Effect of BIBW 2948 BS in COPD

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00423137
• Collaborator: (none)
• Enrollment: 48
• Locations: 6
• Arms: 4
• Actual Duration (Months): 17.7
• Patients Per Site: 8
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Study of BIBW 2948 BS in Patients with COPD and Chronic Bronchitis

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive; Bronchitis, Chronic	Drug: BIBW 2948 BS; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Effects of a 4-week Treatment of 15 and 30 mg b.i.d BIBW2948 BS (Inhalation Powder, Hard Capsule for HandiHaler®) on Epithelial Mucin Stores and the Safety and Efficacy in COPD Patients With Symptoms Associated With Chronic Bronchitis
• Actual Study Start Date: Jan 17, 2007
• Actual Primary Completion Date: Jul 9, 2008
• Actual Study Completion Date: Jul 9, 2008

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo - low dose Twice daily (b.i.d.)	Drug: Placebo; Capsule
Placebo Comparator: Placebo - high dose Twice daily (b.i.d.)	Drug: Placebo; Capsule
Experimental: BIBW2948 - low dose Twice daily (b.i.d.)	Drug: BIBW 2948 BS; Capsule
Experimental: BIBW2948 - high dose Twice daily (b.i.d.)	Drug: BIBW 2948 BS; Capsule

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Volume of Mucin Per Surface Area of Basal Lamina [At baseline (visit 2) and at visit 5.]

   Change from baseline in volume of mucin per surface area of basal lamina. Volume of mucin per surface area of basal lamina (vs mu,bala) was determined by stereologic quantification of Periodic Acid Schiff's (AB/PAS) reagent staining in endobronchial biopsies at visit 2 (baseline) and at the end of the 4-week period of randomized treatment (visit 5).

Secondary Outcome Measures

1. Change From Baseline of Volume of Mucin Per Volume of Epithelium (Vv mu, ep) in Endobronchial Biopsies [At baseline (visit 2) and at visit 5.]

   Change from baseline of volume of mucin per volume of epithelium (Vv mu, ep) in endobronchial biopsies. The volume of mucin per volume of epithelium (Vv mu, ep), as measured by stereological quantification of AB/PAS staining in endobronchial biopsies was performed at baseline (visit 2) and at the end of the 4-week period of randomised treatment (visit 5).

2. Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) [At baseline (visit 2) and at visit 5.]

   Change from baseline in bronchoalveolar lavage (BAL) cell differential (in %). Differential cell counts were performed on bronchoalveolar lavage samples obtained during visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).

3. Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count [At baseline (visit 2) and at visit 5.]

   Change from baseline in bronchoalveolar lavage (BAL) cell count. Total cell counts were performed on bronchoalveolar lavage (BAL) samples obtained during visit 2 (baseline) and at the end of the 4-week period of randomised treatment.

4. Change From Baseline in Log MUC2 Mucin Gene Expression (RNA) Obtained in Epithelial Brushings [At baseline (visit 2) and at visit 5.]

   Change from baseline in log MUC2 Mucin gene expression (RNA) obtained in epithelial brushings. Gene expression levels of the gel-forming mucins (MUC2) were quantified using two-step real time polymerase chain reaction (PCR) from RNA extracted from the cells obtained from the epithelial brushings during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).

5. Change From Baseline in Log Mucin Gene (MUC5AC) Expression Level Obtained in Epithelial Brushings [At baseline (visit 2) and at visit 5.]

   Change from baseline in log mucin gene (MUC5AC) expression level obtained in epithelial brushings. Gene expression levels of the gel-forming mucins (MUC5AC) were quantified using two-step real time polymerase chain reaction (PCR) from RNA extracted from the cells obtained from the epithelial brushings during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).

6. Change From Baseline in Log Mucin Gene (MUC5B) Expression Level Obtained in Epithelial Brushings [At baseline (visit 2) and at visit 5.]

   Change from baseline in log mucin gene (MUC5B) expression level obtained in epithelial brushings. Gene expression levels of the gel-forming mucins (MUC5B) were quantified using two-step real time polymerase chain reaction (PCR) from RNA extracted from the cells obtained from the epithelial brushings during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).

