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

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ClinicalTrials.gov Identifier: NCT01509677
Recruitment Status : Completed
First Posted : January 13, 2012
Results First Posted : November 29, 2019
Last Update Posted : November 29, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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.


Condition or disease Intervention/treatment Phase
COPD Chronic Obstructive Pulmonary Disease Drug: Roflumilast Drug: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 158 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : February 1, 2012
Actual Primary Completion Date : February 1, 2016
Actual Study Completion Date : February 1, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD Lung Diseases
Drug Information available for: Roflumilast

Arm Intervention/treatment
Active Comparator: Roflumilast
500 μg tablet, once daily, oral administration in the morning after breakfast
Drug: Roflumilast
500 μg tablet, once daily, oral administration in the morning after breakfast
Other Name: Daxas

Placebo Comparator: Placebo
tablet, once daily, oral administration in the morning after breakfast
Drug: Placebo
tablet, once daily, oral administration in the morning after breakfast
Other Name: Placebo to Roflumilast




Primary Outcome Measures :
  1. Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue. [ Time Frame: 16 weeks ]
  2. Change in Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue [ Time Frame: Baseline to 16 weeks ]

Secondary Outcome Measures :
  1. CD68+ Count in Biopsied Material (Submucosa) [ Time Frame: 16 weeks ]
  2. CD68+ Cell Count in Biopsied Material (Submucosa): Poisson Regression (Ratio) [ Time Frame: 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.

  3. Change From V2 to V6 in CD68+ Cell Count (Cells/mm^2) in Biopsied Material (Submucosa) (ITT) [ Time Frame: Baseline and 16 weeks ]
  4. CD4+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model [ Time Frame: 16 weeks ]
    CD4+ Cell Counts in biopsied Material (submucosa):poisson regression model. Clarification: Measure type "Number" refers to "Risk of each treatment group".

  5. CD45+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model [ Time Frame: 16 weeks ]
    CD45+ Cell Counts in biopsied Material (submucosa):poisson regression model. Clarification: Measure type "Number" refers to "treatment risk"

  6. Neutrophils Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model [ Time Frame: Baseline to 14 weeks ]
    Neutrophils Cell Counts in biopsied Material (submucosa):poisson regression model. Clarification: Measure type "Number" refers to "Treatment risk"

  7. CD8+ Cell Count in Biopsied Material (Bronchial Epithelium): Poisson Regression Model [ Time Frame: 16 weeks ]
    CD8+ Cell Count in biopsied material (Bronchial Epithelium): poisson regression model. Clarification: Measure Type "Number" refers to "Treatment risk"

  8. CD68+ Cell Count in Biopsied Material (Bronchial Epithelium):Poisson Regression Model [ Time Frame: 16 weeks ]
    CD68+ Cell Count in biopsied material (Bronchial Epithelium):poisson regression model. Clarification: Measure type "Number" refers to "Treatment Risk"

  9. 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 ]
  10. Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Macrophages/mL): Between-Treatment Difference [ Time Frame: Baseline to 14 weeks ]
  11. Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Eosinophils/mL): Between-Treatment Difference [ Time Frame: Baseline to 14 weeks ]
  12. Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Lymphocytes/mL): Between-Treatment Difference [ Time Frame: BAseline to 14 weeks ]
  13. Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Neutrophils/mL) [ Time Frame: Baseline to 14 weeks ]
  14. Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Macrophages/mL) [ Time Frame: Baseline to 14 weeks ]
  15. Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Eosinophils/mL) [ Time Frame: Baseline to 14 weeks ]
  16. Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Lymphocytes)/mL) [ Time Frame: Baseline to 14 weeks ]
  17. 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 ]
  18. 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 ]
  19. 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 ]
  20. 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 ]
  21. 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 ]
  22. 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 ]
  23. 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 ]
  24. 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 ]
  25. 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 ]
  26. 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 ]
  27. 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 ]
  28. 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 ]
  29. Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FEV1 (L)) [ Time Frame: Baseline to 16 weeks ]
  30. Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FVC (L)) [ Time Frame: Baseline to 16 weeks ]
  31. Wicoxon Signed-rank Test for Change From V2 to V6 in Post-bronchodilator FEV1/FVC [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01509677


Locations
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Denmark
Kobenhavn NV, Denmark
København NV, Denmark, DK-2400
Germany
Freiburg, Germany
Grosshansdorf, Germany
Hannover, Germany
Heidelberg, Germany
Immenhausen, Germany
Kiel, Germany
Mainz, Germany
Poland
Bialystok, Poland
Krakow, Poland
Lodz, Poland, 90-153
Lodz, Poland
Sweden
Lund, Sweden
United Kingdom
Cottingham, United Kingdom
Dafen, United Kingdom
Leicester, United Kingdom
London, United Kingdom
Manchester, United Kingdom
Norwich, United Kingdom, NR4 7UY
Sponsors and Collaborators
AstraZeneca
Investigators
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Study Director: AstraZeneca AstraZeneca AstraZeneca
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01509677    
Other Study ID Numbers: RO-2455-402-RD
2011-000582-13 ( EudraCT Number )
U1111-1155-8767 ( Registry Identifier: WHO )
D7120C00003 ( Other Identifier: Sponsor Identifier )
First Posted: January 13, 2012    Key Record Dates
Results First Posted: November 29, 2019
Last Update Posted: November 29, 2019
Last Verified: November 2019
Keywords provided by AstraZeneca:
Roflumilast
Chronic Obstructive Pulmonary Disease
COPD
Additional relevant MeSH terms:
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Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases