Clinical trial NCT01509677: Trial to Assess the Anti-inflammatory Effects of Roflumilast in Chronic Obstructive Pulmonary Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COPD
Chronic Obstructive Pulmonary Disease
Keywords: Roflumilast
Chronic Obstructive Pulmonary Disease
COPD
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2012-01-13
Enrollment: 158
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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 exclusion criteria may apply

Primary outcomes:
measure: Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue.
timeFrame: 16 weeks
measure: Change in Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue
timeFrame: Baseline to 16 weeks
Secondary outcomes:
measure: CD68+ Count in Biopsied Material (Submucosa)
timeFrame: 16 weeks
measure: CD68+ Cell Count in Biopsied Material (Submucosa): Poisson Regression (Ratio)
timeFrame: 16 weeks
measure: Change From V2 to V6 in CD68+ Cell Count (Cells/mm^2) in Biopsied Material (Submucosa) (ITT)
timeFrame: Baseline and 16 weeks
measure: CD4+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model
timeFrame: 16 weeks
measure: CD45+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model
timeFrame: 16 weeks
measure: Neutrophils Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model
timeFrame: Baseline to 14 weeks
measure: CD8+ Cell Count in Biopsied Material (Bronchial Epithelium): Poisson Regression Model
timeFrame: 16 weeks
measure: CD68+ Cell Count in Biopsied Material (Bronchial Epithelium):Poisson Regression Model
timeFrame: 16 weeks
measure: Change From V1 to V5 in Absolute Cell Count in Induced Sputum (10^6 Neutrophils/mL): Between-Treatment Difference
timeFrame: Baseline to 14 weeks
measure: Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Macrophages/mL): Between-Treatment Difference
timeFrame: Baseline to 14 weeks
measure: Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Eosinophils/mL): Between-Treatment Difference
timeFrame: Baseline to 14 weeks
measure: Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Lymphocytes/mL): Between-Treatment Difference
timeFrame: BAseline to 14 weeks
measure: Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Neutrophils/mL)
timeFrame: Baseline to 14 weeks
measure: Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Macrophages/mL)
timeFrame: Baseline to 14 weeks
measure: Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Eosinophils/mL)
timeFrame: Baseline to 14 weeks
measure: Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Lymphocytes)/mL)
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (Alfa- 2-Macroglobulin (µg/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MCP-1 (pg/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (TIMP-1 (ng/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (VEGF (pg/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (Alfa-2-Macroglobulin (µg/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MCP-1(pg/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (TIMP-1(ng/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (VEGF(pg/mL))
timeFrame: Baseline to 14 weeks
measure: Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FEV1 (L))
timeFrame: Baseline to 16 weeks
measure: Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FVC (L))
timeFrame: Baseline to 16 weeks
measure: Wicoxon Signed-rank Test for Change From V2 to V6 in Post-bronchodilator FEV1/FVC
timeFrame: Baseline to 16 weeks
Other outcomes:
Locations:
city: Kobenhavn NV
country: Denmark
city: København NV
country: Denmark
city: Freiburg
country: Germany
city: Grosshansdorf
country: Germany
city: Hannover
country: Germany
city: Heidelberg
country: Germany
city: Immenhausen
country: Germany
city: Kiel
country: Germany
city: Mainz
country: Germany
city: Bialystok
country: Poland
city: Krakow
country: Poland
city: Lodz
country: Poland
city: Lodz
country: Poland
city: Lund
country: Sweden
city: Cottingham
country: United Kingdom
city: Dafen
country: United Kingdom
city: Leicester
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Norwich
country: United Kingdom
Study officials:
affiliation: AstraZeneca
name: AstraZeneca AstraZeneca
role: STUDY_DIRECTOR
References:
citation: Rabe KF, Watz H, Baraldo S, Pedersen F, Biondini D, Bagul N, Hanauer G, Gohring UM, Purkayastha D, Roman J, Alagappan VKT, Saetta M. Anti-inflammatory effects of roflumilast in chronic obstructive pulmonary disease (ROBERT): a 16-week, randomised, placebo-controlled trial. Lancet Respir Med. 2018 Nov;6(11):827-836. doi: 10.1016/S2213-2600(18)30331-X. Epub 2018 Sep 14.