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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01509677
• Collaborator: (none)
• Enrollment: 158
• Locations: 20
• Arms: 2
• Actual Duration (Months): 48
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Feb 1, 2012
• Actual Primary Completion Date: Feb 1, 2016
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

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 Names: 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 Names: Placebo to Roflumilast

Outcome Measures

Primary Outcome Measures

1. Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue. [16 weeks]

2. Change in Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue [Baseline to 16 weeks]

Secondary Outcome Measures

1. CD68+ Count in Biopsied Material (Submucosa) [16 weeks]

2. 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.

3. Change From V2 to V6 in CD68+ Cell Count (Cells/mm^2) in Biopsied Material (Submucosa) (ITT) [Baseline and 16 weeks]

4. 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".

5. 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"

6. 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"

7. 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"

8. 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"

9. Change From V1 to V5 in Absolute Cell Count in Induced Sputum (10^6 Neutrophils/mL): Between-Treatment Difference [Baseline to 14 weeks]

10. Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Macrophages/mL): Between-Treatment Difference [Baseline to 14 weeks]

11. Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Eosinophils/mL): Between-Treatment Difference [Baseline to 14 weeks]

12. Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Lymphocytes/mL): Between-Treatment Difference [BAseline to 14 weeks]

13. Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Neutrophils/mL) [Baseline to 14 weeks]

14. Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Macrophages/mL) [Baseline to 14 weeks]

15. Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Eosinophils/mL) [Baseline to 14 weeks]

16. Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Lymphocytes)/mL) [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)) [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)) [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)) [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)) [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)) [Baseline to 14 weeks]

22. Change From Baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of Interest (FAS) (VEGF (pg/mL)) [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)) [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)) [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)) [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)) [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)) [Baseline to 14 weeks]

28. Change From Baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of Interest (FAS) (VEGF(pg/mL)) [Baseline to 14 weeks]

29. Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FEV1 (L)) [Baseline to 16 weeks]

30. Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FVC (L)) [Baseline to 16 weeks]

31. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Kobenhavn NV		Denmark
2		København NV		Denmark	DK-2400
3		Freiburg		Germany
4		Grosshansdorf		Germany
5		Hannover		Germany
6		Heidelberg		Germany
7		Immenhausen		Germany
8		Kiel		Germany
9		Mainz		Germany
10		Bialystok		Poland
11		Krakow		Poland
12		Lodz		Poland	90-153
13		Lodz		Poland
14		Lund		Sweden
15		Cottingham		United Kingdom
16		Dafen		United Kingdom
17		Leicester		United Kingdom
18		London		United Kingdom
19		Manchester		United Kingdom
20		Norwich		United Kingdom	NR4 7UY

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: AstraZeneca AstraZeneca, AstraZeneca

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• RO-2455-402-RD Updated Protocol v 6.0 (Amendment 12)

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01509677
• Other Study ID Numbers: RO-2455-402-RD; 2011-000582-13; U1111-1155-8767; D7120C00003
• First Posted: Jan 13, 2012
• Last Update Posted: Nov 29, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by AstraZeneca: Roflumilast; Chronic Obstructive Pulmonary Disease; COPD
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive

Study Results

Participant Flow

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Period Title: Overall Study
STARTED	79	79
COMPLETED	76	73
NOT COMPLETED	3	6

Baseline Characteristics

Arm/Group Title	R500	Placebo	Total
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast	Total of all reporting groups
Overall Participants	79	79	158
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64 (8.23)	62.5 (8.43)	63.2 (8.34)
Age, Customized (Number) [Number]
Between 18 and 65 years	37 46.8%	46 58.2%	83 52.5%
>=65 years	42 53.2%	33 41.8%	75 47.5%
Sex: Female, Male (Count of Participants)
Female	19 24.1%	18 22.8%	37 23.4%
Male	60 75.9%	61 77.2%	121 76.6%
Race/Ethnicity, Customized (Number) [Number]
Asian	0 0%	1 1.3%	1 0.6%
Black or African American	1 1.3%	0 0%	1 0.6%
White	77 97.5%	77 97.5%	154 97.5%
Other	1 1.3%	1 1.3%	2 1.3%
Region of Enrollment (Number) [Number]
Europe	79 100%	79 100%	158 100%

Outcome Measures

1. Primary Outcome

Title	Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	49	46
Mean (Standard Deviation) [CD8+ cells count]	442.4 (312.74)	427.1 (261.42)

2. Primary Outcome

Title	Change in Number of CD8+ Inflammatory Cells in Bronchial Biopsy Tissue
Time Frame	Baseline to 16 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	49	46
Mean (Standard Deviation) [cells/mm^2]	13.4 (302.69)	29.4 (298.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided test at 5% significant level
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7922
	Comments	This is p-value testing significance of "treatment" effect
	Method	Poisson regression model
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7917
	Comments
	Method	Poisson regression model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.120
	Estimation Comments

3. Secondary Outcome

Title	CD68+ Count in Biopsied Material (Submucosa)
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	49	46
Mean (Standard Deviation) [CD68+ Count]	149.1 (113.91)	124.4 (93.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided, 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7145
	Comments	This is p-value testing significance of "treatment" effect
	Method	Poisson regression model
	Comments

4. Secondary Outcome

Title	CD68+ Cell Count in Biopsied Material (Submucosa): Poisson Regression (Ratio)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	49	46
Number [CD68+ Cell Count]	126.8 (NA)	121.6 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7136
	Comments
	Method	Poisson regression model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.119
	Estimation Comments

5. Secondary Outcome

Title	Change From V2 to V6 in CD68+ Cell Count (Cells/mm^2) in Biopsied Material (Submucosa) (ITT)
Time Frame	Baseline and 16 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	49	46
Least Squares Mean (Standard Error) [CD68+ Cell Count (cells/mm^2)]	6.1 (10.99)	-5.3 (11.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4606
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11.4
	Confidence Interval	() 95%; -19.2 to 42.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.45
	Estimation Comments

6. Secondary Outcome

Title	CD4+ Cell Counts in Biopsied Material (Submucosa):Poisson Regression Model
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	48	46
Number [CD4+ Cell Counts]	304.6 (NA)	255.0 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2744
	Comments
	Method	Poisson regression model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.194
	Estimation Comments

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	49	46
Number [CD45+ Cell Counts]	818.4 (NA)	960.3 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1128
	Comments
	Method	Poisson regression model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.086
	Estimation Comments

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	49	46
Number [Neutrophils Cell Counts]	118.6 (NA)	127.7 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.6740
	Comments
	Method	Regression, Linear
	Comments	Poisson regression model
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.164
	Estimation Comments

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	41	37
Number [CD8+ Cell Count]	422.1 (NA)	505.3 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0677
	Comments
	Method	Poisson regression model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	39	32
Number [CD68+ Cell Count]	76.3 (NA)	93.1 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3566
	Comments
	Method	Poisson regression model
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.54 to 1.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.177
	Estimation Comments

11. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	43	44
Least Squares Mean (Standard Error) [10^6 neutrophils/mL]	1.7181 (1.64471)	0.0827 (1.61220)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2 sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.4794
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.6354
	Confidence Interval	(2-Sided) 95%; -2.9429 to 6.2137
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.30185
	Estimation Comments

12. Secondary Outcome

Title	Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Macrophages/mL): Between-Treatment Difference
Time Frame	Baseline to 14 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	43	44
Least Squares Mean (Standard Error) [10^6 macrophages/mL]	0.1017 (0.23396)	-0.3710 (0.22970)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2 sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1541
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4727
	Confidence Interval	(2-Sided) 95%; -0.1810 to 1.1264
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.32866
	Estimation Comments

