Chronic Obstructive Pulmonary Disease, COPD
Conditions
Keywords
Roflumilast, Chronic Obstructive Pulmonary Disease, COPD
Brief summary
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
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.
Interventions
DRUGRoflumilast
500 μg tablet, once daily, oral administration in the morning after breakfast
DRUGPlacebo
tablet, once daily, oral administration in the morning after breakfast
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | 16 weeks | CD4+ Cell Counts in biopsied Material (submucosa):poisson regression model. Clarification: Measure type Number refers to Risk of each treatment group. |
| CD45+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model | 16 weeks | CD45+ Cell Counts in biopsied Material (submucosa):poisson regression model. Clarification: Measure type Number refers to treatment risk |
| Neutrophils Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model | Baseline to 14 weeks | Neutrophils Cell Counts in biopsied Material (submucosa):poisson regression model. Clarification: Measure type Number refers to Treatment risk |
| CD8+ Cell Count in Biopsied Material (Bronchial Epithelium): Poisson Regression Model | 16 weeks | CD8+ Cell Count in biopsied material (Bronchial Epithelium): poisson regression model. Clarification: Measure Type Number refers to Treatment risk |
| CD68+ Cell Count in Biopsied Material (Bronchial Epithelium):Poisson Regression Model | 16 weeks | CD68+ Cell Count in biopsied material (Bronchial Epithelium):poisson regression model. Clarification: Measure type Number refers to Treatment Risk |
| 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 | — |
| CD68+ Count in Biopsied Material (Submucosa) | 16 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 | Baseline to 16 weeks | 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. |
| 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 | — |
| CD68+ Cell Count in Biopsied Material (Submucosa): Poisson Regression (Ratio) | 16 weeks | 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. |
Countries
Denmark, Germany, Poland, Sweden, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| R500 Roflumilast 500 µg | 79 |
| Placebo Placebo to Roflumilast | 79 |
| Total | 158 |
Baseline characteristics
| Characteristic | R500 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64 Years STANDARD_DEVIATION 8.23 | 62.5 Years STANDARD_DEVIATION 8.43 | 63.2 Years STANDARD_DEVIATION 8.34 |
| Age, Customized >=65 years | 42 Participants | 33 Participants | 75 Participants |
| Age, Customized Between 18 and 65 years | 37 Participants | 46 Participants | 83 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 77 Participants | 77 Participants | 154 Participants |
| Region of Enrollment Europe | 79 Participants | 79 Participants | 158 Participants |
| Sex: Female, Male Female | 19 Participants | 18 Participants | 37 Participants |
| Sex: Female, Male Male | 60 Participants | 61 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 69 / 79 | 57 / 79 |
| serious Total, serious adverse events | 8 / 79 | 5 / 79 |
Outcome results
Primary
Change in Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue
Time frame: Baseline to 16 weeks
Population: The CD8+ cells count results in submucosa for the primary outcome were available for 117 patients at V2 (41 missing) and 114 patients at V6 (44 missing). The reason for missing samples was that the sample amount did not reach the minimal area requested per study protocol. See section 11.4.1 in CSR
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change in Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue | 13.4 cells/mm^2 | Standard Deviation 302.69 |
| Placebo | Change in Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue | 29.4 cells/mm^2 | Standard Deviation 298.88 |
Comparison: 2-sided test at 5% significant levelp-value: 0.7922Poisson regression model
p-value: 0.791795% CI: [0.82, 1.3]Poisson regression model
Primary
Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue.
Time frame: 16 weeks
Population: The CD8+ cells count results in submucosa for the primary outcome were available for 117 patients at V2 (41 missing) and 114 patients at V6 (44 missing). The reason for missing samples was that the sample amount did not reach the minimal area requested per study protocol. See section 11.4.1 in CSR
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R500 | Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue. | 442.4 CD8+ cells count | Standard Deviation 312.74 |
| Placebo | Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue. | 427.1 CD8+ cells count | Standard Deviation 261.42 |
Secondary
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
Time frame: 16 weeks
Population: The reason for missing samples was that the sample amount did not reach the minimal area requested per study protocol. See 11.4.7 in CSR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| R500 | CD45+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model | 818.4 CD45+ Cell Counts |
| Placebo | CD45+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model | 960.3 CD45+ Cell Counts |
Comparison: 2-sided 5% testp-value: 0.112895% CI: [0.7, 1.04]Poisson regression model
Secondary
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.
Time frame: 16 weeks
Population: The reason for missing samples was that the sample amount did not reach the minimal area requested per study protocol. See 11.4.7 in CSR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| R500 | CD4+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model | 304.6 CD4+ Cell Counts |
| Placebo | CD4+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model | 255.0 CD4+ Cell Counts |
Comparison: 2-sided 5% testp-value: 0.274495% CI: [0.87, 1.64]Poisson regression model
Secondary
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
Time frame: 16 weeks
Population: The reason for missing samples was that the sample amount did not reach the minimal area requested per study protocol. See 11.4.7 in CSR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| R500 | CD68+ Cell Count in Biopsied Material (Bronchial Epithelium):Poisson Regression Model | 76.3 CD68+ Cell Count |
| Placebo | CD68+ Cell Count in Biopsied Material (Bronchial Epithelium):Poisson Regression Model | 93.1 CD68+ Cell Count |
Comparison: 2-sided 5% testp-value: 0.356695% CI: [0.54, 1.25]Poisson regression model
Secondary
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.
Time frame: 16 weeks
Population: The reason for missing samples was that the sample amount did not reach the minimal area requested per study protocol. See 11.4.7 in CSR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| R500 | CD68+ Cell Count in Biopsied Material (Submucosa): Poisson Regression (Ratio) | 126.8 CD68+ Cell Count |
| Placebo | CD68+ Cell Count in Biopsied Material (Submucosa): Poisson Regression (Ratio) | 121.6 CD68+ Cell Count |
Comparison: 2-sided 5% testp-value: 0.713695% CI: [0.83, 1.3]Poisson regression model
Secondary
CD68+ Count in Biopsied Material (Submucosa)
Time frame: 16 weeks
Population: The reason for missing samples was that the sample amount did not reach the minimal area requested per study protocol. See 11.4.7 in CSR
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| R500 | CD68+ Count in Biopsied Material (Submucosa) | 149.1 CD68+ Count | Standard Deviation 113.91 |
| Placebo | CD68+ Count in Biopsied Material (Submucosa) | 124.4 CD68+ Count | Standard Deviation 93.15 |
Comparison: 2-sided, 5% testp-value: 0.7145Poisson regression model
Secondary
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
Time frame: 16 weeks
Population: The reason for missing samples was that the sample amount did not reach the minimal area requested per study protocol. See 11.4.7 in CSR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| R500 | CD8+ Cell Count in Biopsied Material (Bronchial Epithelium): Poisson Regression Model | 422.1 CD8+ Cell Count |
| Placebo | CD8+ Cell Count in Biopsied Material (Bronchial Epithelium): Poisson Regression Model | 505.3 CD8+ Cell Count |
Comparison: 2-sided 5% testp-value: 0.067795% CI: [0.69, 1.01]Poisson regression model
Secondary
Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FEV1 (L))
Time frame: Baseline to 16 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FEV1 (L)) | 0.028 L | Standard Error 0.0212 |
| Placebo | Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FEV1 (L)) | -0.035 L | Standard Error 0.0212 |
Comparison: 2-sided 5% testp-value: 0.03895% CI: [0.004, 0.122]ANCOVA
Secondary
Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FVC (L))
Time frame: Baseline to 16 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FVC (L)) | 0.031 L | Standard Error 0.0391 |
| Placebo | Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FVC (L)) | -0.033 L | Standard Error 0.391 |
Comparison: 2-sided 5% testp-value: 0.248295% CI: [-0.045, 0.173]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (Alfa-2-Macroglobulin (µg/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (Alfa-2-Macroglobulin (µg/mL)) | -0.05 µg/mL | Standard Error 0.061 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (Alfa-2-Macroglobulin (µg/mL)) | -0.05 µg/mL | Standard Error 0.062 |
Comparison: 2-sided 5% testp-value: 0.998995% CI: [-0.17, 0.17]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL)) | -4.48 pg/mL | Standard Error 0.929 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL)) | -3.92 pg/mL | Standard Error 0.945 |
Comparison: 2-sided 5% testp-value: 0.670195% CI: [-3.15, 2.03]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MCP-1(pg/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MCP-1(pg/mL)) | -24.8 pg/mL | Standard Error 11 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MCP-1(pg/mL)) | -23.4 pg/mL | Standard Error 11.21 |
Comparison: 2-sided 5% testp-value: 0.926195% CI: [-32.4, 29.5]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL)) | 0.8 ng/mL | Standard Error 0.78 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL)) | -1.0 ng/mL | Standard Error 0.79 |
Comparison: 2-sided 5% testp-value: 0.110595% CI: [-0.4, 3.9]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (TIMP-1(ng/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (TIMP-1(ng/mL)) | 2.7 ng/mL | Standard Error 3.19 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (TIMP-1(ng/mL)) | -7.5 ng/mL | Standard Error 3.25 |
Comparison: 2-sided 5% testp-value: 0.025795% CI: [1.2, 19]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (VEGF(pg/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (VEGF(pg/mL)) | 11.3 pg/mL | Standard Error 12.8 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (VEGF(pg/mL)) | -21.5 pg/mL | Standard Error 13.08 |
Comparison: 2-sided 5% testp-value: 0.072895% CI: [-3, 168.6]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (Alfa- 2-Macroglobulin (µg/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (Alfa- 2-Macroglobulin (µg/mL)) | -0.32 µg/mL | Standard Error 0.73 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (Alfa- 2-Macroglobulin (µg/mL)) | -0.48 µg/mL | Standard Error 0.7 |
Comparison: 2-sided 5% testp-value: 0.876995% CI: [-1.84, 2.15]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL)) | -827.3 pg/mL | Standard Error 1995.79 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL)) | -1538.4 pg/mL | Standard Error 1941.08 |
Comparison: 2-sided 5% testp-value: 0.797895% CI: [-4778.3, 6200.5]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MCP-1 (pg/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MCP-1 (pg/mL)) | -95.2 pg/mL | Standard Error 49.23 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MCP-1 (pg/mL)) | -69.3 pg/mL | Standard Error 46.93 |
Comparison: 2-sided 5% testp-value: 0.703395% CI: [-160.3, 108.5]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL)) | 80.1 ng/mL | Standard Error 57.07 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL)) | -8.4 ng/mL | Standard Error 55.44 |
Comparison: 2-sided 5% testp-value: 0.266995% CI: [-68.6, 245.6]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (TIMP-1 (ng/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (TIMP-1 (ng/mL)) | 25.87 ng/mL | Standard Error 13.085 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (TIMP-1 (ng/mL)) | -1.92 ng/mL | Standard Error 12.551 |
Comparison: 2-sided 5% testp-value: 0.126495% CI: [-7.97, 63.55]ANCOVA
Secondary
Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (VEGF (pg/mL))
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (VEGF (pg/mL)) | 253.1 pg/mL | Standard Error 89.46 |
| Placebo | Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (VEGF (pg/mL)) | -43.7 pg/mL | Standard Error 86.84 |
Comparison: 2-sided 5% testp-value: 0.018595% CI: [50.9, 542.7]ANCOVA
Secondary
Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Eosinophils/mL): Between-Treatment Difference
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Eosinophils/mL): Between-Treatment Difference | -0.0986 10^6 eosinophils/mL | Standard Error 0.02639 |
| Placebo | Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Eosinophils/mL): Between-Treatment Difference | -0.0360 10^6 eosinophils/mL | Standard Error 0.02585 |
Comparison: 2 sided 5% testp-value: 0.092795% CI: [-0.1358, 0.0106]ANCOVA
Secondary
Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Lymphocytes/mL): Between-Treatment Difference
Time frame: BAseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Lymphocytes/mL): Between-Treatment Difference | -0.0167 10^6 lymphocytes/mL | Standard Error 0.01167 |
| Placebo | Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Lymphocytes/mL): Between-Treatment Difference | -0.0060 10^6 lymphocytes/mL | Standard Error 0.01141 |
Comparison: 2 sided 5% testp-value: 0.517595% CI: [-0.0435, 0.022]ANCOVA
Secondary
Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Macrophages/mL): Between-Treatment Difference
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Macrophages/mL): Between-Treatment Difference | 0.1017 10^6 macrophages/mL | Standard Error 0.23396 |