7. Change From Baseline in Log Mucin Gene (MUC8) Expression Level Obtained in Epithelial Brushings [At baseline (visit 2) and at visit 5.]

   Change from baseline in log mucin gene (MUC8) expression level obtained in epithelial brushings. Gene expression levels of the gel-forming mucins (MUC8) were quantified using two-step real time polymerase chain reaction (PCR) from RNA extracted from the cells obtained from the epithelial brushings during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).

8. Change From Baseline in Epidermal Growth Factor Receptor (EGRF) Internalization Assay in Epithelial Brushings - Cells With Bright Spots With Marker [At baseline (visit 2) and at visit 5.]

   Change in percentage of cells with bright spots with marker. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in percent (%) control as (visit5/visit2*100).

9. Change From Baseline in Epidermal Growth Factor Receptor (EGRF) Internalization Assay in Epithelial Brushings - EGRF Spots at Nucleus [At baseline (visit 2) and at visit 5.]

   Change in number of EGRF spots at nucleus. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in percent (%) control as (visit5/visit2*100).

10. Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGRF Spots With Marker [At baseline (visit 2) and at visit 5.]

    Change in number of EGRF spots with marker per cell. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in percent (%) control as (visit5/visit2*100).

11. Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - Total Area Bright Spots With Marker [At baseline (visit 2) and at visit 5.]

    Change in total area bright spots with marker. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in percent (%) control as (visit5/visit2*100).

12. Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGFR Spots [At baseline (visit 2) and at visit 5.]

    Change in number of EGFR spots per cell. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in % control as (visit5/visit2*100).

13. Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGFR Spots at Nucleus With Marker [At baseline (visit 2) and at visit 5.]

    Change in number of EGFR spots at nucleus per cell with marker. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in % control as (visit5/visit2*100).

14. Change From Baseline in Number of Goblet Cells Per Surface Area of Basel Lamina [At baseline (visit 2) and at visit 5.]

    Change from baseline in number of goblet cells per surface area of basel lamina, using endobronchial biopsies, taken at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).

15. Change From Baseline in Number of Goblet Cells Per Volume of Epithelium [At baseline (visit 2) and visit 5.]

    Change from baseline in number of goblet cells per volume of epithelium, using endobronchial biopsies, taken at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).

16. Change From Baseline in Goblet Cell Volume [At baseline (visit 2) and visit 5.]

    Change from baseline in goblet cell volume, using endobronchial biopsies, taken at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).

17. Change From Baseline of Interleukin-8 (IL-8) Levels in Bronchoalveolar Lavage [At baseline (visit 2) and at visit 5.]

    Change from baseline of Interleukin-8 (IL-8) levels in bronchoalveolar lavage. IL-8 levels, were measured by enzyme linked immunosorbent assay in bronchoalveolar lavage samples at visit 2 (baseline) and at the end of the 4-week period of treatment (visit 5).

18. Change From Baseline in Myeloperoxidase (MPO) Levels in Bronchoalveolar Lavage [At baseline (visit 2) and at visit 5.]

    Change from baseline in Myeloperoxidase (MPO) levels in bronchoalveolar lavage. Myeloperoxidase (MPO) activity levels were measured by enzyme linked immunosorbent or radioimmunoassay assay in bronchoalveolar lavage samples at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• COPD smokers

• ages between 40 and 70

Exclusion Criteria:

• Significant other diseases

• abnormal hematology

• abnormal liver function

• psychiatric disorders

• pulmonary obstruction

• asthma, allergic rhinitis

• dependance on oxygen

• patients with history of myocardial infarction

• patients with history of cancer

• women of child bearing potential

• antiplatelet or anticoagulation therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1219.5.03 Boehringer Ingelheim Investigational Site	Birmingham	Alabama	United States
2	1219.5.01 Boehringer Ingelheim Investigational Site	San Francisco	California	United States
3	1219.5.02 Boehringer Ingelheim Investigational Site	Denver	Colorado	United States
4	1219.5.04 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania	United States
5	1219.5.06 Boehringer Ingelheim Investigational Site	Freiburg/Breisgau		Germany
6	1219.5.05 Boehringer Ingelheim Investigational Site	Hannover		Germany

