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Clinical Trial Results:
Effect of Roflumilast 500 μg Tablets Once Daily at Acute COPD Exacerbations Treated With Standard Therapy of Oral Steroids and Antibiotics. A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial

Summary
EudraCT number	2011-002905-31
Trial protocol	GB
Global end of trial date	16 Apr 2014

Results information
Results version number	v2(current)
This version publication date	28 Sep 2016
First version publication date	06 Aug 2015
Other versions	v1
Version creation reason	Correction of full data set Update

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

RO-2455-405-RD

ISRCTN number

US NCT number

NCT01473758

WHO universal trial number (UTN)

U1111-1137-4023

Sponsor organisation name

Takeda

Sponsor organisation address

One Takeda Parkway, Deerfield, United States, 60015

Public contact

Medical Director, Clinical Science, Takeda, 1 877-825-3327, trialdisclosures@takeda.com

Scientific contact

Medical Director, Clinical Science, Takeda, 1 877-825-3327, trialdisclosures@takeda.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

30 Jun 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

25 Mar 2014

Global end of trial reached?

Yes

Global end of trial date

16 Apr 2014

Was the trial ended prematurely?

Main objective of the trial

The purpose of this trial is to investigate if roflumilast can reduce the neutrophilic inflammation at acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD). In addition, the potential benefit of roflumilast on severity and recovery periods of acute COPD exacerbations will be assessed using patient diaries and questionnaires.

Protection of trial subjects

All study participants were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Feb 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 81

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in the study at 1 investigative site in the United Kingdom from 16 February 2012 to 25 March 2014.

Screening details

Participants with a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) were enrolled equally in 1 of 2 treatment groups, once a day placebo or roflumilast 500 µg in Cycle 1. Participants were re-randomized in Cycle 2 to once a day placebo or roflumilast 500 µg and are counted as new participants.

Period 1 title

Cycle 1

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer

Are arms mutually exclusive

Yes

Roflumilast 500 μg

Arm description

Roflumilast 500 µg tablet, once daily, orally in the morning after breakfast for 4 weeks added on to standard therapy for acute COPD exacerbations. Eligible participants were rerandomized to receive either roflumilast 500 μg or placebo for 4 weeks in Cycle 2.

Arm type

Active comparator

Investigational medicinal product name

Roflumilast

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Roflumilast 500 µg tablet, once daily, orally in the morning after breakfast for 4 weeks.

Placebo

Arm description

Placebo matching roflumilast tablet, once daily, orally in the morning after breakfast added on to standard therapy for acute COPD exacerbations. Eligible participants were rerandomized to receive either roflumilast 500 μg or placebo for 4 weeks in Cycle 2.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matching roflumilast tablet, once daily, orally in the morning after breakfast.

Number of subjects in period 1	Roflumilast 500 μg	Placebo
Started	38	43
Completed	27	40
Not completed	11	3
Adverse event, non-fatal	10	2
Withdrawal by Subject	1	1

Period 2 title

Cycle 2

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer

Are arms mutually exclusive

Yes

Roflumilast 500 µg

Arm description

Roflumilast 500 µg tablet, once daily, orally in the morning after breakfast for 4 weeks added on to standard therapy for acute COPD exacerbations.

Arm type

Active comparator

Investigational medicinal product name

Roflumilast

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Roflumilast 500 µg tablet, once daily, orally in the morning after breakfast for 4 weeks.

Placebo

Arm description

Placebo matching roflumilast tablet, once daily, orally in the morning after breakfast for 4 weeks added on to standard therapy for acute COPD exacerbations.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matching roflumilast tablet, once daily, orally in the morning after breakfast.

Number of subjects in period 2 ^[1]	Roflumilast 500 µg	Placebo
Started	10	4
Completed	5	4
Not completed	5	0
Adverse event, non-fatal	5	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: With Amendment 5, patients previously enrolled in the trial were allowed to be re-enrolled with a new exacerbation, if they reached a stable disease status since completing the first treatment cycle.

Baseline characteristics

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Reporting group title

Roflumilast 500 μg

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	Roflumilast 500 μg	Placebo	Total
Number of subjects	38	43	81
Age categorical
Units: Subjects
≤ 65 years	7	11	18
> 65 years	31	32	63
Gender categorical
Units: Subjects
Female	16	15	31
Male	22	28	50
Race/Ethnicity, Customized
Units: Subjects
Asian	2	1	3
White	36	42	78
Smoking Status
Units: Subjects
Non-smoker	0	0	0
Current smoker	8	11	19
Former smoker	30	32	62
Baseline COPD Assessment Test (CAT) Total Score
The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients’ health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient’s wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst).
Units: Subjects
< 10	2	3	5
≥ 10	16	25	41
Missing	20	15	35
Weight Category by Body Mass Index (BMI)
Units: Subjects
Underweight	3	0	3
Normal Weight	15	18	33
Overweight	11	15	26
Obese	9	9	18
Missing	0	1	1
Chronic Bronchitis
Units: Subjects
No	14	17	31
Yes	24	26	50
Historical Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
Units: Subjects
< 2	28	28	56
≥ 2	10	15	25

End points

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Reporting group title

Roflumilast 500 μg

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

Roflumilast 500 µg

Reporting group description

Roflumilast 500 µg tablet, once daily, orally in the morning after breakfast for 4 weeks added on to standard therapy for acute COPD exacerbations.

Reporting group title

Placebo

Reporting group description

Placebo matching roflumilast tablet, once daily, orally in the morning after breakfast for 4 weeks added on to standard therapy for acute COPD exacerbations.

Subject analysis set title

Roflumilast 500 µg

Subject analysis set type

Intention-to-treat

Subject analysis set description

Roflumilast 500 µg tablet, once daily, orally in the morning after breakfast for 4 weeks added on to standard therapy for acute COPD exacerbations.

Subject analysis set title

Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

Placebo matching roflumilast tablet, once daily, orally in the morning after breakfast for 4 weeks added on to standard therapy for acute COPD exacerbations. therapy for acute COPD exacerbations. .

Primary: Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Initial Approach)

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End point title

Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Initial Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. An Analysis of Covariance (ANCOVA) model was used with neutrophil count at Baseline and treatment as independent variables, fixed effects. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Primary

End point timeframe

Baseline and Day 14

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	29	37
Units: 10^6 cells/gram sputum
least squares mean (standard error)	-18.705 ± 2.263	-20.109 ± 1.995

Primary Endpoint Analysis

Comparison groups

Placebo v Roflumilast 500 μg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6491 ^[1]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

1.404

Confidence interval

level

95%

sides

2-sided

lower limit

-4.731

upper limit

7.538

Variability estimate

Standard error of the mean

Dispersion value

3.07

Notes
[1] - The model contains neutrophil count at Baseline and treatment as independent variables, fixed effects.

Primary: Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Extended Approach)

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End point title

Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Extended Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. An Analysis of Covariance (ANCOVA) model was used with neutrophil count at Baseline and treatment as independent variables, fixed effects. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Primary

End point timeframe

Baseline and Day 14

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	37	39
Units: 10^6 cells/gram sputum
least squares mean (standard error)	-19.569 ± 1.906	-19.157 ± 1.855

Primary Endpoint Analysis

Comparison groups

Placebo v Roflumilast 500 µg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8786 ^[2]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.412

Confidence interval

level

95%

sides

2-sided

lower limit

-5.766

upper limit

4.943

Variability estimate

Standard error of the mean

Dispersion value

2.687

Notes
[2] - The model contains neutrophil count at Baseline and treatment as independent variables, fixed effects.

Secondary: Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Initial Approach)

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End point title

Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Initial Approach)

End point description

End point type

Secondary

End point timeframe

Day 14

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	16	29
Units: percentage of participants
number (confidence interval 95%)	37.5 (15.2 to 64.6)	55.2 (35.7 to 73.6)

No statistical analyses for this end point

Secondary: Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Extended Approach)

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End point title

Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Extended Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) and were determined with a Neubauer hemocytometer. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Day 14

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	20	31
Units: percentage of participants
number (confidence interval 95%)	45 (23.1 to 68.5)	51.6 (33.1 to 69.8)

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Total Cells (Initial Approach)

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End point title

Change from Baseline in Sputum Marker Total Cells (Initial Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: 10^6 cells/gram sputum
least squares mean (standard error)
Change at Day 7 (n=35, 39)	-25.559 ± 3.529	-27.563 ± 3.334
Change at Day 14 (n=32, 38)	-21.813 ± 2.706	-25.111 ± 2.505
Change at Day 28 (n=25, 37)	-29.2 ± 4.022	-22.218 ± 3.362
Change at Day 56 (n=24, 33)	-24.477 ± 2.708	-26.474 ± 2.341

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Total Cells (Extended Approach)

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End point title

Change from Baseline in Sputum Marker Total Cells (Extended Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	46
Units: 10^6 cells/gram sputum
least squares mean (standard error)
Change at Day 7 (n=45, 43)	-26.634 ± 3.03	-26.335 ± 3.124
Change at Day 14 (n=41, 42)	-23.512 ± 2.448	-25.332 ± 2.471
Change at Day 28 (n=30, 40)	-29.023 ± 3.347	-22.92 ± 2.947
Change at Day 56 (n=28, 36)	-19.551 ± 3.92	-26.855 ± 3.536

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Percentage of Neutrophils (Initial Approach)

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End point title

Change from Baseline in Sputum Marker Percentage of Neutrophils (Initial Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of neutrophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	36	43
Units: percentage of neutrophils
least squares mean (standard error)
Change at Day 7 (n=30, 35)	-11.325 ± 3.837	-14.484 ± 3.559
Change at Day 14 (n=31, 37)	-16.77 ± 3.983	-20.346 ± 3.55
Change at Day 28 (n=24, 34)	-27.76 ± 5.275	-13.837 ± 4.498
Change at Day 56 (n=16, 30)	-19.663 ± 5.561	-17.047 ± 4.229

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Percentage of Neutrophils (Extended Approach)

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End point title

Change from Baseline in Sputum Marker Percentage of Neutrophils (Extended Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of neutrophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. A negative change from Baseline indicates improvement. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	46	46
Units: percentage of neutrophils
least squares mean (standard error)
Change at Day 7 (n=37, 39)	-14.637 ± 3.748	-16.06 ± 3.713
Change at Day 14 (n=39, 40)	-20.69 ± 3.758	-21.052 ± 3.678
Change at Day 28 (n=29, 36)	-29.848 ± 4.721	-14.664 ± 4.371
Change at Day 56 (n=20, 32)	-21.327 ± 5.009	-17.328 ± 4.188

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Percentage of Macrophages (Initial Approach)

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End point title

Change from Baseline in Sputum Marker Percentage of Macrophages (Initial Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of macrophages was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	36	43
Units: percentage of macrophages
least squares mean (standard error)
Change at Day 7 (n=30, 35)	11.393 ± 3.837	15.43 ± 3.559
Change at Day 14 (n=31, 37)	16.062 ± 3.929	20.774 ± 3.506
Change at Day 28 (n=24, 34)	27.535 ± 5.284	13.382 ± 4.503
Change at Day 56 (n=16, 30)	16.593 ± 5.539	15.877 ± 4.171

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Percentage of Macrophages (Extended Approach)

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End point title

Change from Baseline in Sputum Marker Percentage of Macrophages (Extended Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of macrophages was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	46	46
Units: percentage of macrophages
least squares mean (standard error)
Change at Day 7 (n=37, 39)	14.679 ± 3.74	17.228 ± 3.704
Change at Day 14 (n=39, 40)	20.331 ± 3.745	21.599 ± 3.667
Change at Day 28 (n=29, 36)	29.51 ± 4.717	14.463 ± 4.367
Change at Day 56 (n=20, 32)	19.075 ± 5.003	16.322 ± 4.156

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Percentage of Eosinophils (Initial Approach)

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End point title

Change from Baseline in Sputum Marker Percentage of Eosinophils (Initial Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of eosinophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	36	43
Units: percentage of eosinophils
least squares mean (standard error)
Change at Day 7 (n=30, 35)	-0.259 ± 0.245	-0.1 ± 0.225
Change at Day 14 (n=31, 37)	-0.11 ± 0.326	-0.188 ± 0.288
Change at Day 28 (n=24, 34)	0.043 ± 1.209	1.597 ± 1.02
Change at Day 56 (n=16, 30)	2.187 ± 2.278	1.086 ± 1.766

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Percentage of Eosinophils (Extended Approach)

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End point title

Change from Baseline in Sputum Marker Percentage of Eosinophils (Extended Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of eosinophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	46	46
Units: percentage of macrophages
least squares mean (standard error)
Change at Day 7 (n=37, 39)	-0.341 ± 0.206	-0.141 ± 0.202
Change at Day 14 (n=39, 40)	-0.174 ± 0.271	-0.214 ± 0.263
Change at Day 28 (n=29, 36)	0.031 ± 1.044	1.518 ± 0.952
Change at Day 56 (n=20, 32)	1.714 ± 1.969	0.913 ± 1.655

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Percentage of Lymphocyte (Initial Approach)

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End point title

Change from Baseline in Sputum Marker Percentage of Lymphocyte (Initial Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of lymphocytes was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	36	43
Units: percentage of lymphocytes
least squares mean (standard error)
Change at Day 7 (n=30, 35)	0.229 ± 0.353	0.182 ± 0.326
Change at Day 14 (n=31, 37)	0.43 ± 0.254	0.295 ± 0.225
Change at Day 28 (n=24, 34)	0.039 ± 0.183	-0.325 ± 0.155
Change at Day 56 (n=16, 30)	-0.095 ± 0.187	-0.051 ± 0.137

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Percentage of Lymphocytes (Extended Approach)

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End point title

Change from Baseline in Sputum Marker Percentage of Lymphocytes (Extended Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of lymphocytes was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	46	46
Units: percentage of lymphocytes
least squares mean (standard error)
Change at Day 7 (n=37, 39)	0.109 ± 0.308	-0.015 ± 0.303
Change at Day 14 (n=39, 40)	0.309 ± 0.25	0.195 ± 0.243
Change at Day 28 (n=29, 36)	-0.118 ± 0.173	-0.431 ± 0.158
Change at Day 56 (n=20, 32)	-0.203 ± 0.164	-0.208 ± 0.132

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Initial Approach)

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End point title

Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Initial Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-6 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	36	42
Units: pg/mL
least squares mean (standard error)
Change at Day 7 (n=31, 38)	-1317.4 ± 143.748	-934.624 ± 133.217
Change at Day 14 (n=30, 35)	-822.715 ± 221.328	-695.955 ± 206.201
Change at Day 28 (n=22, 35)	-1232.93 ± 212.663	-955.365 ± 174.734
Change at Day 56 (n=22, 29)	-1042.1 ± 225.619	-996.485 ± 196.729

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Extended Approach)

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End point title

Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Extended Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-6 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	46	45
Units: pg/mL
least squares mean (standard error)
Change at Day 7 (n=37, 42)	-1207.68 ± 133.298	-923.325 ± 130.533
Change at Day 14 (n=36, 39)	-725.454 ± 195.921	-705.849 ± 192.89
Change at Day 28 (n=26, 38)	-1115.74 ± 200.367	-877.871 ± 172.95
Change at Day 56 (n=26, 32)	-860.191 ± 206.289	-962.342 ± 189.817

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Initial Approach)

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End point title

Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Initial Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-8 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	36	42
Units: pg/mL
least squares mean (standard error)
Change at Day 7 (n=31, 38)	-174718 ± 45481.71	-227275 ± 41821.02
Change at Day 14 (n=30, 35)	-149198 ± 47388.83	-199516 ± 43965.79
Change at Day 28 (n=22, 35)	-255317 ± 70915.15	-160587 ± 57944.79
Change at Day 56 (n=21, 29)	-204731 ± 50404.33	-223918 ± 43039.57

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Extended Approach)

