BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation

• ClinicalTrials.gov Identifier: NCT00949650
• Recruitment Status: Completed
• First Posted: July 30, 2009
• Results First Posted: November 19, 2013
• Last Update Posted: April 6, 2018
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Carcinoma, Non-Small-Cell Lung; Adenocarcinoma
• Interventions: Drug: Pemetrexed; Drug: BIBW 2992; Drug: Cisplatin
• Enrollment: 345

Participant Flow

Recruitment Details
Pre-assignment Details	Two-arm, randomised (2:1 ratio), open-label, active-controlled, parallel-group comparison. 345 patients were randomised, 5 patients were not treated: 4 patients were not eligible for treatment and 1 patient in the chemotherapy arm refused to take study medication.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Period Title: Overall Study
Started	230 [1]	115 [1]
Completed	0 [2]	0
Not Completed	230	115
Reason Not Completed
Progressive disease	188	19
Completed 6 courses of chemotherapy	0	60
Other Adverse Event (AE)	28	17
Protocol Violation	1	4
Refusal to continue medication	7	11
Not treated	1	4
Other not specified above	5	0
[1] Treated patients.; [2] On treatment at the cut-off date 17MAR2017.

Baseline Characteristics

Arm/Group Title		Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy	Total
Arm/Group Description		Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Total of all reporting groups
Overall Number of Baseline Participants		230	115	345
Baseline Analysis Population Description		Randomised Set (RS): The randomised set includes all patients who were randomised to receive treatment, whether treated or not.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	230 participants	115 participants	345 participants
		60.5 (10.1)	59.9 (10.0)	60.3 (10.1)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	230 participants	115 participants	345 participants
	Female	147 63.9%	77 67.0%	224 64.9%
	Male	83 36.1%	38 33.0%	121 35.1%
Race/Ethnicity, Customized [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	230 participants	115 participants	345 participants
Asian		166	83	249
Non-Asian		64	32	96
		[1] Measure Description: Race (Asian/non-Asian) was a stratification factor.
Epidermal Growth Factor Receptor (EGFR) mutation group [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	230 participants	115 participants	345 participants
EGFR mutation category: L858R		91	47	138
EGFR mutation category: Deletion Exon 19		112	57	169
EGFR mutation category: Other		27	11	38
		[1] Measure Description: EGFR mutation group (L858R/Deletion Exon 19/Other) was a stratification factor.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	230 participants	115 participants	345 participants
ECOG PS 0 (baseline)		92	41	133
ECOG PS 1 (baseline)		138	73	211
ECOG PS 2 (baseline)		0	1	1
		[1] Measure Description: ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction.; Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work.; Ambulatory (>50 percent of waking hours), capable of all self-care, unable to carry out any work activities.; Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours.; Completely disabled, cannot carry on any self-care, totally confined to bed or chair.; Dead.

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) Time
Description	PFS was defined as time from randomisation to disease progression or death whichever occured first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Median time results from unstratified Kaplan-Meier estimates.
Time Frame	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Outcome Measure Data

Analysis Population Description

Randomised set (RS)

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Number of Participants Analyzed	230	115
Median (95% Confidence Interval); Unit of Measure: Months.
	11.17; (9.63 to 13.70)	6.90; (5.39 to 8.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cox Proportional Hazard (PH) regression stratified by epidermal growth factor receptor (EGFR) mutation group and race.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.576
	Confidence Interval	95%; 0.426 to 0.778
	Estimation Comments	Afatinib 40 mg versus Pemetrexed/Cisplatin Chemotherapy.

2. Secondary Outcome

Title	Percentage of Patients With Objective Response (OR)
Description	OR was defined as Complete Response (CR) or Partial Response (PR). Assessed by central independent review according to RECIST 1.1.
Time Frame	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Number of Participants Analyzed	230	115
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of patients with OR.
	56.5; (49.8 to 63.0)	22.6; (15.3 to 31.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Logistic regression stratified for EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.802
	Confidence Interval	95%; 2.855 to 8.075
	Estimation Comments	Afatinib 40 mg-Pemetrexed/Cisplatin Chemotherapy.

