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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 158
- 主要终点
- Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Roflumilast
500 μg tablet, once daily, oral administration in the morning after breakfast
干预措施: Roflumilast (Drug)
Placebo
tablet, once daily, oral administration in the morning after breakfast
干预措施: Placebo (Drug)
结局指标
主要结局
Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue.
时间窗: 16 weeks
Change in Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue
时间窗: Baseline to 16 weeks
次要结局
- CD68+ Count in Biopsied Material (Submucosa)(16 weeks)
- CD4+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model(16 weeks)
- CD45+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model(16 weeks)
- Neutrophils Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model(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)
- CD68+ Cell Count in Biopsied Material (Submucosa): Poisson Regression (Ratio)(16 weeks)
- Change From V2 to V6 in CD68+ Cell Count (Cells/mm^2) in Biopsied Material (Submucosa) (ITT)(Baseline and 16 weeks)
- CD8+ Cell Count in Biopsied Material (Bronchial Epithelium): Poisson Regression Model(16 weeks)
- CD68+ Cell Count in Biopsied Material (Bronchial Epithelium):Poisson Regression Model(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 Lymphocytes/mL): Between-Treatment Difference(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 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 V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Neutrophils/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 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) (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) (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) (MMP Type 9 (ng/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 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) (TIMP-1(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) (VEGF(pg/mL))(Baseline to 14 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)