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End point title

Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Extended Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-8 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	46	45
Units: pg/mL
least squares mean (standard error)
Change at Day 7 (n=37, 42)	-193223 ± 39595.2	-215296 ± 38432.42
Change at Day 14 (n=36, 39)	-172070 ± 41341.33	-195751 ± 40449.87
Change at Day 28 (n=26, 38)	-264788 ± 62440.42	-160441 ± 53963.53
Change at Day 56 (n=25, 32)	-168205 ± 51760.36	-205823 ± 46476.99

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Initial Approach)

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End point title

Change from Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Initial Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker MPO was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	36	42
Units: ng/mL
least squares mean (standard error)
Change at Day 7 (n=31, 38)	-9253.79 ± 1997.077	-4521.4 ± 1863.867
Change at Day 14 (n=30, 35)	-8072.78 ± 2144.895	-6318.88 ± 2002.939
Change at Day 28 (n=22, 35)	-13744.8 ± 2476.123	-5944.18 ± 2041.587
Change at Day 56 (n=22, 29)	-10248.6 ± 2578.146	-9478.46 ± 2234.238

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Extended Approach)

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End point title

Change from Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Extended Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker MPO was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	46	45
Units: ng/mL
least squares mean (standard error)
Change at Day 7 (n=37, 42)	-8606.36 ± 1747.094	-4380.8 ± 1713.047
Change at Day 14 (n=36, 39)	-8380.85 ± 1871.93	-5929.78 ± 1843.806
Change at Day 28 (n=26, 38)	-12692.3 ± 2220.374	-5351 ± 1933.964
Change at Day 56 (n=26, 32)	-9424.23 ± 2275.981	-8527.77 ± 2078.411

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Concentration of Neutrophil Elastase (Initial Approach)

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End point title

Change from Baseline in Sputum Marker Concentration of Neutrophil Elastase (Initial Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker Neutrophil Elastase was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	36	42
Units: µg/mL
least squares mean (standard error)
Change at Day 7 (n=31, 38)	-222995 ± 14887.25	-224606 ± 13669.99
Change at Day 14 (n=30, 35)	-149211 ± 39523.47	-125385 ± 36629.96
Change at Day 28 (n=22, 35)	-200905 ± 25432.98	-149866 ± 20549.57
Change at Day 56 (n=21, 30)	-141986 ± 28278.57	-169390 ± 23767.88

No statistical analyses for this end point

Secondary: Change from Baseline in Sputum Marker Concentration of Neutrophil Elastase (Extended Approach)

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End point title

Change from Baseline in Sputum Marker Concentration of Neutrophil Elastase (Extended Approach)

End point description

Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker Neutrophil Elastase was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	46	45
Units: µg/mL
least squares mean (standard error)
Change at Day 7 (n=37, 42)	-202235 ± 12993.51	-206912 ± 12543.14
Change at Day 14 (n=36, 39)	-143832 ± 34043.87	-110144 ± 33211.58
Change at Day 28 (n=26, 38)	-183452 ± 22560.24	-130613 ± 19255.85
Change at Day 56 (n=25, 33)	-118129 ± 25397.04	-156544 ± 22550.05

No statistical analyses for this end point

Secondary: Change from Baseline in Blood Biomarker Interleukin (IL)-6 (Initial Approach)

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End point title

Change from Baseline in Blood Biomarker Interleukin (IL)-6 (Initial Approach)

End point description

Blood was collected and serum biomarker IL-6 was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: pg/mL
least squares mean (standard error)
Change at Day 7 (n=37, 41)	-12.469 ± 0.782	-11.904 ± 0.742
Change at Day 14 (n=33, 41)	-1.973 ± 1.918	-5.728 ± 1.73
Change at Day 28 (n=28, 40)	-8.108 ± 2.36	-7.243 ± 1.997
Change at Day 56 (n=27, 40)	-11.665 ± 1.129	-9.431 ± 0.937

No statistical analyses for this end point

Secondary: Change from Baseline in Blood Biomarker Interleukin (IL)-6 (Extended Approach)

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End point title

Change from Baseline in Blood Biomarker Interleukin (IL)-6 (Extended Approach)

End point description

Blood was collected and serum biomarker IL-6 was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: pg/mL
least squares mean (standard error)
Change at Day 7 (n=47, 45)	-12.314 ± 0.652	-11.802 ± 0.665
Change at Day 14 (n=43, 45)	1.607 ± 2.543	-6.069 ± 2.49
Change at Day 28 (n=33, 44)	-7.587 ± 2.088	-7.619 ± 1.838
Change at Day 56 (n=32, 44)	-10.811 ± 1.064	-9.604 ± 0.918

No statistical analyses for this end point

Secondary: Change from Baseline in Blood Biomarker Interleukin-1 Beta (IL-1β) (Initial Approach)

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End point title

Change from Baseline in Blood Biomarker Interleukin-1 Beta (IL-1β) (Initial Approach)

End point description

Blood was collected and serum biomarker IL-1β was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: pg/mL
least squares mean (standard error)
Change at Day 7 (n=37, 41)	1.274 ± 0.682	0.378 ± 0.647
Change at Day 14 (n=33, 41)	0.217 ± 0.359	0.495 ± 0.324
Change at Day 28 (n=28, 40)	0.657 ± 0.431	0.541 ± 0.366
Change at Day 56 (n=27, 40)	-0.003 ± 0.329	0.464 ± 0.288

No statistical analyses for this end point

Secondary: Change from Baseline in Blood Biomarker IL-1β (Extended Approach)

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End point title

Change from Baseline in Blood Biomarker IL-1β (Extended Approach)

End point description

Blood was collected and serum biomarker IL-1β was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: pg/mL
least squares mean (standard error)
Change at Day 7 (n=47, 45)	0.35 ± 0.59	-1.002 ± 0.602
Change at Day 14 (n=43, 45)	-0.394 ± 0.355	-0.841 ± 0.349
Change at Day 28 (n=33, 44)	-0.139 ± 0.414	-0.757 ± 0.368
Change at Day 56 (n=32, 44)	-0.799 ± 0.333	-0.806 ± 0.312

No statistical analyses for this end point

Secondary: Change from Baseline in Blood Biomarker C-reactive protein (CRP) (Initial Approach)

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End point title

Change from Baseline in Blood Biomarker C-reactive protein (CRP) (Initial Approach)

End point description

Blood was collected and serum biomarker CRP was measured using Roche Modular Analytics E 170 Module. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: mg/liter(L)
least squares mean (standard error)
Change at Day 7 (n=37, 41)	-15.579 ± 0.485	-16.518 ± 0.461
Change at Day 14 (n=33, 41)	4.836 ± 4.249	-4.369 ± 3.812
Change at Day 28 (n=28, 38)	-9.179 ± 4.11	-8.018 ± 3.533
Change at Day 56 (n=26, 40)	-14.889 ± 1.395	-13.057 ± 1.133

No statistical analyses for this end point

Secondary: Change from Baseline in Blood Biomarker C-reactive protein (CRP) (Extended Approach)

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End point title

Change from Baseline in Blood Biomarker C-reactive protein (CRP) (Extended Approach)

End point description

Blood was collected and serum biomarker CRP was measured using Roche Modular Analytics E 170 Module. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: mg/L
least squares mean (standard error)
Change at Day 7 (n=47, 45)	-16.166 ± 0.41	-16.901 ± 0.417
Change at Day 14 (n=43, 45)	5.72 ± 3.6	-5.257 ± 3.518
Change at Day 28 (n=33, 42)	-8.25 ± 3.802	-9.254 ± 3.375
Change at Day 56 (n=31, 44)	-15.152 ± 1.219	-13.793 ± 1.034

No statistical analyses for this end point

Secondary: Change from Baseline in Blood Biomarker Fibrinogen (Initial Approach)

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End point title

Change from Baseline in Blood Biomarker Fibrinogen (Initial Approach)

End point description

Biomarker Plasma fibrinogen was determined using the method described by Clauss. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	35	42
Units: umol/L
least squares mean (standard error)
Change at Day 7 (n=34, 39)	-3.916 ± 0.286	-3.976 ± 0.261
Change at Day 14 (n=33, 38)	0.404 ± 0.625	-0.184 ± 0.571
Change at Day 28 (n=27, 36)	0.21 ± 0.676	0.014 ± 0.567
Change at Day 56 (n=26, 38)	-2.127 ± 0.625	-1.144 ± 0.515