3. Secondary Outcome

Title	Percentage of Participants With Disease Control (DC)
Description	DC was defined as a patient with OR or Stable Disease (SD). Assessed by central independent review according to the RECIST 1.1.
Time Frame	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Number of Participants Analyzed	230	115
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants with DC.
	90.4; (85.9 to 93.9)	80.9; (72.5 to 87.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0118
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Logistic regression stratified for EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.288
	Confidence Interval	95%; 1.202 to 4.356
	Estimation Comments	Afatinib 40 mg-Pemetrexed/Cisplatin Chemotherapy.

4. Secondary Outcome

Title	Overall Survival (OS) Time
Description	OS was defined as time from randomisation to death.
Time Frame	From randomisation to cut-off date (17MAR2017).

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Number of Participants Analyzed	230	115
Median (95% Confidence Interval); Unit of Measure: Months.
	28.16; (24.64 to 33.58)	28.22; (20.73 to 33.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7916
	Comments	Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3850
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cox PH regression stratified by EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.880
	Confidence Interval	95%; 0.660 to 1.174
	Estimation Comments	Afatinib 40 mg-Pemetrexed/Cisplatin Chemotherapy.

5. Secondary Outcome

Title	Tumour Shrinkage
Description	Tumour shrinkage was calculated as the minimum Sum of Diameters (SoD) of target lesions from all post-baseline tumour assessments, as read by the central independent review. The mean of these minimum values were presented after adjusting for baseline SoD, EGFR mutation group and race.
Time Frame	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Outcome Measure Data

Analysis Population Description

RS. There were only 203 patients in the Afatinib 40 mg arm and 101 patients in the Pemetrexed/Cisplatin Chemotherapy with tumour measurements.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Number of Participants Analyzed	203	101
Mean (Standard Error); Unit of Measure: mm.
	33.19 (1.12)	43.00 (1.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	Adjusted for baseline SoD, EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.82
	Confidence Interval	95%; -13.64 to -5.99
	Estimation Comments	Afatinib 40 mg-Pemetrexed/Cisplatin Chemotherapy.

6. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	Because the PFS was longer for patients in the Afatinib arm than for patients in the chemotherapy arm, the period of data collection for ECOG status and body weight continued for a longer time in the Afatinib arm.
Time Frame	Baseline and throughout the trial until progression (every 3 weeks), up to 28 months.

Outcome Measure Data

Analysis Population Description

RS. Only patients with baseline and at least one post-baseline assessment were included.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Number of Participants Analyzed	224	109
Mean (Standard Deviation); Unit of Measure: Kg.
Change from baseline at lowest value	-3.95 (3.91)	-2.68 (2.90)
Change from baseline at last value	-1.19 (5.36)	-0.29 (4.02)

7. Secondary Outcome

Title	Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
Description	ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction.; Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work.; Ambulatory (>50 percent of waking hours), capable of all self-care, unable to carry out any work activities.; Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours.; Completely disabled, cannot carry on any self-care, totally confined to bed or chair.; Dead.
Time Frame	Throughout the trial until progression (every 3 weeks), up to 28 months.

Outcome Measure Data

Analysis Population Description

RS. Only patients with baseline and at least one post-baseline assessment were included.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Number of Participants Analyzed	228	111
Measure Type: Number; Unit of Measure: Participants
ECOG PS 0 (last value)	92	41
ECOG PS 1 (last value)	138	73
ECOG PS 2 (last value)	0	1

8. Secondary Outcome

Title	Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing
Description	HRQOL was measured by European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 (QLQ-C30) and its lung cancer specific module LC13 (QLQ-LC13). Analysis for cough is based on QLQ-LC13 question 1. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
Time Frame	Throughout the trial until progression (every 3 weeks).

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Number of Participants Analyzed	230	115
Median (95% Confidence Interval); Unit of Measure: Months.
	26.97 [1]; (19.22 to NA)	8.02 [2]; (4.44 to NA)

[1]

As only 82 patients (35.7 percent) in the Afatinib 40 mg deteriorated, the upper limit of Confidence Interval (CI) was not estimable.

