A chronic obstructive pulmonary disease (COPD) trial investigating roflumilast on safety and effectiveness in China, Hong Kong and Singapore: - ACROSS

Study identifier:RO-2455-301-RD

ClinicalTrials.gov identifier:NCT01313494

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A 6-month, double-blind, randomised, multicenter, multinational trial to investigate the effect of 500 µg roflumilast tablets once daily versus placebo on pulmonary function in patients with COPD. The ACROSS Trial

Medical condition

COPD

Phase

Phase 3

Healthy volunteers

Study drug

Roflumilast, Placebo, Salbutamol

Sex

All

Actual Enrollment

626

Study type

Interventional

Age

40 Years - 80 Years

Date

Study Start Date: 01 Mar 2011

Primary Completion Date: 01 May 2012

Study Completion Date: 01 May 2012

Study design

Allocation: Randomized
Endpoint Classification: None
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Sept 2016 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Location

Shanghai, China

Location

Guangzhou, China

Location

Shijiazhuang, China

Location

Hangzhou, China

Location

Chongqing, China

Location

Chengdu, China

Location

Beijing, China

Location

Changsha, China

Arms	Assigned Interventions
Experimental: Roflumilast Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Drug: Roflumilast Roflumilast tablets Drug: Salbutamol Salbutamol (given by MDI and spacer) used as rescue medication on an ass needed basis throughout the trial, and was used for post-bronchodilator spirometry tests at all study visits.
Placebo Comparator: Placebo Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.	Drug: Placebo Placebo tablets Drug: Salbutamol Salbutamol (given by MDI and spacer) used as rescue medication on an ass needed basis throughout the trial, and was used for post-bronchodilator spirometry tests at all study visits.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants took part in the study at 43 investigative sites in mainland China, Hong Kong and Singapore from 04 Mar 2011 to 16 May 2012.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants with a diagnosis of chronic obstructive pulmonary disease (COPD) were randomized in 1 of 2 treatment groups (placebo and roflumilast 500 μg once daily).

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Participant Flow: Overall Study

	Roflumilast	Placebo
STARTED	313	313
Safety Set	315^[1]	311^[2]
COMPLETED	246	263
NOT COMPLETED	67	50

[1]	2 patients in the placebo arm were misallocated and may have received roflumilast in error.
[2]	2 patients in the placebo arm were misallocated and may have received roflumilast in error.

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Baseline Measures

	Roflumilast	Placebo	Total
Number of Participants [units: Participants]	313	313	626
Age Continuous [units: Years] Mean ± Standard Deviation	64.2 ± 8.76	64.0 ± 8.27	64.1 ± 8.51
Gender, Male/Female [units: Participants]
Female	30	27	57
Male	283	286	569
Race (NIH/OMB) [units: Participants]
American Indian or Alaska Native	0	0	0
Asian	313	313	626
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	0	0
White	0	0	0
More than one race	0	0	0
Unknown or Not Reported	0	0	0
Height [units: cm] Mean ± Standard Deviation	166.2 ± 7.27	165.9 ± 7.12	166.1 ± 7.20
Weight [units: kg] Mean ± Standard Deviation	60.4 ± 11.00	61.8 ± 10.54	61.1 ± 10.78
Body Mass Index (BMI) [units: kg/m^2] Mean ± Standard Deviation	21.8 ± 3.42	22.4 ± 3.43	22.1 ± 3.44
Chronic obstructive pulmonary disease (COPD) severity ^[1] [units: Participants]
Mild	1	1	2
Moderate	28	16	44
Severe	196	204	400
Very severe	88	92	180
COPD disease characteristics [units: Participants]
Predominantly chronic bronchitis	56	61	117
Combined emphysema and chronic bronchitis	217	216	433
Predominantly emphysema	40	36	76
Smoking status [units: Participants]
Former smoker	238	221	459
Current smoker	75	92	167
Cigarette pack years [units: pack years] Mean ± Standard Deviation	37.2 ± 21.18	37.5 ± 23.00	37.4 ± 22.09
Pre-bronchodilator forced expiratory volume in the first second (FEV1) [units: Liters] Mean ± Standard Deviation	0.8 ± 0.31	0.8 ± 0.24	0.8 ± 0.28
Post-bronchodilator FEV1 [units: Liters] Mean ± Standard Deviation	1.0 ± 0.35	0.9 ± 0.27	0.9 ± 0.31
Pre-bronchodilator FEV1 predicted [units: Percent of predicted] Mean ± Standard Deviation	32.7 ± 10.23	32.7 ± 9.00	32.7 ± 9.63
Post-bronchodilator FEV1 predicted [units: Percent of predicted] Mean ± Standard Deviation	36.8 ± 11.42	36.4 ± 10.13	36.6 ± 10.79
FEV1 reversibility increase [units: mL] Mean ± Standard Deviation	108.4 ± 110.83	94.8 ± 104.71	101.6 ± 107.94
FEV1 reversibility % increase ^[2] [units: Percent reversibility] Mean ± Standard Deviation	13.6 ± 15.29	11.8 ± 13.15	12.7 ± 14.27
Post-bronchodilator FEV1/forced vital capacity (FVC) ^[3] [units: FEV1/FVC percent] Mean ± Standard Deviation	35.8 ± 9.69	35.3 ± 8.92	35.5 ± 9.31

Outcome Measures

1. Primary Outcome Measure: Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) [ Time Frame: Baseline to Week 24 ]

Measure Type	Primary
Measure Name	Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)
Measure 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 centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV1, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population included all randomly assigned patients who took at least 1 dose of trial treatment after randomization. Patients were assigned to the treatment group based on the treatment to which they were randomly assigned. Only patients with available data at Baseline and with at least 1 post-baseline measurement are included.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) [units: liters] Least Squares Mean (Standard Error)	0.049 (0.009)	-0.022 (0.009)

Statistical Analysis 1 for Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Repeated measures ANCOVA]
P-Value^[4]	<0.0001
Other^[5]	0.071
Standard Error of the mean	± 0.012
95% Confidence Interval	( 0.046 to 0.095 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The primary endpoint was tested in a confirmatory manner with a 2-sided significance level of 5%.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Independent variables: treatment, baseline value of pre-bronchodilator FEV1, time and a treatment-by-time interaction.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Change from Baseline in Post-bronchodilator FEV1 [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change from Baseline in Post-bronchodilator FEV1
Measure 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 centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV1, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from Baseline in Post-bronchodilator FEV1 [units: liters] Least Squares Mean (Standard Error)	0.045 (0.009)	-0.023 (0.009)

No statistical analysis provided for Change from Baseline in Post-bronchodilator FEV1

3. Secondary Outcome Measure: Change from baseline in Pre-bronchodilator Forced Vital Capacity (FVC) [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Pre-bronchodilator Forced Vital Capacity (FVC)
Measure Description	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 centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Pre-bronchodilator Forced Vital Capacity (FVC) [units: liters] Least Squares Mean (Standard Error)	0.100 (0.017)	-0.009 (0.017)

No statistical analysis provided for Change from baseline in Pre-bronchodilator Forced Vital Capacity (FVC)

4. Secondary Outcome Measure: Change from baseline in Post-bronchodilator Forced Vital Capacity (FVC) [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Post-bronchodilator Forced Vital Capacity (FVC)
Measure Description	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 centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Post-bronchodilator Forced Vital Capacity (FVC) [units: liters] Least Squares Mean (Standard Error)	0.094 (0.017)	-0.007 (0.016)

No statistical analysis provided for Change from baseline in Post-bronchodilator Forced Vital Capacity (FVC)

5. Secondary Outcome Measure: Change from baseline in Pre-bronchodilator Forced expiratory flow 25-75% [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Pre-bronchodilator Forced expiratory flow 25-75%
Measure Description	Forced expiratory flow 25-75% (FEF25-75%) is the flow (or speed) of air coming out of the lung during the middle half of a forced expiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Pre-bronchodilator Forced expiratory flow 25-75% [units: liters/second] Least Squares Mean (Standard Error)	0.023 (0.005)	-0.010 (0.005)

No statistical analysis provided for Change from baseline in Pre-bronchodilator Forced expiratory flow 25-75%

6. Secondary Outcome Measure: Change from baseline in Post-bronchodilator Forced expiratory flow 25-75% [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Post-bronchodilator Forced expiratory flow 25-75%
Measure Description	Forced expiratory flow 25-75% (FEF25-75%) is the flow (or speed) of air coming out of the lung during the middle half of a forced expiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Post-bronchodilator Forced expiratory flow 25-75% [units: liters/second] Least Squares Mean (Standard Error)	0.022 (0.005)	-0.008 (0.005)

No statistical analysis provided for Change from baseline in Post-bronchodilator Forced expiratory flow 25-75%

7. Secondary Outcome Measure: Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3) [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3)
Measure Description	FEV3 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV3, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3) [units: liters] Least Squares Mean (Standard Error)	0.072 (0.012)	-0.030 (0.012)

No statistical analysis provided for Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3)

8. Secondary Outcome Measure: Change from baseline in Post-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3) [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Post-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3)
Measure Description	FEV3 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV3, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Post-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3) [units: liters] Least Squares Mean (Standard Error)	0.064 (0.012)	-0.030 (0.011)

No statistical analysis provided for Change from baseline in Post-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3)

9. Secondary Outcome Measure: Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6) [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6)
Measure Description	FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first six seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV6, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6) [units: liters] Least Squares Mean (Standard Error)	0.084 (0.014)	-0.031 (0.014)

No statistical analysis provided for Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6)

10. Secondary Outcome Measure: Change from baseline in Post-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6) [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Post-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6)
Measure Description	FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV6, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	304
Change from baseline in Post-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6) [units: liters] Least Squares Mean (Standard Error)	0.078 (0.013)	-0.032 (0.013)

No statistical analysis provided for Change from baseline in Post-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6)

11. Secondary Outcome Measure: Change from baseline in Pre-bronchodilator Peak expiratory flow rate (PEF) [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Pre-bronchodilator Peak expiratory flow rate (PEF)
Measure Description	PEF is the maximal flow (or speed) achieved during the maximally forced expiration initiated at full inspiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Pre-bronchodilator Peak expiratory flow rate (PEF) [units: liters/minute] Least Squares Mean (Standard Error)	0.096 (0.027)	-0.036 (0.026)

No statistical analysis provided for Change from baseline in Pre-bronchodilator Peak expiratory flow rate (PEF)

12. Secondary Outcome Measure: Change from baseline in Post-bronchodilator Peak expiratory flow rate (PEF) [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Post-bronchodilator Peak expiratory flow rate (PEF)
Measure Description	PEF is the maximal flow (or speed) achieved during the maximally forced expiration initiated at full inspiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Post-bronchodilator Peak expiratory flow rate (PEF) [units: liters/minute] Least Squares Mean (Standard Error)	0.099 (0.027)	-0.030 (0.027)

No statistical analysis provided for Change from baseline in Post-bronchodilator Peak expiratory flow rate (PEF)

13. Secondary Outcome Measure: Change from baseline in Pre-bronchodilator Ratio of forced expiratory volume after 1 second to forced vital capacity [ Time Frame: Baseline and Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Pre-bronchodilator Ratio of forced expiratory volume after 1 second to forced vital capacity
Measure Description	The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication.
Time Frame	Baseline and Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data; last observation carried forward (LOCF) was used.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Pre-bronchodilator Ratio of forced expiratory volume after 1 second to forced vital capacity [units: percent FEV1/FVC] Median (Full Range)	-0.570 (-14.32 to 28.35)	-1.370 (-19.81 to 27.36)

No statistical analysis provided for Change from baseline in Pre-bronchodilator Ratio of forced expiratory volume after 1 second to forced vital capacity