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00423137
• Other Study ID Numbers: 1219.5; 2006-001975-40
• First Posted: Jan 18, 2007
• Last Update Posted: Nov 19, 2021
• Last Verified: Oct 1, 2021

• Additional relevant MeSH terms: Bronchitis; Bronchitis, Chronic; Pulmonary Disease, Chronic Obstructive

Study Results

Participant Flow

Recruitment Details	A randomized, double-blind, placebo-controlled, parallel group study to evaluate the effects of a 4-week treatment of 15 and 30 mg two times daily (b.i.d) BIBW2948 BS on epithelial mucin stores and the safety and efficacy in Chronic Obstructive Pulmonary (COPD) patients with symptoms associated with chronic bronchitis
Pre-assignment Detail	All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria.

Arm/Group Title	Placebo 15 Milligram b.i.d	Placebo 30 Milligram b.i.d	BIBW2948 15 Milligram b.i.d	BIBW2948 30 Milligram b.i.d
Arm/Group Description	Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.	Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.	Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.	Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.
Period Title: Overall Study
STARTED	11	12	13	12
COMPLETED	10	12	7	10
NOT COMPLETED	1	0	6	2

Baseline Characteristics

Arm/Group Title	Placebo 15 Milligram b.i.d	Placebo 30 Milligram b.i.d	BIBW2948 15 Milligram b.i.d	BIBW2948 30 Milligram b.i.d	Total
Arm/Group Description	Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.	Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.	Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.	Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.	Total of all reporting groups
Overall Participants	11	12	13	12	48
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.5 (7.30)	56.4 (7.00)	54.0 (7.99)	59.0 (7.83)	56.2 (7.54)
Sex: Female, Male (Count of Participants)
Female	3 27.3%	3 25%	7 53.8%	3 25%	16 33.3%
Male	8 72.7%	9 75%	6 46.2%	9 75%	32 66.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 18.2%	2 16.7%	1 7.7%	1 8.3%	6 12.5%
White	9 81.8%	10 83.3%	12 92.3%	11 91.7%	42 87.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Volume of Mucin Per Surface Area of Basal Lamina
Description	Change from baseline in volume of mucin per surface area of basal lamina. Volume of mucin per surface area of basal lamina (vs mu,bala) was determined by stereologic quantification of Periodic Acid Schiff's (AB/PAS) reagent staining in endobronchial biopsies at visit 2 (baseline) and at the end of the 4-week period of randomized treatment (visit 5).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on placebo treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks. And oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.	All patients on BIBW2948 treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks. And oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.
Measure Participants	23	25
Least Squares Mean (Standard Error) [micrometer^3/micrometer^2]	2.565 (1.836)	1.180 (1.676)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5305
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the ANCOVA model with treatment, centre, and baseline.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-1.385
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.181
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline of Volume of Mucin Per Volume of Epithelium (Vv mu, ep) in Endobronchial Biopsies
Description	Change from baseline of volume of mucin per volume of epithelium (Vv mu, ep) in endobronchial biopsies. The volume of mucin per volume of epithelium (Vv mu, ep), as measured by stereological quantification of AB/PAS staining in endobronchial biopsies was performed at baseline (visit 2) and at the end of the 4-week period of randomised treatment (visit 5).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	22	14
Least Squares Mean (Standard Error) [millimeter^3/millimeter^3]	0.013 (0.028)	-0.036 (0.026)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1498
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the ANCOVA model with treatment, centre, and baseline.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-0.049
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.033
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

3. Secondary Outcome

Title	Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %)
Description	Change from baseline in bronchoalveolar lavage (BAL) cell differential (in %). Differential cell counts were performed on bronchoalveolar lavage samples obtained during visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	20	11
Eosinophil [%]	0.46	2.03
Epithelial [%]	-3.22	-0.71
Lymphocyte [%]	-0.15	-0.42
Macrophage [%]	2.48	-8.68
Neutrophil [%]	0.15	7.47
Squamous [%]	0.31	0.40

4. Secondary Outcome

Title	Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count
Description	Change from baseline in bronchoalveolar lavage (BAL) cell count. Total cell counts were performed on bronchoalveolar lavage (BAL) samples obtained during visit 2 (baseline) and at the end of the 4-week period of randomised treatment.
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	20	11
Eosinophil	0.001	0.005
Epithelial	-0.001	-0.007
Lymphocyte	-0.001	0.001
Macrophage	0.016	-0.206
Neutrophil	-0.001	0.004
Squamous	0.000	0.000

5. Secondary Outcome

Title	Change From Baseline in Log MUC2 Mucin Gene Expression (RNA) Obtained in Epithelial Brushings
Description	Change from baseline in log MUC2 Mucin gene expression (RNA) obtained in epithelial brushings. Gene expression levels of the gel-forming mucins (MUC2) were quantified using two-step real time polymerase chain reaction (PCR) from RNA extracted from the cells obtained from the epithelial brushings during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	20	12
Least Squares Mean (Standard Error) [Log (fold change)]	0.076 (0.343)	0.411 (0.325)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4472
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the ANCOVA model with treatment, centre, and baseline.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	0.335
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.434
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

6. Secondary Outcome

Title	Change From Baseline in Log Mucin Gene (MUC5AC) Expression Level Obtained in Epithelial Brushings
Description	Change from baseline in log mucin gene (MUC5AC) expression level obtained in epithelial brushings. Gene expression levels of the gel-forming mucins (MUC5AC) were quantified using two-step real time polymerase chain reaction (PCR) from RNA extracted from the cells obtained from the epithelial brushings during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	20	12
Least Squares Mean (Standard Error) [Log (fold change)]	0.074 (0.275)	-0.067 (0.247)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6829
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the ANCOVA model with treatment, centre, and baseline.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-0.141
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.342
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

7. Secondary Outcome

Title	Change From Baseline in Log Mucin Gene (MUC5B) Expression Level Obtained in Epithelial Brushings
Description	Change from baseline in log mucin gene (MUC5B) expression level obtained in epithelial brushings. Gene expression levels of the gel-forming mucins (MUC5B) were quantified using two-step real time polymerase chain reaction (PCR) from RNA extracted from the cells obtained from the epithelial brushings during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	20	12
Least Squares Mean (Standard Error) [Log (fold change)]	-0.377 (0.309)	0.194 (0.296)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1565
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the ANCOVA model with treatment, centre, and baseline.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	0.571
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.391
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

8. Secondary Outcome

Title	Change From Baseline in Log Mucin Gene (MUC8) Expression Level Obtained in Epithelial Brushings
Description	Change from baseline in log mucin gene (MUC8) expression level obtained in epithelial brushings. Gene expression levels of the gel-forming mucins (MUC8) were quantified using two-step real time polymerase chain reaction (PCR) from RNA extracted from the cells obtained from the epithelial brushings during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	20	12
Least Squares Mean (Standard Error) [Log (fold change)]	0.639 (0.961)	1.720 (0.865)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3709
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the ANCOVA model with treatment, centre, and baseline.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	1.081
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.185
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

9. Secondary Outcome

Title	Change From Baseline in Epidermal Growth Factor Receptor (EGRF) Internalization Assay in Epithelial Brushings - Cells With Bright Spots With Marker
Description	Change in percentage of cells with bright spots with marker. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in percent (%) control as (visit5/visit2*100).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	16	9
Least Squares Mean (Standard Error) [Percentage of baseline level]	103.122 (9.889)	51.039 (13.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0044
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the one way ANOVA model with Treatment.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-52.083
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16.48
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

10. Secondary Outcome

Title	Change From Baseline in Epidermal Growth Factor Receptor (EGRF) Internalization Assay in Epithelial Brushings - EGRF Spots at Nucleus
Description	Change in number of EGRF spots at nucleus. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in percent (%) control as (visit5/visit2*100).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	16	9
Least Squares Mean (Standard Error) [Percentage of baseline level]	112.955 (13.15)	45.943 (17.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0056
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the one way ANOVA model with Treatment.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-67.012
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.29
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

11. Secondary Outcome

Title	Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGRF Spots With Marker
Description	Change in number of EGRF spots with marker per cell. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in percent (%) control as (visit5/visit2*100).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	16	9
Least Squares Mean (Standard Error) [Percentage of baseline level]	106.671 (11.05)	44.100 (14.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0025
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the one way ANOVA model with Treatment.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-62.571
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.42
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

12. Secondary Outcome

Title	Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - Total Area Bright Spots With Marker
Description	Change in total area bright spots with marker. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in percent (%) control as (visit5/visit2*100).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	16	9
Least Squares Mean (Standard Error) [Percentage of baseline level]	95.397 (11.28)	55.330 (15.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0439
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the one way ANOVA model with Treatment.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-40.067
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.80
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

13. Secondary Outcome

Title	Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGFR Spots
Description	Change in number of EGFR spots per cell. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in % control as (visit5/visit2*100).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	16	9
Least Squares Mean (Standard Error) [Percentage of baseline level]	117.074 (12.78)	59.614 (17.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0129
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the one way ANOVA model with Treatment.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-57.460
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.30
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

14. Secondary Outcome

Title	Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGFR Spots at Nucleus With Marker
Description	Change in number of EGFR spots at nucleus per cell with marker. The degree of EGFR internalization (and hence activation) was measured using antibody or ligand labeling techniques in epithelial brushing samples obtained during the endobronchial biopsy at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5). Measurements visit 2 are used to standardize measurements at visit 5, and the standardized visit 5 value is calculated in % control as (visit5/visit2*100).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	16	9
Least Squares Mean (Standard Error) [Percentage of baseline level]	110.045 (10.27)	54.713 (13.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0037
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the one way ANOVA model with Treatment.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-55.332
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.11
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

15. Secondary Outcome

Title	Change From Baseline in Number of Goblet Cells Per Surface Area of Basel Lamina
Description	Change from baseline in number of goblet cells per surface area of basel lamina, using endobronchial biopsies, taken at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	21	11
Least Squares Mean (Standard Error) [cells/micrometer^2]	0.001 (0.0008)	0.001 (0.0008)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9076
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the ANCOVA model with treatment, centre, and baseline.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-0.0000
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0010
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

16. Secondary Outcome

Title	Change From Baseline in Number of Goblet Cells Per Volume of Epithelium
Description	Change from baseline in number of goblet cells per volume of epithelium, using endobronchial biopsies, taken at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).
Time Frame	At baseline (visit 2) and visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	21	11
Least Squares Mean (Standard Error) [Cells/micrometer^3]	14332.8 (12812)	879.408 (12583)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4121
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the ANCOVA model with treatment, centre, and baseline.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-13453
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 16118
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

17. Secondary Outcome

Title	Change From Baseline in Goblet Cell Volume
Description	Change from baseline in goblet cell volume, using endobronchial biopsies, taken at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).
Time Frame	At baseline (visit 2) and visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	21	11
Least Squares Mean (Standard Error) [micrometer^3]	-607.26 (239.71)	-685.87 (236.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7948
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the ANCOVA model with treatment, centre, and baseline.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	-78.619
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 298.91
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

18. Secondary Outcome

Title	Change From Baseline of Interleukin-8 (IL-8) Levels in Bronchoalveolar Lavage
Description	Change from baseline of Interleukin-8 (IL-8) levels in bronchoalveolar lavage. IL-8 levels, were measured by enzyme linked immunosorbent assay in bronchoalveolar lavage samples at visit 2 (baseline) and at the end of the 4-week period of treatment (visit 5).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	21	12
Least Squares Mean (Standard Error) [nanogram per milliliter]	-0.069 (0.070)	0.126 (0.077)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0640
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the ANCOVA model with treatment, centre, and baseline.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	0.195
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.101
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

19. Secondary Outcome

Title	Change From Baseline in Myeloperoxidase (MPO) Levels in Bronchoalveolar Lavage
Description	Change from baseline in Myeloperoxidase (MPO) levels in bronchoalveolar lavage. Myeloperoxidase (MPO) activity levels were measured by enzyme linked immunosorbent or radioimmunoassay assay in bronchoalveolar lavage samples at visit 2 (baseline) and at the end of the 4-week period of randomised treatment (visit 5).
Time Frame	At baseline (visit 2) and at visit 5.

Outcome Measure Data

Analysis Population Description

The treated set (TS), included all treated patients. Only patients with non-missing outcome measures were included. Results are reported by pooled treatment groups (i.e. pooled group of placebo vs. pooled group of BIBW-treated patients), as defined in the statistical analysis plan.

Arm/Group Title	Placebo Total	BIBW2948 Total
Arm/Group Description	All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).	All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).
Measure Participants	21	12
Least Squares Mean (Standard Error) [microgram per deciliter]	-0.003 (0.003)	0.005 (0.003)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Total, BIBW2948 Total
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0587
	Comments
	Method	ANCOVA
	Comments	The adjusted least squares mean is estimated based on the ANCOVA model with treatment, centre, and baseline.
Method of Estimation	Estimation Parameter	Difference of least square means
	Estimated Value	0.007
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.004
	Estimation Comments	Difference to Placebo [Treatment-Placebo]

Adverse Events

Time Frame	From first drug intake until last drug intake + 14 days, up to 4 weeks + 14 days.
Adverse Event Reporting Description	The treated set (TS), included all treated patients.
Arm/Group Title	Placebo 15 Milligram b.i.d		Placebo 30 Milligram b.i.d		Placebo Total		BIBW2948 15 Milligram b.i.d		BIBW2948 30 Milligram b.i.d		BIBW2948 Total		Total
Arm/Group Description	Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.		Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.		All patients on Placebo Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of placebo for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of placebo for HandiHaler® (30 mg in total) twice daily (b.i.d).		Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.		Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d) over a treatment period of 4 weeks.		All patients on BIBW2948 Treatment. Oral inhalation of two 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (15 mg in total) twice daily (b.i.d). And Oral inhalation of four 7.5 milligram (mg) capsules of BIBW2948 for HandiHaler® (30 mg in total) twice daily (b.i.d).		All patients in the study combined. (Placebo + BIBW2948)
All Cause Mortality
	Placebo 15 Milligram b.i.d		Placebo 30 Milligram b.i.d		Placebo Total		BIBW2948 15 Milligram b.i.d		BIBW2948 30 Milligram b.i.d		BIBW2948 Total		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		0/48 (0%)
Serious Adverse Events
	Placebo 15 Milligram b.i.d		Placebo 30 Milligram b.i.d		Placebo Total		BIBW2948 15 Milligram b.i.d		BIBW2948 30 Milligram b.i.d		BIBW2948 Total		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/12 (0%)		0/23 (0%)		3/13 (23.1%)		1/12 (8.3%)		4/25 (16%)		4/48 (8.3%)
Cardiac disorders
Angina unstable	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
Infections and infestations
Bronchitis	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
Investigations
Alanine aminotransferase increased	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Aspartate aminotransferase increased	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Blood lactate dehydrogenase increased	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Gamma-glutamyltransferase increased	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Psychiatric disorders
Alcohol abuse	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
Other (Not Including Serious) Adverse Events
	Placebo 15 Milligram b.i.d		Placebo 30 Milligram b.i.d		Placebo Total		BIBW2948 15 Milligram b.i.d		BIBW2948 30 Milligram b.i.d		BIBW2948 Total		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/11 (81.8%)		9/12 (75%)		18/23 (78.3%)		11/13 (84.6%)		9/12 (75%)		20/25 (80%)		38/48 (79.2%)
Cardiac disorders
Bundle branch block right	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Ear and labyrinth disorders
Sudden hearing loss	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Tinnitus	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Gastrointestinal disorders
Abdominal pain	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Constipation	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Diarrhoea	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Gastritis	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
Lip ulceration	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Nausea	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Toothache	0/11 (0%)		1/12 (8.3%)		1/23 (4.3%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		2/48 (4.2%)
Vomiting	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
General disorders
Chest pain	2/11 (18.2%)		1/12 (8.3%)		3/23 (13%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		3/48 (6.3%)
Chills	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Influenza like illness	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Non-cardiac chest pain	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Oedema peripheral	2/11 (18.2%)		0/12 (0%)		2/23 (8.7%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		2/48 (4.2%)
Pyrexia	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		2/13 (15.4%)		1/12 (8.3%)		3/25 (12%)		4/48 (8.3%)
Hepatobiliary disorders
Cirrhosis alcoholic	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
Infections and infestations
Hordeolum	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Nasopharyngitis	2/11 (18.2%)		0/12 (0%)		2/23 (8.7%)		2/13 (15.4%)		0/12 (0%)		2/25 (8%)		4/48 (8.3%)
Respiratory tract infection	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Investigations
Alanine aminotransferase increased	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Aspartate aminotransferase increased	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Blood lactate dehydrogenase increased	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Oxygen saturation decreased	0/11 (0%)		0/12 (0%)		0/23 (0%)		2/13 (15.4%)		0/12 (0%)		2/25 (8%)		2/48 (4.2%)
Pulmonary function test decreased	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
Metabolism and nutrition disorders
Anorexia	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Decreased appetite	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Hypercholesterolaemia	0/11 (0%)		1/12 (8.3%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Polydipsia	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Musculoskeletal and connective tissue disorders
Muscle spasms	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Musculoskeletal pain	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Nervous system disorders
Dizziness	0/11 (0%)		1/12 (8.3%)		1/23 (4.3%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		2/48 (4.2%)
Headache	0/11 (0%)		3/12 (25%)		3/23 (13%)		2/13 (15.4%)		2/12 (16.7%)		4/25 (16%)		7/48 (14.6%)
Lethargy	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Sinus headache	0/11 (0%)		1/12 (8.3%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Syncope	0/11 (0%)		1/12 (8.3%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Psychiatric disorders
Insomnia	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Renal and urinary disorders
Nocturia	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
Renal colic	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		1/12 (8.3%)		2/25 (8%)		2/48 (4.2%)
Cough	2/11 (18.2%)		4/12 (33.3%)		6/23 (26.1%)		4/13 (30.8%)		2/12 (16.7%)		6/25 (24%)		12/48 (25%)
Dysphonia	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
Dyspnoea	1/11 (9.1%)		2/12 (16.7%)		3/23 (13%)		1/13 (7.7%)		1/12 (8.3%)		2/25 (8%)		5/48 (10.4%)
Dyspnoea at rest	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
Dyspnoea exertional	2/11 (18.2%)		0/12 (0%)		2/23 (8.7%)		3/13 (23.1%)		0/12 (0%)		3/25 (12%)		5/48 (10.4%)
Epistaxis	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Hypoxia	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
Increased bronchial secretion	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		2/48 (4.2%)
Increased viscosity of bronchial secretion	1/11 (9.1%)		0/12 (0%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Obstructive airways disorder	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Oropharyngeal pain	2/11 (18.2%)		2/12 (16.7%)		4/23 (17.4%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		4/48 (8.3%)
Respiratory failure	0/11 (0%)		0/12 (0%)		0/23 (0%)		1/13 (7.7%)		0/12 (0%)		1/25 (4%)		1/48 (2.1%)
Sinus congestion	0/11 (0%)		1/12 (8.3%)		1/23 (4.3%)		0/13 (0%)		0/12 (0%)		0/25 (0%)		1/48 (2.1%)
Sputum discoloured	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)
Wheezing	0/11 (0%)		0/12 (0%)		0/23 (0%)		0/13 (0%)		1/12 (8.3%)		1/25 (4%)		1/48 (2.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.