[2]

As only 44 patients (38.3 percent) in the Pemetrexed/Cisplatin Chemotherapy deteriorated, the upper limit of the CI was not estimable.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0062
	Comments	Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2133
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cox PH regression stratified by EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.589
	Confidence Interval	95%; 0.401 to 0.866
	Estimation Comments	Afatinib 40 mg vs. Pemetrexed/Cisplatin Chemotherapy, if HR<1 then favours Afatinib 40 mg.

9. Secondary Outcome

Title	HRQOL: Time to Deterioration in Dyspnoea
Description	HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for dyspnoea is based on composite of QLQ-LC13 questions 3-5. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
Time Frame	Throughout the trial until progression (every 3 weeks).

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Number of Participants Analyzed	230	115
Median (95% Confidence Interval); Unit of Measure: Months.
	10.41; (5.59 to 15.93)	2.86; (2.17 to 4.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0129
	Comments	Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0078
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cox PH regression stratified by EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.680
	Confidence Interval	95%; 0.499 to 0.927
	Estimation Comments	Afatinib 40 mg vs. Pemetrexed/Cisplatin Chemotherapy, if HR<1 then favours Afatinib 40 mg.

10. Secondary Outcome

Title	HRQOL: Time to Deterioration in Pain
Description	HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for pain is based on composite of QLQ-C30 questions 9 and 19. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.
Time Frame	Throughout the trial until progression (every 3 weeks).

Outcome Measure Data

Analysis Population Description

RS.

Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description:	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Number of Participants Analyzed	230	115
Median (95% Confidence Interval); Unit of Measure: Months.
	4.17; (2.79 to 5.59)	3.09; (2.17 to 3.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1882
	Comments	Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib 40 mg, Pemetrexed/Cisplatin Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0427
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cox PH regression stratified by EGFR mutation group and race.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.826
	Confidence Interval	95%; 0.618 to 1.104
	Estimation Comments	Afatinib 40 mg vs. Pemetrexed/Cisplatin Chemotherapy, if HR<1 then favours Afatinib 40 mg.

11. Secondary Outcome

Title	Trough Plasma Concentrations of Afatinib at Day 22
Description	Trough plasma concentrations of Afatinib at Day 22 (course 2, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.
Time Frame	Day 22.

Outcome Measure Data

Analysis Population Description

Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.

Arm/Group Title	Afatinib 20 mg	Afatinib 30 mg	Afatinib 40 mg	Afatinib 50 mg
Arm/Group Description:	Patients received Afatinib monotherapy 20 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 30 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Overall Number of Participants Analyzed	0	11	165	3
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL.
		21.8; (36.6%)	28.0; (85.0%)	29.9; (46.1%)

12. Secondary Outcome

Title	Trough Plasma Concentrations of Afatinib at Day 29
Description	Trough plasma concentrations of Afatinib at day 29 (course 2, visit 2) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.
Time Frame	Day 29.

Outcome Measure Data

Analysis Population Description

Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.

Arm/Group Title	Afatinib 20 mg	Afatinib 30 mg	Afatinib 40 mg	Afatinib 50 mg
Arm/Group Description:	Patients received Afatinib monotherapy 20 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 30 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Overall Number of Participants Analyzed	0	25	143	16
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL.
		28.0; (82.4%)	25.8; (69.5%)	29.6; (79.2%)

13. Secondary Outcome

Title	Trough Plasma Concentrations of Afatinib at Day 43
Description	Trough plasma concentrations of Afatinib at Day 43 (course 3, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.
Time Frame	Day 43.

Outcome Measure Data

Analysis Population Description

Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.

Arm/Group Title	Afatinib 20 mg	Afatinib 30 mg	Afatinib 40 mg	Afatinib 50 mg
Arm/Group Description:	Patients received Afatinib monotherapy 20 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 30 mg film-coated tablets orally once daily after a dose reduction.	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Overall Number of Participants Analyzed	2	39	126	14
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL.
	24.4; (260%)	24.7; (63.9%)	23.5; (66.2%)	27.5; (64.4%)