No statistical analyses for this end point

Secondary: Change from Baseline in Blood Biomarker Fibrinogen (Extended Approach)

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End point title

Change from Baseline in Blood Biomarker Fibrinogen (Extended Approach)

End point description

Biomarker Plasma fibrinogen was determined using the method described by Clauss. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	45	46
Units: umol/L
least squares mean (standard error)
Change at Day 7 (n=44, 43)	-3.971 ± 0.246	-3.839 ± 0.244
Change at Day 14 (n=43, 42)	0.051 ± 0.521	-0.148 ± 0.519
Change at Day 28 (n=32, 40)	0.147 ± 0.599	-0.091 ± 0.524
Change at Day 56 (n=31, 42)	-2.155 ± 0.533	-1.162 ± 0.462

No statistical analyses for this end point

Secondary: Change from Baseline in Blood Biomarker Glucose (Initial Approach)

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End point title

Change from Baseline in Blood Biomarker Glucose (Initial Approach)

End point description

Blood was collected and analyzed for serum glucose levels. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	37	43
Units: mmol/L
least squares mean (standard error)
Change at Day 7 (n=37, 41)	1.617 ± 0.426	1.027 ± 0.397
Change at Day 14 (n=33, 41)	1 ± 0.3	0.432 ± 0.27
Change at Day 28 (n=28, 40)	0.067 ± 0.156	-0.02 ± 0.129
Change at Day 56 (n=27, 40)	0.255 ± 0.272	0.226 ± 0.23

No statistical analyses for this end point

Secondary: Change from Baseline in Blood Biomarker Glucose (Extended Approach)

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End point title

Change from Baseline in Blood Biomarker Glucose (Extended Approach)

End point description

Blood was collected and analyzed for serum glucose levels. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	47	47
Units: mmol/L
least squares mean (standard error)
Change at Day 7 (n=46, 45)	1.767 ± 0.408	0.973 ± 0.408
Change at Day 14 (n=42, 45)	0.942 ± 0.254	0.364 ± 0.246
Change at Day 28 (n=33, 44)	0.061 ± 0.139	-0.008 ± 0.119
Change at Day 56 (n=32, 43)	0.189 ± 0.235	0.215 ± 0.21

No statistical analyses for this end point

Secondary: Change from Baseline in Forced Expiratory Volume (FEV1) (Initial Approach)

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End point title

Change from Baseline in Forced Expiratory Volume (FEV1) (Initial Approach)

End point description

FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	37	43
Units: liters
least squares mean (standard error)
Change at Day 7 (n=37, 41)	0.051 ± 0.031	0.01 ± 0.029
Change at Day 14 (n=33, 41)	0.083 ± 0.035	0.028 ± 0.031
Change at Day 28 (n=28, 40)	0.095 ± 0.037	0.001 ± 0.031
Change at Day 56 (n=27, 40)	0.064 ± 0.039	0.01 ± 0.033

No statistical analyses for this end point

Secondary: Change from Baseline in Forced Expiratory Volume (FEV1) (Extended Approach)

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End point title

Change from Baseline in Forced Expiratory Volume (FEV1) (Extended Approach)

End point description

FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	47	47
Units: liters
least squares mean (standard error)
Change at Day 7 (n=47, 45)	0.063 ± 0.027	0.012 ± 0.028
Change at Day 14 (n= 43, 45)	0.062 ± 0.029	0.018 ± 0.029
Change at Day 28 (n=33, 44)	0.084 ± 0.031	-0.003 ± 0.028
Change at Day 56 (n=32, 44)	0.05 ± 0.034	0.005 ± 0.03

No statistical analyses for this end point

Secondary: Change from Baseline in Forced Vital Capacity (FVC) (Initial Approach)

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End point title

Change from Baseline in Forced Vital Capacity (FVC) (Initial Approach)

End point description

Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	37	43
Units: liters
least squares mean (standard error)
Change at Day 7 (n=37, 41)	0.002 ± 0.06	0.057 ± 0.056
Change at Day 14 (n=33, 41)	0.039 ± 0.062	0.166 ± 0.056
Change at Day 28 (n=28, 40)	0.039 ± 0.072	0.075 ± 0.062
Change at Day 56 (n=27, 40)	0.044 ± 0.072	0.086 ± 0.062

No statistical analyses for this end point

Secondary: Change from Baseline in Forced Vital Capacity (FVC) (Extended Approach)

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End point title

Change from Baseline in Forced Vital Capacity (FVC) (Extended Approach)

End point description

Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	47	47
Units: liters
least squares mean (standard error)
Change at Day 7 (n=47, 45)	0.048 ± 0.052	0.062 ± 0.053
Change at Day 14 (n=43, 45)	0.046 ± 0.054	0.146 ± 0.053
Change at Day 28 (n=33, 44)	0.053 ± 0.062	0.067 ± 0.057
Change at Day 56 (n=32, 44)	0.034 ± 0.065	0.084 ± 0.058

No statistical analyses for this end point

Secondary: Change from Baseline in FEV1/FVC (Initial Approach)

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End point title

Change from Baseline in FEV1/FVC (Initial Approach)

End point description

FEV1/FVC is the percentage of the vital capacity which is expired in the first second of maximal expiration. In healthy patients the FEV1/FVC is usually around 70%. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	37	43
Units: percent
least squares mean (standard error)
Change at Day 7 (n=37, 41)	1.575 ± 0.933	-1.064 ± 0.87
Change at Day 14 (n=33, 41)	1.874 ± 1.012	-1.796 ± 0.914
Change at Day 28 (n=28, 40)	2.35 ± 1.138	-1.029 ± 0.982
Change at Day 56 (n=27, 40)	1.636 ± 0.951	-1.669 ± 0.828

No statistical analyses for this end point

Secondary: Change from Baseline in FEV1/FVC (Extended Approach)

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End point title

Change from Baseline in FEV1/FVC (Extended Approach)

End point description

FEV1/FVC is the percentage of the vital capacity which is expired in the first second of maximal expiration. In healthy patients the FEV1/FVC is usually around 70%. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Day 7, Day 14, Day 28 and Day 56

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	47	47
Units: percent
least squares mean (standard error)
Change at Day 7 (n=47, 45)	1.282 ± 0.795	-1.128 ± 0.799
Change at Day 14 (n=43, 45)	1.394 ± 0.85	-1.83 ± 0.834
Change at Day 28 (n=33, 44)	2.045 ± 0.974	-1.198 ± 0.888
Change at Day 56 (n=32, 44)	1.393 ± 0.827	-1.881 ± 0.765

No statistical analyses for this end point

Secondary: Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Initial Approach)

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End point title

Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Initial Approach)

End point description

The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients’ health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient’s wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst). Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: score on a scale
arithmetic mean (standard deviation)
Week 1 (n=27, 34)	19.4 ± 6.65	19.2 ± 7.2
Week 2 (n=28, 36)	17.1 ± 7.86	17.1 ± 7.48
Week 3 (n=24, 37)	15.9 ± 7.84	16 ± 7.9
Week 4 (n=23, 38)	15.1 ± 7.85	15.8 ± 8.42
Week 5 (n=21, 37)	14.2 ± 7.41	14.9 ± 8.04
Week 6 (n=19, 37)	12.9 ± 6.85	15.4 ± 8.23
Week 7 (n=20, 33)	13.9 ± 8.93	14.7 ± 8.48
Week 8 (n=18, 30)	12.8 ± 7.85	15.6 ± 8.25

No statistical analyses for this end point

Secondary: Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Extended Approach)

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End point title

Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Extended Approach)

End point description

The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients’ health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient’s wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst). Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: score on a scale
arithmetic mean (standard deviation)
Week 1 (n=37, 38)	20.4 ± 7.26	19.3 ± 7.03
Week 2 (n=37, 40)	18.2 ± 8.54	17.2 ± 7.32
Week 3 (n=29, 41)	16.2 ± 8.08	16.1 ± 7.73
Week 4 (n=27, 42)	16 ± 8.21	15.9 ± 8.26
Week 5 (n=25, 41)	14 ± 7.28	15.1 ± 7.93
Week 6 (n=23, 41)	12.9 ± 6.58	15.4 ± 8.12
Week 7 (n=24, 37)	13.5 ± 8.38	14.8 ± 8.44
Week 8 (n=19, 30)	13 ± 7.68	15.6 ± 8.25

No statistical analyses for this end point

Secondary: Change from Stable State in Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Initial Approach)

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End point title

Change from Stable State in Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Initial Approach)

End point description

The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients’ health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient’s wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst). A negative change from Baseline indicates improvement. Covariates for MMRM are stable state value, treatment, time point, and treatment by time point interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: score on a scale
least squares mean (standard error)
Change at Week 1 (n=27, 34)	6.448 ± 1.503	2.695 ± 1.096
Change at Week 2 (n=28, 36)	3.778 ± 1.239	0.804 ± 0.911
Change at Week 3 (n=24, 37)	2.002 ± 0.915	0.278 ± 0.669
Change at Week 4 (n=23, 38)	0.559 ± 0.739	0.277 ± 0.536
Change at Week 5 (n=21, 37)	-0.412 ± 0.613	-0.392 ± 0.448
Change at Week 6 (n=19, 37)	-0.924 ± 0.411	-0.062 ± 0.297
Change at Week 7 (n=20, 33)	-0.228 ± 0.342	0.048 ± 0.253
Change at Week 8 (n=18, 30)	0.002 ± 0.059	-0.048 ± 0.044

No statistical analyses for this end point

Secondary: Change From Stable State in Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Extended Approach)

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End point title

Change From Stable State in Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Extended Approach)

End point description

The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients' health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient's wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst). A negative change from Baseline indicates improvement. Covariates for MMRM are stable state value, treatment, time point, and treatment by time point interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: scores on a scale
least squares mean (standard error)
Week 1 (n=37, 38)	6.232 ± 1.424	3.009 ± 1.052
Week 2 (n=37, 40)	3.558 ± 1.178	1.074 ± 0.876
Week 3 (n=29, 41)	2.044 ± 0.847	0.458 ± 0.627
Week 4 (n=27, 42)	0.545 ± 0.732	0.429 ± 0.534
Week 5 (n=25, 41)	-0.347 ± 0.621	-0.17 ± 0.459
Week 6 (n=23, 41)	-0.668 ± 0.402	-0.043 ± 0.295
Week 7 (n=24, 37)	-0.121 ± 0.31	0.014 ± 0.232
Week 8 (n=19, 30)	-0.01 ± 0.061	-0.031 ± 0.045

No statistical analyses for this end point

Secondary: Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Initial Approach)

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End point title

Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Initial Approach)

End point description

End point type

Secondary

End point timeframe

Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: score on a scale
arithmetic mean (standard deviation)
Week 1 (n=25, 35)	45.2 ± 8.54	45.1 ± 8.5
Week 2 (n=28, 36)	41.2 ± 11.39	42.4 ± 9.07
Week 3 (n=24, 38)	38.8 ± 11.22	40 ± 10.22
Week 4 (n=23, 38)	38.3 ± 11	40.2 ± 11.26
Week 5 (n=21, 37)	35.9 ± 11.11	39.1 ± 10.55
Week 6 (n=19, 37)	35.1 ± 9.75	39.4 ± 11.05
Week 7 (n=20, 34)	35.6 ± 13.69	38.7 ± 12.05
Week 8 (n=18, 32)	34.4 ± 11.5	39.4 ± 11.34

No statistical analyses for this end point

Secondary: Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Extended Approach)

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End point title

Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Extended Approach)

End point description

The EXACT-PRO questionnaire is a new, validated, and standardized measure to evaluate the frequency, severity, and duration of COPD exacerbations. It is a 14-item daily diary, and scores range from 0 to 100, with higher scores indicating worse health status. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: score on a scale
arithmetic mean (standard deviation)
Week 1 (n=35, 39)	45.6 ± 9.19	45 ± 8.39
Week 2 (n=37, 40)	42 ± 11.07	42.3 ± 8.81
Week 3 (n=29, 42)	39 ± 11.27	39.9 ± 9.82
Week 4 (n=27, 42)	38.8 ± 11.37	40.3 ± 10.9
Week 5 (n=25, 41)	35.3 ± 11.03	39.1 ± 10.13
Week 6 (n=23, 41)	33.9 ± 10.45	39.4 ± 10.62
Week 7 (n=24, 38)	34.3 ± 13.09	38.7 ± 11.52
Week 8 (n=19, 33)	34 ± 11.3	39.6 ± 11.25

No statistical analyses for this end point

Secondary: Change from Stable State in Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Initial Approach)

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End point title

Change from Stable State in Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Initial Approach)

End point description

The EXACT-PRO questionnaire is a new, validated, and standardized measure to evaluate the frequency, severity, and duration of COPD exacerbations. It is a 14-item daily diary, and scores range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, time point, treatment by time point and baseline by time point interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: score on a scale
least squares mean (standard error)
Change at Week 1 (n=25, 35)	6.182 ± 3.271	4.753 ± 2.385
Change at Week 2 (n=28, 36)	4.423 ± 2.538	1.558 ± 1.864
Change at Week 3 (n=24, 38)	2.08 ± 2.041	0.317 ± 1.494
Change at Week 4 (n=23, 38)	0.002 ± 2.003	0.657 ± 1.459
Change at Week 5 (n=21, 37)	-1.058 ± 1.748	-0.307 ± 1.276
Change at Week 6 (n=19, 37)	-1.688 ± 1.015	-0.002 ± 0.738
Change at Week 7 (n=20, 34)	-0.773 ± 0.698	0.002 ± 0.514
Change at Week 8 (n=18, 32)	-0.19 ± 0.259	-0.154 ± 0.191

No statistical analyses for this end point

Secondary: Change From Stable State in Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Extended Approach)

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End point title

Change From Stable State in Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Extended Approach)

End point description

The EXACT-PRO questionnaire is a new, validated, and standardized measure to evaluate the frequency, severity, and duration of COPD exacerbations. It is a 14-item daily diary, and scores range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, time point, treatment by time point and baseline by time point interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: score on a scale
least squares mean (standard error)
Week 1 (n=35, 39)	7.163 ± 2.859	4.697 ± 2.077
Week 2 (n=37, 40)	4.839 ± 2.259	1.433 ± 1.652
Week 3 (n=29, 42)	2.988 ± 1.87	0.179 ± 1.363
Week 4 (n=27, 42)	0.909 ± 1.861	0.743 ± 1.344
Week 5 (n=25, 41)	-0.657 ± 1.554	-0.318 ± 1.129
Week 6 (n=23, 41)	-0.889 ± 0.976	-0.14 ± 0.706
Week 7 (n=24, 38)	-0.311 ± 0.654	-0.075 ± 0.479
Week 8 9n=19, 33)	-0.24 ± 0.244	-0.115 ± 0.178

No statistical analyses for this end point

Secondary: Change from Stable State in Diaries Peak Expiratory Flow (PEF) Weekly Average (Initial Approach)

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End point title

Change from Stable State in Diaries Peak Expiratory Flow (PEF) Weekly Average (Initial Approach)

End point description

Morning post-medication PEF (the best of 3 attempts measured with a mini-Wright peak-flow meter) was recorded in a daily diary. A positive change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: liters/minute
least squares mean (standard error)
Change at Week 1 (n=37, 38)	-16.551 ± 5.144	-9.915 ± 4.442
Change at Week 2 (n=35, 40)	-6.067 ± 4.564	-0.304 ± 3.899
Change at Week 3 (n=35, 40)	-4.996 ± 3.914	0.687 ± 3.36
Change at Week 4 (n=29, 39)	-4.595 ± 3.421	-0.42 ± 2.737
Change at Week 5 (n=28, 38)	-3.557 ± 4.061	-1.224 ± 3.287
Change at Week 6 (n=27, 37)	-3.795 ± 4.546	-5.559 ± 3.68
Change at Week 7 (n=27, 36)	-7.178 ± 5.212	-4.186 ± 4.264
Change at Week 8 (n=27, 35)	-2.887 ± 5.388	-0.956 ± 4.418

No statistical analyses for this end point

Secondary: Change from Stable State in Diaries Peak Expiratory Flow (PEF) Weekly Average (Extended Approach)

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End point title

Change from Stable State in Diaries Peak Expiratory Flow (PEF) Weekly Average (Extended Approach)

End point description

Morning post-medication PEF (the best of 3 attempts measured with a mini-Wright peak-flow meter) was recorded in a daily diary. A positive change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: liters/minute
least squares mean (standard error)
Change at Week 1 (n=46, 42)	-13.958 ± 4.147	-8.447 ± 3.865
Change at Week 2 (n=44, 44)	-5.776 ± 3.772	1.029 ± 3.488
Change at Week 3 (n=44, 44)	-5.36 ± 3.676	2.038 ± 3.421
Change at Week 4 (n=37, 43)	-6.66 ± 3.546	1.133 ± 3.126
Change at Week 5 (n=33, 42)	-5.568 ± 3.847	0.269 ± 3.396
Change at Week 6 (n=32, 41)	-2.186 ± 3.515	-4.596 ± 3.076
Change at Week 7 (n=31, 40)	-8.513 ± 4.544	-1.974 ± 3.952
Change at Week 8 (n=31, 39)	-4.563 ± 4.741	0.95 ± 4.091

No statistical analyses for this end point

Secondary: Change from Stable State in Diaries Symptom Score Weekly Average (Initial Approach)

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End point title

Change from Stable State in Diaries Symptom Score Weekly Average (Initial Approach)

End point description

Any increase in the following respiratory symptoms: dyspnea, sputum purulence, sputum amount, wheeze, sore throat, cough, fever, symptoms of a common cold, ie, nasal congestion and discharge over the previous 24 hours were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: score on a scale
least squares mean (standard error)
Change at Week 1 (n=38, 42)	2.93 ± 0.286	2.587 ± 0.254
Change at Week 2 (n=37, 42)	1.13 ± 0.314	1.331 ± 0.272
Change at Week 3 (n=35, 42)	0.906 ± 0.299	0.79 ± 0.258
Change at Week 4 (n=30, 40)	0.552 ± 0.298	0.922 ± 0.248
Change at Week 5 (n=29, 39)	0.413 ± 0.305	0.882 ± 0.254
Change at Week 6 (n=28, 39)	0.141 ± 0.31	0.681 ± 0.258
Change at Week 7 (n=27, 37)	0.442 ± 0.0294	0.673 ± 0.243
Change at Week 8 (n=27, 36)	0.626 ± 0.361	0.612 ± 0.297

No statistical analyses for this end point

Secondary: Change from Stable State in Diaries Symptom Score Weekly Average (Extended Approach)

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End point title

Change from Stable State in Diaries Symptom Score Weekly Average (Extended Approach)

End point description

Any increase in the following respiratory symptoms: dyspnea, sputum purulence, sputum amount, wheeze, sore throat, cough, fever, symptoms of a common cold, ie, nasal congestion and discharge over the previous 24 hours were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: score on a scale
least squares mean (standard error)
Change at Week 1 (n=48, 46)	3.11 ± 0.257	2.593 ± 0.246
Change at Week 2 (n=47, 46)	1.171 ± 0.285	1.402 ± 0.267
Change at Week 3 (n=44, 46)	0.85 ± 0.267	0.802 ± 0.25
Change at Week 4 (n=38, 44)	0.751 ± 0.312	0.924 ± 0.282
Change at Week 5 (n=34, 43)	0.437 ± 0.287	0.907 ± 0.259
Change at Week 6 (n=33, 43)	0.041 ± 0.257	0.661 ± 0.231
Change at Week 7 (n=31, 41)	0.503 ± 0.247	0.533 ± 0.216
Change at Week 8 (n=31, 40)	0.451 ± 0.274	0.53 ± 0.237

No statistical analyses for this end point

Secondary: Change from Stable State in Diaries Treatment Score Weekly Average (Initial Approach)

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End point title

Change from Stable State in Diaries Treatment Score Weekly Average (Initial Approach)

End point description

Any changes in the participant’s usual treatment were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: score on a scale
least squares mean (standard error)
Change at Week 1 (n=38, 42)	0.849 ± 0.194	0.769 ± 0.174
Change at Week 2 (n=37, 42)	0.682 ± 0.19	0.804 ± 0.167
Change at Week 3 (n=35, 42)	0.281 ± 0.115	0.188 ± 0.099
Change at Week 4 (n=30, 40)	0.185 ± 0.118	0.217 ± 0.099
Change at Week 5 (n=29, 39)	0.13 ± 0.123	0.263 ± 0.103
Change at Week 6 (n=28, 39)	0.128 ± 0.13	0.204 ± 0.108
Change at Week 7 (n=27, 37)	0.112 ± 0.117	0.135 ± 0.097
Change at Week 8 (n=27, 36)	0.122 ± 0.101	0.127 ± 0.084

No statistical analyses for this end point

Secondary: Change from Stable State in Diaries Treatment Score Weekly Average (Extended Approach)

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End point title

Change from Stable State in Diaries Treatment Score Weekly Average (Extended Approach)

End point description

Any changes in the participant’s usual treatment were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: score on a scale
least squares mean (standard error)
Change at Week 1 (n=48, 46)	0.787 ± 0.17	0.73 ± 0.162
Change at Week 2 (n=47, 46)	0.767 ± 0.172	0.78 ± 0.161
Change at Week 3 (n=44, 46)	0.338 ± 0.103	0.177 ± 0.095
Change at Week 4 (n=38, 44)	0.379 ± 0.144	0.206 ± 0.129
Change at Week 5 (n=34, 43)	0.191 ± 0.107	0.244 ± 0.096
Change at Week 6 (n=33, 43)	0.127 ± 0.107	0.196 ± 0.096
Change at Week 7 (n=31, 41)	0.179 ± 0.116	0.156 ± 0.103
Change at Week 8 (n=31, 40)	0.084 ± 0.086	0.171 ± 0.075

No statistical analyses for this end point

Secondary: Change from Stable State in Diaries Hours Out of the Home Weekly Average (Initial Approach)

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End point title

Change from Stable State in Diaries Hours Out of the Home Weekly Average (Initial Approach)

End point description

Estimates of the length of time the participants were out of their own home on the previous day were recorded in a daily diary. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: hours
least squares mean (standard error)
Change at Week 1 (n=34, 34)	-1.313 ± 0.416	-0.105 ± 0.391
Change at Week 2 (n=34, 38)	-0.974 ± 0.359	-0.328 ± 0.333
Change at Week 3 (n=34, 40)	-1.077 ± 0.374	0.226 ± 0.335
Change at Week 4 (n=28, 39)	-1.131 ± 0.414	-0.306 ± 0.354
Change at Week 5 (n=26, 38)	-0.826 ± 0.465	0.28 ± 0.407
Change at Week 6 (n=25, 35)	-1.154 ± 0.448	-0.062 ± 0.386
Change at Week 7 (n=26, 35)	-1.194 ± 0.449	-0.34 ± 0.394
Change at Week 8 (n=26, 34)	-0.812 ± 0.532	0.037 ± 0.458

No statistical analyses for this end point

Secondary: Change from Stable State in Diaries Hours Out of the Home Weekly Average (Extended Approach)

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End point title

Change from Stable State in Diaries Hours Out of the Home Weekly Average (Extended Approach)