| Placebo | Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Macrophages/mL): Between-Treatment Difference | -0.3710 10^6 macrophages/mL | Standard Error 0.2297 |
Comparison: 2 sided 5% testp-value: 0.154195% CI: [-0.181, 1.1264]ANCOVA
Secondary
Change From V1 to V5 in Absolute Cell Count in Induced Sputum (10^6 Neutrophils/mL): Between-Treatment Difference
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From V1 to V5 in Absolute Cell Count in Induced Sputum (10^6 Neutrophils/mL): Between-Treatment Difference | 1.7181 10^6 neutrophils/mL | Standard Error 1.64471 |
| Placebo | Change From V1 to V5 in Absolute Cell Count in Induced Sputum (10^6 Neutrophils/mL): Between-Treatment Difference | 0.0827 10^6 neutrophils/mL | Standard Error 1.6122 |
Comparison: 2 sided 5% testp-value: 0.479495% CI: [-2.9429, 6.2137]ANCOVA
Secondary
Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Eosinophils/mL)
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Eosinophils/mL) | -1.826 10^6 eosinophils/m | Standard Error 0.5214 |
| Placebo | Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Eosinophils/mL) | -0.041 10^6 eosinophils/m | Standard Error 0.52 |
Comparison: 2-sided 5 % testp-value: 0.012795% CI: [-3.324, -0.409]ANCOVA
Secondary
Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Lymphocytes)/mL)
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Lymphocytes)/mL) | -0.137 10^6 lymphocytes)/mL | Standard Error 0.1332 |
| Placebo | Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Lymphocytes)/mL) | -0.086 10^6 lymphocytes)/mL | Standard Error 1.329 |
Comparison: 2-sided 5 % testp-value: 0.786295% CI: [-0.423, 0.321]ANCOVA
Secondary
Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Macrophages/mL)
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Macrophages/mL) | 0.315 10^6 macrophages/mL | Standard Error 2.1328 |
| Placebo | Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Macrophages/mL) | -0.826 10^6 macrophages/mL | Standard Error 2.1316 |
Comparison: 2-sided 5 % testp-value: 0.705295% CI: [-4.835, 7.117]ANCOVA
Secondary
Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Neutrophils/mL)
Time frame: Baseline to 14 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Neutrophils/mL) | 2.527 10^6 neutrophils/mL | Standard Error 2.3571 |
| Placebo | Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Neutrophils/mL) | 0.382 10^6 neutrophils/mL | Standard Error 2.3535 |
Comparison: 2-sided 5 % testp-value: 0.520595% CI: [-4.466, 8.757]ANCOVA
Secondary
Change From V2 to V6 in CD68+ Cell Count (Cells/mm^2) in Biopsied Material (Submucosa) (ITT)
Time frame: Baseline and 16 weeks
Population: The reason for missing samples was that the sample amount did not reach the minimal area requested per study protocol. See 11.4.7 in CSR
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| R500 | Change From V2 to V6 in CD68+ Cell Count (Cells/mm^2) in Biopsied Material (Submucosa) (ITT) | 6.1 CD68+ Cell Count (cells/mm^2) | Standard Error 10.99 |
| Placebo | Change From V2 to V6 in CD68+ Cell Count (Cells/mm^2) in Biopsied Material (Submucosa) (ITT) | -5.3 CD68+ Cell Count (cells/mm^2) | Standard Error 11.05 |
Comparison: 2-sided 5% testp-value: 0.460695% CI: [-19.2, 42.1]ANCOVA
Secondary
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
Time frame: Baseline to 14 weeks
Population: The reason for missing samples was that the sample amount did not reach the minimal area requested per study protocol. See 11.4.7 in CSR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| R500 | Neutrophils Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model | 118.6 Neutrophils Cell Counts |
| Placebo | Neutrophils Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model | 127.7 Neutrophils Cell Counts |
Comparison: 2-sided 5% testp-value: 0.67495% CI: [0.66, 1.31]Regression, Linear
Secondary
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.
Time frame: Baseline to 16 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| R500 | Wicoxon Signed-rank Test for Change From V2 to V6 in Post-bronchodilator FEV1/FVC | 0.5 ratio |
| Placebo | Wicoxon Signed-rank Test for Change From V2 to V6 in Post-bronchodilator FEV1/FVC | -0.5 ratio |
Comparison: 2 sided 5 % testp-value: 0.262995% CI: [-2, 1]Wilcoxon (Mann-Whitney)