patients administered 40 milligram (mg) film-coated tablet once daily orally for the first 28-day treatment course. Dose escalation to 50 mg once daily was allowed at the beginning of the second 28-day treatment course, if patients met specified safety and compliance criteria. Dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day, was required in the presence of known drug-related adverse events.	Erlotinib n=395 participants at risk Patients administered 150 mg film-coated tablet once daily orally, with dose reduction to 100 mg/day or 50 mg/day in the presence of known drug-related adverse events.
Blood and lymphatic system disorders Anaemia	7.9% 31/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	10.4% 41/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Gastrointestinal disorders Constipation	11.0% 43/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	10.6% 42/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Gastrointestinal disorders Diarrhoea	72.4% 284/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	40.0% 158/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Gastrointestinal disorders Nausea	20.7% 81/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	15.7% 62/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Gastrointestinal disorders Stomatitis	13.8% 54/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	5.3% 21/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Gastrointestinal disorders Vomiting	12.2% 48/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	9.6% 38/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
General disorders Asthenia	15.6% 61/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	12.2% 48/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
General disorders Chest pain	3.6% 14/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	5.1% 20/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
General disorders Fatigue	16.6% 65/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	17.0% 67/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
General disorders Mucosal inflammation	12.8% 50/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	3.5% 14/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
General disorders Pyrexia	8.2% 32/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	8.4% 33/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Infections and infestations Paronychia	10.5% 41/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	4.6% 18/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Investigations Weight decreased	9.7% 38/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	12.9% 51/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Metabolism and nutrition disorders Decreased appetite	24.0% 94/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	25.3% 100/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Musculoskeletal and connective tissue disorders Back pain	5.6% 22/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	6.3% 25/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	5.1% 20/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	5.1% 20/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Musculoskeletal and connective tissue disorders Pain in extremity	3.6% 14/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	5.8% 23/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Nervous system disorders Dizziness	3.1% 12/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	5.3% 21/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Psychiatric disorders Insomnia	5.1% 20/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	4.3% 17/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Respiratory, thoracic and mediastinal disorders Cough	16.6% 65/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	17.0% 67/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Respiratory, thoracic and mediastinal disorders Dyspnoea	17.3% 68/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	17.5% 69/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Respiratory, thoracic and mediastinal disorders Epistaxis	6.9% 27/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	2.5% 10/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Respiratory, thoracic and mediastinal disorders Haemoptysis	11.2% 44/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	9.9% 39/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Respiratory, thoracic and mediastinal disorders Productive cough	3.6% 14/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	5.3% 21/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Skin and subcutaneous tissue disorders Dermatitis acneiform	9.7% 38/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	14.2% 56/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Skin and subcutaneous tissue disorders Dry skin	9.2% 36/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	11.9% 47/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Skin and subcutaneous tissue disorders Pruritus	9.7% 38/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	13.2% 52/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.
Skin and subcutaneous tissue disorders Rash	50.0% 196/392 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.	47.3% 187/395 • From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). All adverse events (AEs) reported for this trial are on treatment AEs.