13. Secondary Outcome

Title	Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Eosinophils/mL): Between-Treatment Difference
Time Frame	Baseline to 14 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	43	44
Least Squares Mean (Standard Error) [10^6 eosinophils/mL]	-0.0986 (0.02639)	-0.0360 (0.02585)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2 sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0927
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0626
	Confidence Interval	(2-Sided) 95%; -0.1358 to 0.0106
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.03681
	Estimation Comments

14. Secondary Outcome

Title	Change From V1 to V5 in Absolute Cell Count inInduced Sputum (10^6 Lymphocytes/mL): Between-Treatment Difference
Time Frame	BAseline to 14 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	43	44
Least Squares Mean (Standard Error) [10^6 lymphocytes/mL]	-0.0167 (0.01167)	-0.0060 (0.01141)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2 sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5175
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0107
	Confidence Interval	(2-Sided) 95%; -0.0435 to 0.0220
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.01647
	Estimation Comments

15. Secondary Outcome

Title	Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Neutrophils/mL)
Time Frame	Baseline to 14 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	45	44
Least Squares Mean (Standard Error) [10^6 neutrophils/mL]	2.527 (2.3571)	0.382 (2.3535)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5 % test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5205
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.146
	Confidence Interval	(2-Sided) 95%; -4.466 to 8.757
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.3253
	Estimation Comments

16. Secondary Outcome

Title	Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Macrophages/mL)
Time Frame	Baseline to 14 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	45	44
Least Squares Mean (Standard Error) [10^6 macrophages/mL]	0.315 (2.1328)	-0.826 (2.1316)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5 % test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7052
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.141
	Confidence Interval	(2-Sided) 95%; -4.835 to 7.117
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.0057
	Estimation Comments

17. Secondary Outcome

Title	Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Eosinophils/mL)
Time Frame	Baseline to 14 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	45	44
Least Squares Mean (Standard Error) [10^6 eosinophils/m]	-1.826 (0.5214)	-0.041 (0.5200)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5 % test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0127
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.867
	Confidence Interval	(2-Sided) 95%; -3.324 to -0.409
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7331
	Estimation Comments

18. Secondary Outcome

Title	Change From V1 to V5 in Differential Cell Count in Induced Sputum(10^6 Lymphocytes)/mL)
Time Frame	Baseline to 14 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	45	44
Least Squares Mean (Standard Error) [10^6 lymphocytes)/mL]	-0.137 (0.1332)	-0.086 (1.329)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5 % test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7862
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.051
	Confidence Interval	(2-Sided) 95%; -0.423 to 0.321
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1871
	Estimation Comments

19. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	54	57
Least Squares Mean (Standard Error) [µg/mL]	-0.32 (0.730)	-0.48 (0.700)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.8769
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -1.84 to 2.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.005
	Estimation Comments

20. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	54	56
Least Squares Mean (Standard Error) [pg/mL]	-827.3 (1995.79)	-1538.4 (1941.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7978
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	711.1
	Confidence Interval	(2-Sided) 95%; -4778.3 to 6200.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2768.79
	Estimation Comments

21. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	55	57
Least Squares Mean (Standard Error) [ng/mL]	80.1 (57.07)	-8.4 (55.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2669
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	88.5
	Confidence Interval	(2-Sided) 95%; -68.6 to 245.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 79.26
	Estimation Comments

22. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	53	57
Least Squares Mean (Standard Error) [pg/mL]	-95.2 (49.23)	-69.3 (46.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7033
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-25.9
	Confidence Interval	(2-Sided) 95%; -160.3 to 108.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 67.78
	Estimation Comments

23. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	54	57
Least Squares Mean (Standard Error) [ng/mL]	25.87 (13.085)	-1.92 (12.551)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1264
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	27.79
	Confidence Interval	(2-Sided) 95%; -7.97 to 63.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.039
	Estimation Comments

24. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	55	57
Least Squares Mean (Standard Error) [pg/mL]	253.1 (89.46)	-43.7 (86.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0185
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	296.8
	Confidence Interval	(2-Sided) 95%; 50.9 to 542.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 124.07
	Estimation Comments

25. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	68	66
Least Squares Mean (Standard Error) [µg/mL]	-0.05 (0.061)	-0.05 (0.062)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.9989
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.17 to 0.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.086
	Estimation Comments

26. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	68	66
Least Squares Mean (Standard Error) [pg/mL]	-4.48 (0.929)	-3.92 (0.945)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.6701
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 95%; -3.15 to 2.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.309
	Estimation Comments

27. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	68	66
Least Squares Mean (Standard Error) [ng/mL]	0.8 (0.78)	-1.0 (0.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1105
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 95%; -0.4 to 3.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.10
	Estimation Comments

28. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	68	66
Least Squares Mean (Standard Error) [pg/mL]	-24.8 (11.0)	-23.4 (11.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.9261
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -32.4 to 29.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.62
	Estimation Comments

29. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	68	66
Least Squares Mean (Standard Error) [ng/mL]	2.7 (3.19)	-7.5 (3.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0257
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.1
	Confidence Interval	(2-Sided) 95%; 1.2 to 19.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.49
	Estimation Comments

30. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	68	66
Least Squares Mean (Standard Error) [pg/mL]	11.3 (12.80)	-21.5 (13.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0728
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	32.8
	Confidence Interval	(2-Sided) 95%; -3.0 to 168.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.11
	Estimation Comments

31. Secondary Outcome

Title	Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FEV1 (L))
Time Frame	Baseline to 16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	77	77
Least Squares Mean (Standard Error) [L]	0.028 (0.0212)	-0.035 (0.0212)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0380
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.063
	Confidence Interval	(2-Sided) 95%; 0.004 to 0.122
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0300
	Estimation Comments

32. Secondary Outcome

Title	Change From Baseline in Lung Function Variables: Between-Treatment Differences (FAS) (FVC (L))
Time Frame	Baseline to 16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	77	77
Least Squares Mean (Standard Error) [L]	0.031 (0.0391)	-0.033 (0.391)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2-sided 5% test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2482
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.064
	Confidence Interval	(2-Sided) 95%; -0.045 to 0.173
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0552
	Estimation Comments

