Effect of BIBW 2948 BS in COPD

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

Official Title
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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

Conditions
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Pulmonary Disease, Chronic Obstructive, Bronchitis, Chronic

Intervention / Treatment
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* Drug: BIBW 2948 BS
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo - low dose<br>Twice daily (b.i.d.) | Drug: Placebo<br>* Capsule<br>|
| Placebo Comparator: Placebo - high dose<br>Twice daily (b.i.d.) | Drug: Placebo<br>* Capsule<br>|
| Experimental: BIBW2948 - low dose<br>Twice daily (b.i.d.) | Drug: BIBW 2948 BS<br>* Capsule<br>|
| Experimental: BIBW2948 - high dose<br>Twice daily (b.i.d.) | Drug: BIBW 2948 BS<br>* Capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | At baseline (visit 2) and at visit 5. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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. | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and visit 5. | 
| 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). | At baseline (visit 2) and visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. | 
| 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). | At baseline (visit 2) and at visit 5. |