14. Secondary Outcome Measure: Change from baseline in Post-bronchodilator Ratio of forced expiratory volume after 1 second to forced vital capacity [ Time Frame: Baseline and Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Post-bronchodilator Ratio of forced expiratory volume after 1 second to forced vital capacity
Measure Description	The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol.
Time Frame	Baseline and Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data; last observation carried forward (LOCF) was used.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Post-bronchodilator Ratio of forced expiratory volume after 1 second to forced vital capacity [units: percent FEV1/FVC] Median (Full Range)	-0.320 (-16.38 to 18.30)	-0.940 (-23.53 to 33.77)

No statistical analysis provided for Change from baseline in Post-bronchodilator Ratio of forced expiratory volume after 1 second to forced vital capacity

15. Secondary Outcome Measure: Change from baseline in Pre-bronchodilator Ratio of forced expiratory volume after 1 second to forced expiratory volume after 6 seconds [ Time Frame: Baseline and Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Pre-bronchodilator Ratio of forced expiratory volume after 1 second to forced expiratory volume after 6 seconds
Measure Description	The FEV1/FEV6 ratio represents the percentage of the volume of air expired in the first six seconds that is expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication.
Time Frame	Baseline and Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data; last observation carried forward (LOCF) was used.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	305
Change from baseline in Pre-bronchodilator Ratio of forced expiratory volume after 1 second to forced expiratory volume after 6 seconds [units: percentage of FEV1/FEV6] Median (Full Range)	-0.210 (-14.05 to 27.48)	-0.950 (-17.09 to 21.03)

No statistical analysis provided for Change from baseline in Pre-bronchodilator Ratio of forced expiratory volume after 1 second to forced expiratory volume after 6 seconds

16. Secondary Outcome Measure: Change from baseline in Post-bronchodilator Ratio of forced expiratory volume after 1 second to forced expiratory volume after 6 seconds [ Time Frame: Baseline and Week 24 ]

Measure Type	Secondary
Measure Name	Change from baseline in Post-bronchodilator Ratio of forced expiratory volume after 1 second to forced expiratory volume after 6 seconds
Measure Description	The FEV1/FEV6 ratio represents the percentage of the volume of air expired in the first six seconds that is expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol.
Time Frame	Baseline and Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data; last observation carried forward (LOCF) was used.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	295	304
Change from baseline in Post-bronchodilator Ratio of forced expiratory volume after 1 second to forced expiratory volume after 6 seconds [units: percentage of FEV1/FEV6] Mean (Full Range)	-0.340 (-25.56 to 17.08)	-0.420 (-20.53 to 25.55)

No statistical analysis provided for Change from baseline in Post-bronchodilator Ratio of forced expiratory volume after 1 second to forced expiratory volume after 6 seconds

17. Secondary Outcome Measure: Change From Baseline in COPD Symptom Scores [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change From Baseline in COPD Symptom Scores
Measure Description	Symptoms of chronic bronchitis with respect to cough and sputum production were assessed daily by the patient and recorded in a diary. Symptoms were assessed on a 4-point scale as follows: Cough: 0: no cough; 1: mild cough (at some time during the day); 2: moderate cough (regularly during the day); 3: severe cough (never free of cough or feeling free of need to cough). Sputum production: 0: no sputum production (unnoticeable); 1: mild sputum production (noticeable as a problem); 2: moderate sputum production (frequent inconvenience); 3: severe sputum production (constant problem). Change from Baseline is reported for cough and sputum separately, and for the sum of the 2 scores (range 0 - 6). Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	284	299
Change From Baseline in COPD Symptom Scores [units: units on a scale] Least Squares Mean (Standard Error)
Score Sum (n=282, 296)	0.013 (0.054)	0.064 (0.053)
Cough (n=284, 299)	-0.019 (0.029)	0.036 (0.028)
Sputum (n=284, 296)	0.035 (0.030)	0.037 (0.029)

No statistical analysis provided for Change From Baseline in COPD Symptom Scores

18. Secondary Outcome Measure: Change From Baseline in Use of Rescue Medication [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Change From Baseline in Use of Rescue Medication
Measure Description	Salbutamol (given by metered dose inhaler and spacer) was used as rescue medication according to the individual needs of a patient. Each use was documented in the patient’s paper diary. Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	286	293
Change From Baseline in Use of Rescue Medication [units: puffs/day] Least Squares Mean (Standard Error)	-0.485 (0.134)	-0.518 (0.131)

No statistical analysis provided for Change From Baseline in Use of Rescue Medication

19. Secondary Outcome Measure: Transition Dyspnoea Index (TDI) Total Score at Week 24 [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Transition Dyspnoea Index (TDI) Total Score at Week 24
Measure Description	The TDI is a recognized questionnaire to measure dyspnoea (shortness of breath) in patients with COPD. Questions from the TDI were used to assess the 3 components: "change in functional impairment", "change in magnitude of task" and "change in magnitude of effort". Transitions or changes from baseline are rated from -3 (major deterioration) to +3 (major improvement), and summed to give a total score ranging from -9 to +9. Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time Frame	Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with available data.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	299	305
Transition Dyspnoea Index (TDI) Total Score at Week 24 [units: units on a scale] Least Squares Mean (Standard Error)	1.335 (0.124)	1.396 (0.122)

No statistical analysis provided for Transition Dyspnoea Index (TDI) Total Score at Week 24

20. Secondary Outcome Measure: Percentage of Participants with Moderate or Severe COPD Exacerbations [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Name	Percentage of Participants with Moderate or Severe COPD Exacerbations
Measure Description	A COPD exacerbation is an event characterised by a worsening in the patient’s baseline dyspnoea, or cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management, and may be accompanied by increased wheeze, chest tightness, purulent sputum and symptoms of cold and/or fatigue. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
Time Frame	24 weeks
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	313	313
Percentage of Participants with Moderate or Severe COPD Exacerbations [units: percentage of participants]
No exacerbations	81.8	84.7
One exacerbation	15.0	12.8
Two exacerbations	2.6	1.9
Three exacerbations	0.6	0.6

No statistical analysis provided for Percentage of Participants with Moderate or Severe COPD Exacerbations

21. Secondary Outcome Measure: Mean Rate of Moderate or Severe COPD Exacerbations per Patient per Year [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Name	Mean Rate of Moderate or Severe COPD Exacerbations per Patient per Year
Measure Description	The mean rate of COPD exacerbations per patient per year rate = (number of exacerbations per treatment group/time to study withdrawal per treatment group) * 365. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
Time Frame	24 weeks
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	313	313
Mean Rate of Moderate or Severe COPD Exacerbations per Patient per Year [units: exacerbations per patient per year]	0.55	0.44

No statistical analysis provided for Mean Rate of Moderate or Severe COPD Exacerbations per Patient per Year

22. Secondary Outcome Measure: Time to onset of first moderate or severe COPD exacerbation [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Name	Time to onset of first moderate or severe COPD exacerbation
Measure Description	Time to onset of a COPD exacerbation is defined as onset date of COPD exacerbation – date of first intake of study drug + 1 day. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
Time Frame	24 weeks
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population with at least one moderate or severe exacerbation

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	57	48
Time to onset of first moderate or severe COPD exacerbation [units: days] Median (Full Range)	67.0 (3 to 165)	86.0 (2 to 168)

No statistical analysis provided for Time to onset of first moderate or severe COPD exacerbation

23. Secondary Outcome Measure: Time to Onset of Second Moderate or Severe COPD Exacerbation [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Name	Time to Onset of Second Moderate or Severe COPD Exacerbation
Measure Description	Time to onset of a COPD exacerbation is defined as onset date of COPD exacerbation – date of first intake of study drug + 1 day. At least 10 days between the stop date of an exacerbation and the start date of the following exacerbation was required for these to be be considered as two separate COPD exacerbations. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
Time Frame	24 weeks
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population who experienced a second moderate to severe COPD exacerbation.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	10	8
Time to Onset of Second Moderate or Severe COPD Exacerbation [units: days] Median (Full Range)	119.5 (50 to 166)	117.0 (71 to 163)