End point description

Estimates of the length of time the participants were out of their own home on the previous day were recorded in a daily diary. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: hours
least squares mean (standard error)
Change at Week 1 (n=42, 38)	-1.472 ± 0.353	-0.276 ± 0.344
Change at Week 2 (n=43, 42)	-1.305 ± 0.319	-0.472 ± 0.307
Change at Week 3 (n=42, 44)	-1.314 ± 0.343	0.099 ± 0.0324
Change at Week 4 (n=35, 43)	-1.328 ± 0.357	-0.266 ± 0.325
Change at Week 5 (n=31, 42)	-0.833 ± 0.402	0.158 ± 0.369
Change at Week 6 (n=30, 39)	-1.271 ± 0.372	-0.247 ± 0.344
Change at Week 7 (n=30, 39)	-1144 ± 0.363	-0.478 ± 0.333
Change at Week 8 (n=30, 38)	-0.714 ± 0.433	-0.068 ± 0.401

No statistical analyses for this end point

Secondary: Exacerbation Length (Initial Approach)

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End point title

Exacerbation Length (Initial Approach)

End point description

Exacerbation length is the period from start of increased symptoms to end of increased symptoms; the last day of an exacerbation was to be followed by 2 days without symptom entries in the diary. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

8 Weeks

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	38	43
Units: days
median (confidence interval 95%)	12 (8 to 18)	14 (10 to 17)

No statistical analyses for this end point

Secondary: Exacerbation Length (Extended Approach)

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End point title

Exacerbation Length (Extended Approach)

End point description

Exacerbation length is the period from start of increased symptoms to end of increased symptoms; the last day of an exacerbation was to be followed by 2 days without symptom entries in the diary. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

8 Weeks

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	48	47
Units: days
median (confidence interval 95%)	13 (9 to 19)	14 (11 to 17)

No statistical analyses for this end point

Secondary: Change from Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Initial Approach)

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End point title

Change from Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Initial Approach)

End point description

Carotid-femoral aortic pulse wave velocity (aPWV) will be measured in a subset of participants to determine changes in arterial stiffness. A negative change from Baseline indicates improvement. Covariates for MMRM are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

End point type

Secondary

End point timeframe

Baseline and Days 14 and 28

End point values	Roflumilast 500 μg	Placebo
Number of subjects analysed	24	28
Units: meters/second
least squares mean (standard error)
Change at Day 14 (n=18, 24)	-0.047 ± 0.337	-0.343 ± 0.29
Change at Day 28 (n=14, 24)	-0.38 ± 0.413	-0.474 ± 0.321

No statistical analyses for this end point

Secondary: Change from Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Extended Approach)

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End point title

Change from Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Extended Approach)

End point description

Carotid-femoral aortic pulse wave velocity (aPWV) will be measured in a subset of participants to determine changes in arterial stiffness. A negative change from Baseline indicates improvement. Covariates for MMRM are baseline value, treatment, visit, and treatment by visit interaction. Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

End point type

Secondary

End point timeframe

Baseline and Days 14 and 28

End point values	Roflumilast 500 µg	Placebo
Number of subjects analysed	34	32
Units: meters/second
least squares mean (standard error)
Change at Day 14 (n=28, 28)	-0.128 ± 0.247	-0.326 ± 0.245
Change at Day 28 (n=19, 28)	-0.316 ± 0.323	-0.511 ± 0.273

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Signing of informed consent until Follow-up Visit (Up to 56 days)

Adverse event reporting additional description

AEs were analyzed using an Initial Approach (all patients treated in Cycle 1) and an Extended Approach (all patients treated in Cycle 1 and patients re-randomized and treated in Cycle 2). The data from the 2 approaches are entered in one table. Please note: a result of 0 corresponds to no patients with AEs for the preferred term > the 5% threshold.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Roflumilast 500 μg (Initial Approach)

Reporting group description

Roflumilast 500 µg tablet, once daily, orally in the morning after breakfast added on to standard therapy for acute COPD exacerbations. Initial Approach Arm includes all participants who received treatment in Cycle 1.

Reporting group title

Placebo (Initial Approach)

Reporting group description

Placebo matching roflumilast tablet, once daily, orally in the morning after breakfast added on to standard therapy for acute COPD exacerbations. Initial Approach Arm includes all participants who received treatment in Cycle 1.

Reporting group title

Roflumilast 500 µg (Extended Approach)

Reporting group description

Roflumilast 500 µg tablet, once daily, orally in the morning after breakfast added on to standard therapy for acute COPD exacerbations. Extended Approach Arm includes all participants who received treatment in Cycle 1 and those participants who were re-randomized and received treatment in Cycle 2.

Reporting group title

Placebo (Extended Approach)

Reporting group description

Placebo matching roflumilast tablet, once daily, orally in the morning after breakfast added on to standard therapy for acute COPD exacerbations. Extended Approach Arm includes all participants who received treatment in Cycle 1 and those participants who were re-randomized and received treatment in Cycle 2.

Serious adverse events	Roflumilast 500 μg (Initial Approach)	Placebo (Initial Approach)	Roflumilast 500 µg (Extended Approach)	Placebo (Extended Approach)
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 38 (10.53%)	1 / 43 (2.33%)	4 / 48 (8.33%)	1 / 47 (2.13%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events
Cardiac disorders
Supraventricular tachycardia
subjects affected / exposed	1 / 38 (2.63%)	0 / 43 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 38 (2.63%)	0 / 43 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 38 (0.00%)	1 / 43 (2.33%)	0 / 48 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 38 (2.63%)	0 / 43 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 38 (2.63%)	0 / 43 (0.00%)	1 / 48 (2.08%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Roflumilast 500 μg (Initial Approach)	Placebo (Initial Approach)	Roflumilast 500 µg (Extended Approach)	Placebo (Extended Approach)
Total subjects affected by non serious adverse events
subjects affected / exposed	35 / 38 (92.11%)	25 / 43 (58.14%)	44 / 48 (91.67%)	28 / 47 (59.57%)
Nervous system disorders
Dizziness
subjects affected / exposed	6 / 38 (15.79%)	1 / 43 (2.33%)	6 / 48 (12.50%)	1 / 47 (2.13%)
occurrences all number	6	1	6	1
Headache
subjects affected / exposed	3 / 38 (7.89%)	2 / 43 (4.65%)	4 / 48 (8.33%)	2 / 47 (4.26%)
occurrences all number	3	2	4	2
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 38 (5.26%)	1 / 43 (2.33%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	1	0	0
Diarrhoea
subjects affected / exposed	25 / 38 (65.79%)	10 / 43 (23.26%)	32 / 48 (66.67%)	11 / 47 (23.40%)
occurrences all number	27	10	34	11
Flatulence
subjects affected / exposed	2 / 38 (5.26%)	0 / 43 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 38 (5.26%)	1 / 43 (2.33%)	3 / 48 (6.25%)	1 / 47 (2.13%)
occurrences all number	2	1	3	1
Nausea
subjects affected / exposed	6 / 38 (15.79%)	3 / 43 (6.98%)	9 / 48 (18.75%)	3 / 47 (6.38%)
occurrences all number	6	3	9	3
Vomiting
subjects affected / exposed	0 / 38 (0.00%)	0 / 43 (0.00%)	3 / 48 (6.25%)	1 / 47 (2.13%)
occurrences all number	0	0	3	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	17 / 38 (44.74%)	13 / 43 (30.23%)	19 / 48 (39.58%)	15 / 47 (31.91%)
occurrences all number	17	14	20	16
Psychiatric disorders
Insomnia
subjects affected / exposed	12 / 38 (31.58%)	2 / 43 (4.65%)	14 / 48 (29.17%)	2 / 47 (4.26%)
occurrences all number	12	2	14	2
Musculoskeletal and connective tissue disorders
Muscle spasms
subjects affected / exposed	2 / 38 (5.26%)	0 / 43 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0
Infections and infestations
Cellulitis
subjects affected / exposed	2 / 38 (5.26%)	0 / 43 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0
Oral candidiasis
subjects affected / exposed	2 / 38 (5.26%)	0 / 43 (0.00%)	0 / 48 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	4 / 38 (10.53%)	2 / 43 (4.65%)	6 / 48 (12.50%)	2 / 47 (4.26%)
occurrences all number	4	2	6	2

More information

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Were there any global substantial amendments to the protocol? Yes

28 Nov 2011

• Oxygen therapy (less than 8 hours daily) was added as allowed concomitant medication in Section 6.8 of the protocol at the request of the Research Ethics Committee. Exclusion criterion E6 ‘Oxygen therapy (more than 8 hours daily)’ remained unchanged, because patients who received home oxygen therapy (more than 8 hours daily) were to be excluded due to possible severe hypoxemia during COPD exacerbation.