Adverse Events

Time Frame	First administration of trial medication until 28 days after last administration of trial medication.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
Arm/Group Description	Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
All-Cause Mortality
	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	72/229 (31.44%)	25/111 (22.52%)
Blood and lymphatic system disorders
Anaemia † 1	0/229 (0.00%)	2/111 (1.80%)
Thrombocytopenia † 1	0/229 (0.00%)	1/111 (0.90%)
Cardiac disorders
Atrial fibrillation † 1	0/229 (0.00%)	1/111 (0.90%)
Mitral valve incompetence † 1	1/229 (0.44%)	0/111 (0.00%)
Myocardial infarction † 1	0/229 (0.00%)	1/111 (0.90%)
Pericardial effusion † 1	1/229 (0.44%)	0/111 (0.00%)
Eye disorders
Cataract † 1	1/229 (0.44%)	0/111 (0.00%)
Gastrointestinal disorders
Abdominal discomfort † 1	1/229 (0.44%)	0/111 (0.00%)
Abdominal pain upper † 1	1/229 (0.44%)	0/111 (0.00%)
Diarrhoea † 1	15/229 (6.55%)	0/111 (0.00%)
Gastritis † 1	1/229 (0.44%)	0/111 (0.00%)
Gastrooesophageal reflux disease † 1	1/229 (0.44%)	0/111 (0.00%)
Haemorrhoids † 1	1/229 (0.44%)	0/111 (0.00%)
Nausea † 1	0/229 (0.00%)	2/111 (1.80%)
Pancreatitis acute † 1	1/229 (0.44%)	0/111 (0.00%)
Stomatitis † 1	1/229 (0.44%)	1/111 (0.90%)
Vomiting † 1	11/229 (4.80%)	3/111 (2.70%)
General disorders
Abasia † 1	0/229 (0.00%)	1/111 (0.90%)
Asthenia † 1	1/229 (0.44%)	2/111 (1.80%)
Death † 1	2/229 (0.87%)	1/111 (0.90%)
Disease progression † 1	2/229 (0.87%)	0/111 (0.00%)
Fatigue † 1	3/229 (1.31%)	1/111 (0.90%)
General physical health deterioration † 1	1/229 (0.44%)	1/111 (0.90%)
Hernia † 1	1/229 (0.44%)	0/111 (0.00%)
Malaise † 1	0/229 (0.00%)	1/111 (0.90%)
Mucosal inflammation † 1	2/229 (0.87%)	0/111 (0.00%)
Pyrexia † 1	2/229 (0.87%)	1/111 (0.90%)
Hepatobiliary disorders
Cholecystitis acute † 1	2/229 (0.87%)	0/111 (0.00%)
Jaundice † 1	1/229 (0.44%)	0/111 (0.00%)
Infections and infestations
Cellulitis † 1	1/229 (0.44%)	1/111 (0.90%)
Device related infection † 1	1/229 (0.44%)	0/111 (0.00%)
Lower respiratory tract infection † 1	2/229 (0.87%)	0/111 (0.00%)
Lung infection † 1	1/229 (0.44%)	0/111 (0.00%)
Meningitis aseptic † 1	1/229 (0.44%)	0/111 (0.00%)
Meningoencephalitis herpetic † 1	0/229 (0.00%)	1/111 (0.90%)
Pneumonia † 1	4/229 (1.75%)	1/111 (0.90%)
Sepsis † 1	1/229 (0.44%)	0/111 (0.00%)
Upper respiratory tract infection † 1	2/229 (0.87%)	0/111 (0.00%)
Urinary tract infection † 1	2/229 (0.87%)	0/111 (0.00%)
Injury, poisoning and procedural complications
Femur fracture † 1	1/229 (0.44%)	0/111 (0.00%)
Lower limb fracture † 1	1/229 (0.44%)	0/111 (0.00%)
Splenic rupture † 1	1/229 (0.44%)	0/111 (0.00%)
Synovial rupture † 1	0/229 (0.00%)	1/111 (0.90%)
Thoracic vertebral fracture † 1	1/229 (0.44%)	0/111 (0.00%)
Tibia fracture † 1	1/229 (0.44%)	0/111 (0.00%)
Investigations
Alanine aminotransferase increased † 1	0/229 (0.00%)	1/111 (0.90%)
Aspartate aminotransferase increased † 1	0/229 (0.00%)	1/111 (0.90%)
Blood sodium decreased † 1	0/229 (0.00%)	1/111 (0.90%)
Liver function test abnormal † 1	1/229 (0.44%)	0/111 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	2/229 (0.87%)	0/111 (0.00%)
Dehydration † 1	3/229 (1.31%)	1/111 (0.90%)
Diabetes with hyperosmolarity † 1	0/229 (0.00%)	1/111 (0.90%)
Hypokalaemia † 1	4/229 (1.75%)	1/111 (0.90%)
Hyponatraemia † 1	1/229 (0.44%)	0/111 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain † 1	0/229 (0.00%)	1/111 (0.90%)
