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

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

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

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.

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.

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.

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. Clarification: Measure type "Number" refers to "treatment risk"

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. Clarification: Measure Type "Number" refers to "Treatment risk"

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

Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Macrophages/mL): Between-Treatment Difference

Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Eosinophils/mL): Between-Treatment Difference

Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Lymphocytes/mL): Between-Treatment Difference

Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (Alfa- 2-Macroglobulin (µg/mL))

Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL))

Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL))

Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (MCP-1 (pg/mL))

Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (TIMP-1 (ng/mL))

Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (VEGF (pg/mL))

Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (Alfa-2-Macroglobulin (µg/mL))

Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (IL-8 (pg/mL))

Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MMP Type 9 (ng/mL))

Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (MCP-1(pg/mL))

Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (TIMP-1(ng/mL))

Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (VEGF(pg/mL))

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.

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

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. Erratum In: Lancet Respir Med. 2018 Oct 12;:

http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_7111&studyid=4560&filename=RO-2455-402-RD_ROBERT_Updated_Protocol_v6.0_(Amendment_12)_-_Redacted.pdf