16 May 2012

• A further objective to investigate the effect of roflumilast on changes in arterial stiffness during recovery from an exacerbation was added. Changes in arterial stiffness from Visit V0 to Visit V2 and Visit V3 were to be measured in a subset of 60 patients by aPWV. A separate patient information sheet and IC were to be signed by patients in this subset. Arterial stiffness has been shown to increase in COPD patients from stable state to exacerbation presentation and remain elevated during the recovery period of the acute exacerbation. As arterial stiffness is a validated measure of cardiovascular risk, and roflumilast is associated with a lower risk of major adverse cardiovascular events, the addition of arterial stiffness measurement was intended to enable exploration of a potential anti-inflammatory effect of roflumilast. • Additional information on standard antibiotic exacerbation treatment was added to include use of antibiotics other than penicillin and clarithromycin in case of allergy or intolerance of these antibiotics. • Additional laboratory parameters were added for standard clinical hematology, coagulation, blood chemistry, and endocrinology tests (erythrocyte mean cell volume, mean cell hemoglobin, and mean cell hemoglobin concentration, prothrombin time, prothrombin time/international normalized ratio, activated partial thromboplastin time, fibrinogen, serum urea, estimated glomerular filtration rate, serum albumin, adjusted serum calcium, inorganic blood phosphate, total cholesterol:high density lipoprotein ratio, serum C reactive protein, serum troponin T, and NT-proBNP). These were to provide additional information on the health status of each patient. Troponin T and NT-proBNP are biomarkers for cardiovascular disease and were of interest for the added arterial stiffness measurements.

16 May 2012

• Additional planned statistical analyses were added: aPWV was to be analyzed by MMRM with change from Visit V0 to Visit V2 and Visit V3 as the dependent variable, and the Visit V0 value, treatment indicator, scheduled visit, and treatment-by-visit interaction as independent variables; serum troponin T and NT-proBNP were to be analyzed by ANCOVA with change from Visit V0 to Visit V3 as the dependent variable, and the Visit V0 value and the treatment group as independent variables.

02 Nov 2012

• The potential ADR ‘angioedema’ was added to the description of the IMP based on a cumulative review of post-marketing reports in which rare (≥1/10,000 to <1/1,000) cases of angioedema were noted with roflumilast in COPD studies (Updated in accordance with IB V6e, 05 October 2012) • The exclusion criterion E6 ‘Oxygen therapy (more than 8 hours daily)’ was removed because new data were available on the tolerability and safety of roflumilast, indicating that roflumilast could be used in patients with more severe COPD, ie, patients who required long-term oxygen therapy. This information was obtained from the 38 patients randomized in the trial to this point: only 2 withdrawals due to tolerability had occurred, and these were related to insomnia and diarrhea. Allowed concomitant medication ‘oxygen therapy (less than 8 hours daily)’ was updated to ‘oxygen therapy’.

23 Nov 2012

• As a consequence of the merger of Nycomed GmbH with Takeda Pharmaceutical Company Ltd. on 31 October 2011, the sponsor of the trial changed in name and legal entity to Takeda Pharma A/S (Denmark).

28 Aug 2013

• The recruitment period was extended to 2 years. • Exclusion criterion E21 was changed: patients previously enrolled in the trial were allowed to re-enroll with a new exacerbation, provided they had reached a stable disease status since completing the first cycle of trial treatment. Patients with recurrent exacerbations within 8 weeks of a previous exacerbation, and hence unstable disease, could not be re-enrolled. • A new approach to the statistical analyses was introduced, to reflect the change to exclusion criterion E21: the primary and confirmatory analyses were to be performed as originally planned, using the data from patients’ first cycle of trial treatment only; all analyses were to be repeated in an exploratory manner including data from both the first cycle and, for re-enrolled patients, the second cycle, and treating re-enrolled patients as if they were new patients. • Storage conditions were specified: IMP was to be stored below 30°

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
16 Apr 2014	Study was terminated due to difficulty in identifying further eligible patients for this exploratory study within a reasonable time.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Effect of Roflumilast 500 μg Tablets Once Daily at Acute COPD Exacerbations Treated With Standard Therapy of Oral Steroids and Antibiotics. A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Initial Approach)

Primary: Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Initial Approach)

Primary: Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Extended Approach)

Primary: Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Extended Approach)

Secondary: Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Initial Approach)

Secondary: Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Initial Approach)

Secondary: Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Extended Approach)

Secondary: Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Total Cells (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Total Cells (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Total Cells (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Total Cells (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Neutrophils (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Neutrophils (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Neutrophils (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Neutrophils (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Macrophages (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Macrophages (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Macrophages (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Macrophages (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Eosinophils (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Eosinophils (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Eosinophils (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Eosinophils (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Lymphocyte (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Lymphocyte (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Lymphocytes (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Percentage of Lymphocytes (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Neutrophil Elastase (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Neutrophil Elastase (Initial Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Neutrophil Elastase (Extended Approach)

Secondary: Change from Baseline in Sputum Marker Concentration of Neutrophil Elastase (Extended Approach)

Secondary: Change from Baseline in Blood Biomarker Interleukin (IL)-6 (Initial Approach)

Secondary: Change from Baseline in Blood Biomarker Interleukin (IL)-6 (Initial Approach)

Secondary: Change from Baseline in Blood Biomarker Interleukin (IL)-6 (Extended Approach)

Secondary: Change from Baseline in Blood Biomarker Interleukin (IL)-6 (Extended Approach)

Secondary: Change from Baseline in Blood Biomarker Interleukin-1 Beta (IL-1β) (Initial Approach)

Secondary: Change from Baseline in Blood Biomarker Interleukin-1 Beta (IL-1β) (Initial Approach)

Secondary: Change from Baseline in Blood Biomarker IL-1β (Extended Approach)

Secondary: Change from Baseline in Blood Biomarker IL-1β (Extended Approach)

Secondary: Change from Baseline in Blood Biomarker C-reactive protein (CRP) (Initial Approach)

Secondary: Change from Baseline in Blood Biomarker C-reactive protein (CRP) (Initial Approach)

Secondary: Change from Baseline in Blood Biomarker C-reactive protein (CRP) (Extended Approach)

Secondary: Change from Baseline in Blood Biomarker C-reactive protein (CRP) (Extended Approach)

Secondary: Change from Baseline in Blood Biomarker Fibrinogen (Initial Approach)

Secondary: Change from Baseline in Blood Biomarker Fibrinogen (Initial Approach)

Secondary: Change from Baseline in Blood Biomarker Fibrinogen (Extended Approach)

Secondary: Change from Baseline in Blood Biomarker Fibrinogen (Extended Approach)

Secondary: Change from Baseline in Blood Biomarker Glucose (Initial Approach)

Secondary: Change from Baseline in Blood Biomarker Glucose (Initial Approach)

Secondary: Change from Baseline in Blood Biomarker Glucose (Extended Approach)

Secondary: Change from Baseline in Blood Biomarker Glucose (Extended Approach)

Secondary: Change from Baseline in Forced Expiratory Volume (FEV1) (Initial Approach)

Secondary: Change from Baseline in Forced Expiratory Volume (FEV1) (Initial Approach)

Secondary: Change from Baseline in Forced Expiratory Volume (FEV1) (Extended Approach)

Secondary: Change from Baseline in Forced Expiratory Volume (FEV1) (Extended Approach)

Secondary: Change from Baseline in Forced Vital Capacity (FVC) (Initial Approach)

Secondary: Change from Baseline in Forced Vital Capacity (FVC) (Initial Approach)

Clinical Trial Results:
Effect of Roflumilast 500 μg Tablets Once Daily at Acute COPD Exacerbations Treated With Standard Therapy of Oral Steroids and Antibiotics. A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial