Bronchitis, Chronic, Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
Study of BIBW 2948 BS in Patients with COPD and Chronic Bronchitis
Interventions
DRUGBIBW 2948 BS
Capsule
DRUGPlacebo
Capsule
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 70 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
Countries
Germany, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 15 Milligram b.i.d 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. | 11 |
| Placebo 30 Milligram b.i.d 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. | 12 |
| BIBW2948 15 Milligram 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. | 13 |
| BIBW2948 30 Milligram b.i.d 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. | 12 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event Other | 0 | 0 | 2 | 0 |
| Overall Study | Adverse Event Study disease worse | 1 | 0 | 3 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo 15 Milligram b.i.d | Total | BIBW2948 30 Milligram b.i.d | BIBW2948 15 Milligram b.i.d | Placebo 30 Milligram b.i.d |
|---|---|---|---|---|---|
| Age, Continuous | 55.5 Years STANDARD_DEVIATION 7.3 | 56.2 Years STANDARD_DEVIATION 7.54 | 59.0 Years STANDARD_DEVIATION 7.83 | 54.0 Years STANDARD_DEVIATION 7.99 | 56.4 Years STANDARD_DEVIATION 7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 42 Participants | 11 Participants | 12 Participants | 10 Participants |
| Sex: Female, Male Female | 3 Participants | 16 Participants | 3 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Male | 8 Participants | 32 Participants | 9 Participants | 6 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 12 | 0 / 23 | 0 / 13 | 0 / 12 | 0 / 25 | 0 / 48 |
| other Total, other adverse events | 9 / 11 | 9 / 12 | 18 / 23 | 11 / 13 | 9 / 12 | 20 / 25 | 38 / 48 |
| serious Total, serious adverse events | 0 / 11 | 0 / 12 | 0 / 23 | 3 / 13 | 1 / 12 | 4 / 25 | 4 / 48 |
Outcome results
Primary
Change From Baseline in Volume of Mucin Per Surface Area of Basal Lamina
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Volume of Mucin Per Surface Area of Basal Lamina | 2.565 micrometer^3/micrometer^2 | Standard Error 1.836 |
| BIBW2948 Total | Change From Baseline in Volume of Mucin Per Surface Area of Basal Lamina | 1.180 micrometer^3/micrometer^2 | Standard Error 1.676 |
p-value: 0.5305ANCOVA
Secondary
Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count
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.
Population: 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 | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Eosinophil | 0.001 Cells per milliliter |
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Epithelial | -0.001 Cells per milliliter |
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Lymphocyte | -0.001 Cells per milliliter |
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Macrophage | 0.016 Cells per milliliter |
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Neutrophil | -0.001 Cells per milliliter |
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Squamous | 0.000 Cells per milliliter |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Neutrophil | 0.004 Cells per milliliter |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Eosinophil | 0.005 Cells per milliliter |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Macrophage | -0.206 Cells per milliliter |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Epithelial | -0.007 Cells per milliliter |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Squamous | 0.000 Cells per milliliter |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Count | Lymphocyte | 0.001 Cells per milliliter |
Secondary
Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %)
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.
Population: 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 | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Lymphocyte [%] | -0.15 Percentage of cells |
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Neutrophil [%] | 0.15 Percentage of cells |
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Epithelial [%] | -3.22 Percentage of cells |
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Squamous [%] | 0.31 Percentage of cells |
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Macrophage [%] | 2.48 Percentage of cells |
| Placebo Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Eosinophil [%] | 0.46 Percentage of cells |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Epithelial [%] | -0.71 Percentage of cells |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Eosinophil [%] | 2.03 Percentage of cells |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Lymphocyte [%] | -0.42 Percentage of cells |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Macrophage [%] | -8.68 Percentage of cells |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Neutrophil [%] | 7.47 Percentage of cells |
| BIBW2948 Total | Change From Baseline in Bronchoalveolar Lavage (BAL) Cell Differential (in %) | Squamous [%] | 0.40 Percentage of cells |
Secondary
Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGFR Spots
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGFR Spots | 117.074 Percentage of baseline level | Standard Error 12.78 |
| BIBW2948 Total | Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGFR Spots | 59.614 Percentage of baseline level | Standard Error 17.04 |
p-value: 0.0129ANCOVA
Secondary
Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGFR Spots at Nucleus With Marker
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGFR Spots at Nucleus With Marker | 110.045 Percentage of baseline level | Standard Error 10.27 |
| BIBW2948 Total | Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGFR Spots at Nucleus With Marker | 54.713 Percentage of baseline level | Standard Error 13.69 |
p-value: 0.0037ANCOVA
Secondary
Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGRF Spots With Marker
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGRF Spots With Marker | 106.671 Percentage of baseline level | Standard Error 11.05 |
| BIBW2948 Total | Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - EGRF Spots With Marker | 44.100 Percentage of baseline level | Standard Error 14.74 |
p-value: 0.0025ANCOVA
Secondary
Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - Total Area Bright Spots With Marker
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - Total Area Bright Spots With Marker | 95.397 Percentage of baseline level | Standard Error 11.28 |
| BIBW2948 Total | Change From Baseline in Epidermal Growth Factor Receptor (EGFR) Internalization Assay in Epithelial Brushings - Total Area Bright Spots With Marker | 55.330 Percentage of baseline level | Standard Error 15.04 |
p-value: 0.0439ANCOVA
Secondary
Change From Baseline in Epidermal Growth Factor Receptor (EGRF) Internalization Assay in Epithelial Brushings - Cells With Bright Spots With Marker
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Epidermal Growth Factor Receptor (EGRF) Internalization Assay in Epithelial Brushings - Cells With Bright Spots With Marker | 103.122 Percentage of baseline level | Standard Error 9.889 |
| BIBW2948 Total | Change From Baseline in Epidermal Growth Factor Receptor (EGRF) Internalization Assay in Epithelial Brushings - Cells With Bright Spots With Marker | 51.039 Percentage of baseline level | Standard Error 13.19 |
p-value: 0.0044ANCOVA
Secondary
Change From Baseline in Epidermal Growth Factor Receptor (EGRF) Internalization Assay in Epithelial Brushings - EGRF Spots at Nucleus
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Epidermal Growth Factor Receptor (EGRF) Internalization Assay in Epithelial Brushings - EGRF Spots at Nucleus | 112.955 Percentage of baseline level | Standard Error 13.15 |
| BIBW2948 Total | Change From Baseline in Epidermal Growth Factor Receptor (EGRF) Internalization Assay in Epithelial Brushings - EGRF Spots at Nucleus | 45.943 Percentage of baseline level | Standard Error 17.53 |
p-value: 0.0056ANCOVA
Secondary
Change From Baseline in Goblet Cell Volume
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Goblet Cell Volume | -607.26 micrometer^3 | Standard Error 239.71 |
