Trial to Assess the Anti-inflammatory Effects of Roflumilast in Chronic Obstructive Pulmonary Disease

Study Overview
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Brief Summary
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The objective of the Biopsy trial is to investigate the effect of roflumilast 500 µg tablets once daily versus placebo on inflammation parameters in bronchial biopsy tissue specimen and additional in sputum and blood serum. Also data on safety status will be obtained. Patients to be included required to have moderate to severe COPD associated with chronic bronchitis. The total duration of this randomized, multicentre, phase III trial is 24 weeks maximum.

Detailed Description
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This was a multicenter, double-blind, randomized, parallel group, phase 3 study. Patients included had a history of COPD (GOLD stage II-III, in Germany stage II only) with chronic productive cough. There were 2 parallel treatment arms (placebo and roflumilast 500 μg once daily). A 1 to 1 randomization scheme was used, that is, patients were allocated to roflumilast 500 μg or placebo in equal proportions. Randomization was stratified by concomitant LABA use. The total duration of this study was 24 weeks maximum per patient. The study consisted of the following periods: Single-blind placebo run-in period (6 weeks) with visits at Week -6 (visit 0 [V0]), Week -2 (V1), and Week 0 (V2, randomization visit), during which all patients received placebo. Double-blind treatment period (16 weeks) during which patients received either roflumilast or matching placebo with visits at Week 6 (V4), Week 14 (V5), and Week 16 (V6). An additional visit (V3) within 2 weeks after bronchoscopy/bronchial biopsy was performed purely as a safety visit. The exact timing of this safety visit was to be determined by the investigator. Safety follow-up. All AEs were followed up to 30 days after the double-blind treatment period. An additional safety visit, V7, was scheduled within 2 weeks after the second bronchoscopy. The exact timing of the safety visit was to be determined by the investigator. Patients were required not to take any food or drink overnight for at least 8 hours prior to returning to the study center for each visit. Patients were also asked to avoid strenuous exercise for 8 hours prior to each study visit and to avoid smoking for 4 hours prior to each study visit. For visits where patients did not undergo blood collections or biopsies, the fasting requirement was only mandated if clinically indicated, per investigator judgment.

Official Title
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A 16-week, Randomized, Placebo-controlled, Double Blind, and Parallel Group Trial to Assess the Anti-inflammatory Effects of Roflumilast in Chronic Obstructive Pulmonary Disease

Conditions
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COPD, Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Roflumilast
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Major Inclusion Criteria: Giving written informed consent History of COPD (according to GOLD 2009) for at least 12 months prior to baseline visit V0 associated with chronic productive cough for at least three months in each of the two years prior to baseline visit V0 (with other causes of productive cough excluded) Outpatients 40-80 years of age Post-bronchodilator 30% ≤FEV1 ≤80% predicted Post-bronchodilator FEV1/FVC ratio ≤70% Current or former smokers with smoking history ≥20 pack years Main Exclusion Criteria: • Criteria affecting the read-out parameters of the trial: Clinical instability, defined as experiencing a COPD exacerbation six months prior to V0 An upper/lower respiratory tract infection which has not resolved four weeks prior to V0 Diagnosis of asthma and/or other relevant lung disease Known alpha-1-antitrypsin deficiency Suspicion or diagnosis of a bleeding disorders irrespective of its pathophysiological mechanism Other protocol-defined exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Roflumilast<br>500 μg tablet, once daily, oral administration in the morning after breakfast | Drug: Roflumilast<br>* 500 μg tablet, once daily, oral administration in the morning after breakfast<br>* Other names: Daxas;|
| Placebo Comparator: Placebo<br>tablet, once daily, oral administration in the morning after breakfast | Drug: Placebo<br>* tablet, once daily, oral administration in the morning after breakfast<br>* Other names: Placebo to Roflumilast;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue. |  | 16 weeks | 
| Change in Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue |  | Baseline to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD68+ Count in Biopsied Material (Submucosa) |  | 16 weeks | 
| CD68+ Cell Count in Biopsied Material (Submucosa): Poisson Regression (Ratio) | CD68+ Cell Count in Biopsied Material (submucosa): Poisson regression (ratio). Clarification: Measure type described as Number refers to Risk of each treatment group. It is not possible to select risk from this template so number was selected instead. This issue applies to similar variables reporting poisson regression. | 16 weeks | 
| Change From V2 to V6 in CD68+ Cell Count (Cells/mm^2) in Biopsied Material (Submucosa) (ITT) |  | Baseline and 16 weeks | 
| CD4+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model | CD4+ Cell Counts in biopsied Material (submucosa):poisson regression model. Clarification: Measure type Number refers to Risk of each treatment group. | 16 weeks | 
| CD45+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model | CD45+ Cell Counts in biopsied Material (submucosa):poisson regression model. Clarification: Measure type Number refers to treatment risk | 16 weeks | 
| Neutrophils Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model | Neutrophils Cell Counts in biopsied Material (submucosa):poisson regression model. Clarification: Measure type Number refers to Treatment risk | Baseline to 14 weeks | 
| CD8+ Cell Count in Biopsied Material (Bronchial Epithelium): Poisson Regression Model | CD8+ Cell Count in biopsied material (Bronchial Epithelium): poisson regression model. Clarification: Measure Type Number refers to Treatment risk | 16 weeks | 
| CD68+ Cell Count in Biopsied Material (Bronchial Epithelium):Poisson Regression Model | CD68+ Cell Count in biopsied material (Bronchial Epithelium):poisson regression model. Clarification: Measure type Number refers to Treatment Risk | 16 weeks | 
| Change From V1 to V5 in Absolute Cell Count in Induced Sputum (10^6 Neutrophils/mL): Between-Treatment Difference |  | Baseline to 14 weeks | 
| Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Macrophages/mL): Between-Treatment Difference |  | Baseline to 14 weeks | 
| Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Eosinophils/mL): Between-Treatment Difference |  | Baseline to 14 weeks | 
| Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Lymphocytes/mL): Between-Treatment Difference |  | BAseline to 14 weeks | 
| Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Neutrophils/mL) |  | Baseline to 14 weeks | 
| Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Macrophages/mL) |  | Baseline to 14 weeks | 
| Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Eosinophils/mL) |  | Baseline to 14 weeks | 
| Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Lymphocytes)/mL) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (Alfa- 2-Macroglobulin (µg/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MCP-1 (pg/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (TIMP-1 (ng/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (VEGF (pg/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (Alfa-2-Macroglobulin (µg/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MCP-1(pg/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (TIMP-1(ng/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (VEGF(pg/mL)) |  | Baseline to 14 weeks | 
| Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FEV1 (L)) |  | Baseline to 16 weeks | 
| Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FVC (L)) |  | Baseline to 16 weeks | 
| Wicoxon Signed-rank Test for Change From V2 to V6 in Post-bronchodilator FEV1/FVC | Wilcoxon test is a non-parametric test to evaluate differences among treatments in the variable that is being reported here. The data reported in the outcome measure data table are hodges Lehmann estimate of change from baseline in FEV1/FVC ratio. | Baseline to 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Roflumilast, Chronic Obstructive Pulmonary Disease, COPD