33. Secondary Outcome

Title	Wicoxon Signed-rank Test for Change From V2 to V6 in Post-bronchodilator FEV1/FVC
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R500	Placebo
Arm/Group Description	Roflumilast 500 µg	Placebo to Roflumilast
Measure Participants	77	77
Median (95% Confidence Interval) [ratio]	0.5	-0.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	R500, Placebo
	Comments	2 sided 5 % test
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2629
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Between treatment difference
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-1.00
	Confidence Interval	(2-Sided) 95%; -2.00 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	16 weeks
Arm/Group Title	R500		Placebo
Arm/Group Description	Roflumilast 500 µg		Placebo to Roflumilast
All Cause Mortality
	R500		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	R500		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/79 (10.1%)		5/79 (6.3%)
Congenital, familial and genetic disorders
Hydrocele	0/79 (0%)	0	1/79 (1.3%)	1
Gastrointestinal disorders
Dyspepsia	1/79 (1.3%)	1	0/79 (0%)	0
General disorders
Incarcerated hernia	0/79 (0%)	0	1/79 (1.3%)	1
Infections and infestations
Diverticulitis	1/79 (1.3%)	1	0/79 (0%)	0
Pneumonia	0/79 (0%)	0	1/79 (1.3%)	1
Investigations
Influenza A virus test positive	1/79 (1.3%)	1	0/79 (0%)	0
Musculoskeletal and connective tissue disorders
Synovial cyst	1/79 (1.3%)	1	0/79 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma	1/79 (1.3%)	1	0/79 (0%)	0
Rectal cancer	1/79 (1.3%)	1	0/79 (0%)	0
Psychiatric disorders
Depression	1/79 (1.3%)	1	0/79 (0%)	0
Reproductive system and breast disorders
Spermatocele	0/79 (0%)	0	1/79 (1.3%)	1
Respiratory, thoracic and mediastinal disorders
COPD	3/79 (3.8%)	3	1/79 (1.3%)	1
Dyspnoea	1/79 (1.3%)	1	0/79 (0%)	0
Pneumothorax	0/79 (0%)	0	1/79 (1.3%)	1
Other (Not Including Serious) Adverse Events
	R500		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	69/79 (87.3%)		57/79 (72.2%)
Gastrointestinal disorders
Diarrhoea	11/79 (13.9%)	11	4/79 (5.1%)	4
Dry mouth	0/79 (0%)	0	3/79 (3.8%)	3
Nausea	6/79 (7.6%)	6	1/79 (1.3%)	1
Vomiting	5/79 (6.3%)	5	2/79 (2.5%)	2
General disorders
Fatigue	3/79 (3.8%)	3	3/79 (3.8%)	3
Infections and infestations
Eye infection	2/79 (2.5%)	2	0/79 (0%)	0
Herpes zoster	2/79 (2.5%)	2	0/79 (0%)	0
Influenza	0/79 (0%)	0	2/79 (2.5%)	2
Nasopharyngitis	13/79 (16.5%)	14	12/79 (15.2%)	15
Rhinitis	3/79 (3.8%)	3	3/79 (3.8%)	3
Urinary tract infection	2/79 (2.5%)	2	0/79 (0%)	0
Viral infection	0/79 (0%)	0	2/79 (2.5%)	2
Injury, poisoning and procedural complications
Laceration	0/79 (0%)	0	2/79 (2.5%)	2
Procedural pain	3/79 (3.8%)	3	0/79 (0%)	0
Investigations
Forced expiratory volume decreased	0/79 (0%)	0	3/79 (3.8%)	3
Weight decreased	6/79 (7.6%)	6	2/79 (2.5%)	2
White blood cell count increased	2/79 (2.5%)	2	0/79 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	2/79 (2.5%)	2	1/79 (1.3%)	1
Musculoskeletal and connective tissue disorders
Back pain	5/79 (6.3%)	5	2/79 (2.5%)	2
Muscle spasms	2/79 (2.5%)	2	2/79 (2.5%)	2
Musculoskeletal chest pain	2/79 (2.5%)	2	0/79 (0%)	0
Myalgia	3/79 (3.8%)	5	0/79 (0%)	0
Pain in extremity	2/79 (2.5%)	2	0/79 (0%)	0
Synovial cyst	2/79 (2.5%)	2	0/79 (0%)	0
Nervous system disorders
Dizziness	3/79 (3.8%)	3	0/79 (0%)	0
Haedache	4/79 (5.1%)	4	3/79 (3.8%)	3
Lethargy	3/79 (3.8%)	4	0/79 (0%)	0
Tremor	3/79 (3.8%)	3	0/79 (0%)	0
Psychiatric disorders
Insomnia	7/79 (8.9%)	7	2/79 (2.5%)	2
Respiratory, thoracic and mediastinal disorders
Bronchial polyp	1/79 (1.3%)	1	2/79 (2.5%)	2
COPD	9/79 (11.4%)	10	12/79 (15.2%)	13
Cough	10/79 (12.7%)	11	12/79 (15.2%)	12
Dyspnoea	3/79 (3.8%)	3	1/79 (1.3%)	1
Haemoptysis	3/79 (3.8%)	4	0/79 (0%)	0
Oropharyngeal pain	2/79 (2.5%)	2	0/79 (0%)	0
Productive cough	0/79 (0%)	0	2/79 (2.5%)	3
Rhinorrhoea	1/79 (1.3%)	1	3/79 (3.8%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.