Bone pain † 1	1/229 (0.44%)	0/111 (0.00%)
Muscular weakness † 1	0/229 (0.00%)	1/111 (0.90%)
Pain in extremity † 1	1/229 (0.44%)	0/111 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression † 1	3/229 (1.31%)	2/111 (1.80%)
Metastases to central nervous system † 1	3/229 (1.31%)	0/111 (0.00%)
Metastases to lung † 1	0/229 (0.00%)	1/111 (0.90%)
Metastases to meninges † 1	1/229 (0.44%)	0/111 (0.00%)
Neoplasm progression † 1	2/229 (0.87%)	0/111 (0.00%)
Nervous system disorders
Depressed level of consciousness † 1	1/229 (0.44%)	0/111 (0.00%)
Epilepsy † 1	1/229 (0.44%)	0/111 (0.00%)
Headache † 1	1/229 (0.44%)	0/111 (0.00%)
Intracranial pressure increased † 1	1/229 (0.44%)	0/111 (0.00%)
Loss of consciousness † 1	1/229 (0.44%)	0/111 (0.00%)
Partial seizures † 1	1/229 (0.44%)	0/111 (0.00%)
Seizure † 1	3/229 (1.31%)	0/111 (0.00%)
Syncope † 1	0/229 (0.00%)	1/111 (0.90%)
Psychiatric disorders
Confusional state † 1	3/229 (1.31%)	0/111 (0.00%)
Schizophreniform disorder † 1	0/229 (0.00%)	1/111 (0.90%)
Renal and urinary disorders
Acute kidney injury † 1	0/229 (0.00%)	1/111 (0.90%)
Acute prerenal failure † 1	1/229 (0.44%)	1/111 (0.90%)
Renal failure † 1	1/229 (0.44%)	0/111 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	2/229 (0.87%)	0/111 (0.00%)
Bronchospasm † 1	0/229 (0.00%)	1/111 (0.90%)
Dyspnoea † 1	4/229 (1.75%)	2/111 (1.80%)
Epistaxis † 1	0/229 (0.00%)	1/111 (0.90%)
Haemoptysis † 1	1/229 (0.44%)	1/111 (0.90%)
Interstitial lung disease † 1	1/229 (0.44%)	0/111 (0.00%)
Pleural effusion † 1	2/229 (0.87%)	3/111 (2.70%)
Pneumothorax † 1	1/229 (0.44%)	1/111 (0.90%)
Pulmonary artery thrombosis † 1	0/229 (0.00%)	1/111 (0.90%)
Pulmonary embolism † 1	2/229 (0.87%)	1/111 (0.90%)
Respiratory arrest † 1	1/229 (0.44%)	0/111 (0.00%)
Respiratory failure † 1	1/229 (0.44%)	0/111 (0.00%)
Skin and subcutaneous tissue disorders
Dermatitis † 1	1/229 (0.44%)	0/111 (0.00%)
Vascular disorders
Deep vein thrombosis † 1	2/229 (0.87%)	0/111 (0.00%)
Hypotension † 1	1/229 (0.44%)	0/111 (0.00%)
Superior vena cava syndrome † 1	1/229 (0.44%)	0/111 (0.00%)
Thrombosis † 1	0/229 (0.00%)	1/111 (0.90%)
Venous thrombosis † 1	1/229 (0.44%)	1/111 (0.90%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 19.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Afatinib 40 mg	Pemetrexed/Cisplatin Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	229/229 (100.00%)	108/111 (97.30%)
Blood and lymphatic system disorders
Anaemia † 1	19/229 (8.30%)	29/111 (26.13%)
Leukopenia † 1	6/229 (2.62%)	21/111 (18.92%)
Neutropenia † 1	4/229 (1.75%)	35/111 (31.53%)
Thrombocytopenia † 1	1/229 (0.44%)	8/111 (7.21%)
Eye disorders
Dry eye † 1	14/229 (6.11%)	0/111 (0.00%)
Vision blurred † 1	12/229 (5.24%)	2/111 (1.80%)
Gastrointestinal disorders
Abdominal pain † 1	13/229 (5.68%)	5/111 (4.50%)
Abdominal pain upper † 1	15/229 (6.55%)	8/111 (7.21%)
Cheilitis † 1	22/229 (9.61%)	0/111 (0.00%)
Constipation † 1	37/229 (16.16%)	39/111 (35.14%)
Diarrhoea † 1	216/229 (94.32%)	25/111 (22.52%)
Dyspepsia † 1	21/229 (9.17%)	7/111 (6.31%)
Mouth ulceration † 1	24/229 (10.48%)	3/111 (2.70%)
Nausea † 1	65/229 (28.38%)	75/111 (67.57%)
Stomatitis † 1	88/229 (38.43%)	10/111 (9.01%)
Vomiting † 1	53/229 (23.14%)	50/111 (45.05%)
General disorders
Asthenia † 1	16/229 (6.99%)	14/111 (12.61%)
Chest pain † 1	16/229 (6.99%)	14/111 (12.61%)
Fatigue † 1	45/229 (19.65%)	39/111 (35.14%)
Malaise † 1	7/229 (3.06%)	6/111 (5.41%)
Mucosal inflammation † 1	67/229 (29.26%)	5/111 (4.50%)
Oedema † 1	7/229 (3.06%)	13/111 (11.71%)
Oedema peripheral † 1	17/229 (7.42%)	8/111 (7.21%)
Pyrexia † 1	28/229 (12.23%)	6/111 (5.41%)
Infections and infestations
Conjunctivitis † 1	28/229 (12.23%)	3/111 (2.70%)
Cystitis † 1	15/229 (6.55%)	1/111 (0.90%)
Folliculitis † 1	12/229 (5.24%)	0/111 (0.00%)
Nasopharyngitis † 1	39/229 (17.03%)	9/111 (8.11%)
Paronychia † 1	132/229 (57.64%)	0/111 (0.00%)
Upper respiratory tract infection † 1	29/229 (12.66%)	4/111 (3.60%)
Urinary tract infection † 1	19/229 (8.30%)	5/111 (4.50%)
Investigations
Alanine aminotransferase increased † 1	27/229 (11.79%)	3/111 (2.70%)
Aspartate aminotransferase increased † 1	22/229 (9.61%)	1/111 (0.90%)
Blood creatinine increased † 1	5/229 (2.18%)	10/111 (9.01%)
Haemoglobin decreased † 1	3/229 (1.31%)	13/111 (11.71%)
Neutrophil count decreased † 1	1/229 (0.44%)	8/111 (7.21%)
Weight decreased † 1	44/229 (19.21%)	16/111 (14.41%)
Metabolism and nutrition disorders
Decreased appetite † 1	70/229 (30.57%)	61/111 (54.95%)
Hypokalaemia † 1	21/229 (9.17%)	4/111 (3.60%)
Hyponatraemia † 1	4/229 (1.75%)	6/111 (5.41%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	21/229 (9.17%)	6/111 (5.41%)
Back pain † 1	37/229 (16.16%)	13/111 (11.71%)
Muscle spasms † 1	20/229 (8.73%)	0/111 (0.00%)
Musculoskeletal pain † 1	21/229 (9.17%)	2/111 (1.80%)
Myalgia † 1	12/229 (5.24%)	1/111 (0.90%)
Pain in extremity † 1	20/229 (8.73%)	4/111 (3.60%)
Nervous system disorders
Dizziness † 1	28/229 (12.23%)	12/111 (10.81%)
Dysgeusia † 1	18/229 (7.86%)	9/111 (8.11%)
Headache † 1	37/229 (16.16%)	19/111 (17.12%)
Psychiatric disorders
Insomnia † 1	37/229 (16.16%)	10/111 (9.01%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	39/229 (17.03%)	21/111 (18.92%)
Dyspnoea † 1	18/229 (7.86%)	12/111 (10.81%)
Epistaxis † 1	41/229 (17.90%)	1/111 (0.90%)
Hiccups † 1	5/229 (2.18%)	10/111 (9.01%)
Nasal inflammation † 1	15/229 (6.55%)	0/111 (0.00%)
Oropharyngeal pain † 1	13/229 (5.68%)	3/111 (2.70%)
Rhinorrhoea † 1	16/229 (6.99%)	7/111 (6.31%)
Skin and subcutaneous tissue disorders
Acne † 1	52/229 (22.71%)	0/111 (0.00%)
Alopecia † 1	30/229 (13.10%)	20/111 (18.02%)
Dermatitis acneiform † 1	32/229 (13.97%)	0/111 (0.00%)
Dry skin † 1	72/229 (31.44%)	2/111 (1.80%)
Nail disorder † 1	14/229 (6.11%)	0/111 (0.00%)
Palmar-plantar erythrodysaesthesia syndrome † 1	19/229 (8.30%)	0/111 (0.00%)
Pruritus † 1	50/229 (21.83%)	1/111 (0.90%)
Rash † 1	145/229 (63.32%)	11/111 (9.91%)
Skin exfoliation † 1	13/229 (5.68%)	0/111 (0.00%)
Skin fissures † 1	16/229 (6.99%)	0/111 (0.00%)
Vascular disorders
Hypertension † 1	14/229 (6.11%)	14/111 (12.61%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 19.1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Boehringer Ingelheim Call Center
• Organization: Boehringer Ingelheim
• Phone: 1-800-243-0127
• EMail: clintriage.rdg@boehringer-ingelheim.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wu YL, Sequist LV, Tan EH, Geater SL, Orlov S, Zhang L, Lee KH, Tsai CM, Kato T, Barrios CH, Schuler M, Hirsh V, Yamamoto N, O'Byrne K, Boyer M, Mok T, Peil B, Marten A, Chih-Hsin Yang J, Paz-Ares L, Park K. Afatinib as First-line Treatment of Older Patients With EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Subgroup Analyses of the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 Trials. Clin Lung Cancer. 2018 Jul;19(4):e465-e479. doi: 10.1016/j.cllc.2018.03.009. Epub 2018 Mar 17.

Yang JC, Sequist LV, Zhou C, Schuler M, Geater SL, Mok T, Hu CP, Yamamoto N, Feng J, O'Byrne K, Lu S, Hirsh V, Huang Y, Sebastian M, Okamoto I, Dickgreber N, Shah R, Marten A, Massey D, Wind S, Wu YL. Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials. Ann Oncol. 2016 Nov;27(11):2103-2110. doi: 10.1093/annonc/mdw322. Epub 2016 Sep 6.

Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-Line Afatinib versus Chemotherapy in Patients with Non-Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. doi: 10.1016/j.jtho.2015.11.014. Epub 2016 Jan 25.

Kato T, Yoshioka H, Okamoto I, Yokoyama A, Hida T, Seto T, Kiura K, Massey D, Seki Y, Yamamoto N. Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non-small cell lung cancer harboring activating EGFR mutations: Subgroup analysis of LUX-Lung 3. Cancer Sci. 2015 Sep;106(9):1202-11. doi: 10.1111/cas.12723. Epub 2015 Jul 25.

Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. doi: 10.1016/S1470-2045(15)00026-1. Epub 2015 Jun 4.

Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. doi: 10.1016/S1470-2045(14)71173-8. Epub 2015 Jan 12.

Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. doi: 10.1200/JCO.2012.46.1764. Epub 2013 Jul 1.

Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. doi: 10.1200/JCO.2012.44.2806. Epub 2013 Jul 1.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00949650
• Other Study ID Numbers: 1200.32; 2008-005615-18 ( EudraCT Number )
• First Submitted: July 29, 2009
• First Posted: July 30, 2009
• Results First Submitted: August 8, 2013
• Results First Posted: November 19, 2013
• Last Update Posted: April 6, 2018