| BIBW2948 Total | Change From Baseline in Goblet Cell Volume | -685.87 micrometer^3 | Standard Error 236.65 |
p-value: 0.7948ANCOVA
Secondary
Change From Baseline in Log MUC2 Mucin Gene Expression (RNA) Obtained in Epithelial Brushings
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Log MUC2 Mucin Gene Expression (RNA) Obtained in Epithelial Brushings | 0.076 Log (fold change) | Standard Error 0.343 |
| BIBW2948 Total | Change From Baseline in Log MUC2 Mucin Gene Expression (RNA) Obtained in Epithelial Brushings | 0.411 Log (fold change) | Standard Error 0.325 |
p-value: 0.4472ANCOVA
Secondary
Change From Baseline in Log Mucin Gene (MUC5AC) Expression Level Obtained in Epithelial Brushings
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Log Mucin Gene (MUC5AC) Expression Level Obtained in Epithelial Brushings | 0.074 Log (fold change) | Standard Error 0.275 |
| BIBW2948 Total | Change From Baseline in Log Mucin Gene (MUC5AC) Expression Level Obtained in Epithelial Brushings | -0.067 Log (fold change) | Standard Error 0.247 |
p-value: 0.6829ANCOVA
Secondary
Change From Baseline in Log Mucin Gene (MUC5B) Expression Level Obtained in Epithelial Brushings
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Log Mucin Gene (MUC5B) Expression Level Obtained in Epithelial Brushings | -0.377 Log (fold change) | Standard Error 0.309 |
| BIBW2948 Total | Change From Baseline in Log Mucin Gene (MUC5B) Expression Level Obtained in Epithelial Brushings | 0.194 Log (fold change) | Standard Error 0.296 |
p-value: 0.1565ANCOVA
Secondary
Change From Baseline in Log Mucin Gene (MUC8) Expression Level Obtained in Epithelial Brushings
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Log Mucin Gene (MUC8) Expression Level Obtained in Epithelial Brushings | 0.639 Log (fold change) | Standard Error 0.961 |
| BIBW2948 Total | Change From Baseline in Log Mucin Gene (MUC8) Expression Level Obtained in Epithelial Brushings | 1.720 Log (fold change) | Standard Error 0.865 |
p-value: 0.3709ANCOVA
Secondary
Change From Baseline in Myeloperoxidase (MPO) Levels in Bronchoalveolar Lavage
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Myeloperoxidase (MPO) Levels in Bronchoalveolar Lavage | -0.003 microgram per deciliter | Standard Error 0.003 |
| BIBW2948 Total | Change From Baseline in Myeloperoxidase (MPO) Levels in Bronchoalveolar Lavage | 0.005 microgram per deciliter | Standard Error 0.003 |
p-value: 0.0587ANCOVA
Secondary
Change From Baseline in Number of Goblet Cells Per Surface Area of Basel Lamina
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Number of Goblet Cells Per Surface Area of Basel Lamina | 0.001 cells/micrometer^2 | Standard Error 0.0008 |
| BIBW2948 Total | Change From Baseline in Number of Goblet Cells Per Surface Area of Basel Lamina | 0.001 cells/micrometer^2 | Standard Error 0.0008 |
p-value: 0.9076ANCOVA
Secondary
Change From Baseline in Number of Goblet Cells Per Volume of Epithelium
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline in Number of Goblet Cells Per Volume of Epithelium | 14332.8 Cells/micrometer^3 | Standard Error 12812 |
| BIBW2948 Total | Change From Baseline in Number of Goblet Cells Per Volume of Epithelium | 879.408 Cells/micrometer^3 | Standard Error 12583 |
p-value: 0.4121ANCOVA
Secondary
Change From Baseline of Interleukin-8 (IL-8) Levels in Bronchoalveolar Lavage
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline of Interleukin-8 (IL-8) Levels in Bronchoalveolar Lavage | -0.069 nanogram per milliliter | Standard Error 0.07 |
| BIBW2948 Total | Change From Baseline of Interleukin-8 (IL-8) Levels in Bronchoalveolar Lavage | 0.126 nanogram per milliliter | Standard Error 0.077 |
p-value: 0.064ANCOVA
Secondary
Change From Baseline of Volume of Mucin Per Volume of Epithelium (Vv mu, ep) in Endobronchial Biopsies
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.
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Total | Change From Baseline of Volume of Mucin Per Volume of Epithelium (Vv mu, ep) in Endobronchial Biopsies | 0.013 millimeter^3/millimeter^3 | Standard Error 0.028 |
| BIBW2948 Total | Change From Baseline of Volume of Mucin Per Volume of Epithelium (Vv mu, ep) in Endobronchial Biopsies | -0.036 millimeter^3/millimeter^3 | Standard Error 0.026 |
p-value: 0.1498ANCOVA