No statistical analysis provided for Time to Onset of Second Moderate or Severe COPD Exacerbation

24. Secondary Outcome Measure: Number of participants with adverse events [ Time Frame: 24 weeks ]

Measure Type	Secondary
Measure Name	Number of participants with adverse events
Measure Description	An adverse event (AE) is any untoward medical occurrence in a clinical trial participant regardless of causal relationship to study drug and regardless whether study drug has been administered. A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. A non-serious AE is any AE that does not meet the criteria above. Each AE was assessed by the Investigator as either 'related' or 'not related' to study drug.
Time Frame	24 weeks
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population, all randomized patients who took at least 1 dose of the trial treatment after randomization.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	315	311
Number of participants with adverse events [units: participants]
All AEs	213	196
Non-serious AEs	189	172
Serious AEs (including death)	62	48
Death	2	2
Serious AEs not including death	60	46
AEs with suggested relationship to trial treatment	65	18
AEs leading to withdrawal from the trial	15	2
AEs not recovered at trial termination	54	45
AEs with changes in concomitant medication	164	155

No statistical analysis provided for Number of participants with adverse events

Serious Adverse Events

Time Frame	24 weeks.
Additional Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Serious Adverse Events

Roflumilast

Placebo

Total, serious adverse events

# participants affected / at risk

62/315 (19.68%)

48/311 (15.43%)

Cardiac disorders

Acute myocardial infarction¹,^†

# participants affected / at risk

2/315 (0.63%)

0/311 (0.00%)

Cardiac disorders

Angina unstable¹,^†

# participants affected / at risk

1/315 (0.32%)

1/311 (0.32%)

Cardiac disorders

Cardiac failure¹,^†

# participants affected / at risk

1/315 (0.32%)

1/311 (0.32%)

Cardiac disorders

Cor pulmonale chronic¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Cardiac disorders

Myocardial infarction¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Congenital, familial and genetic disorders

Hydrocele¹,^†

# participants affected / at risk

0/315 (0.00%)

1/311 (0.32%)

Gastrointestinal disorders

Colonic polyp¹,^†

# participants affected / at risk

1/315 (0.32%)

2/311 (0.64%)

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Gastrointestinal disorders

Rectal haemorrhage¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Hepatobiliary disorders

Hepatitis B¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Hepatobiliary disorders

Liver injury¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Infections and infestations

Appendicitis¹,^†

# participants affected / at risk

1/315 (0.32%)

1/311 (0.32%)

Infections and infestations

Herpes zoster infection neurological¹,^†

# participants affected / at risk

0/315 (0.00%)

1/311 (0.32%)

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

2/315 (0.63%)

2/311 (0.64%)

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Injury, poisoning and procedural complications

Laceration¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Injury, poisoning and procedural complications

Thermal burn¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Bladder cancer¹,^†

# participants affected / at risk

0/315 (0.00%)

1/311 (0.32%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Multiple myeloma¹,^†

# participants affected / at risk

0/315 (0.00%)

1/311 (0.32%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Prostate cancer¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Rectal cancer¹,^†

# participants affected / at risk

2/315 (0.63%)

0/311 (0.00%)

Nervous system disorders

Cerebral infarction¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Nervous system disorders

Hypoxic-ischaemic encephalopathy¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Renal and urinary disorders

Nephrolithiasis¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Renal and urinary disorders

Ureteric dilatation¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Reproductive system and breast disorders

Benign prostatic hyperplasia¹,^†

# participants affected / at risk

2/315 (0.63%)

1/311 (0.32%)

Reproductive system and breast disorders

Epididymitis¹,^†

# participants affected / at risk

0/315 (0.00%)

1/311 (0.32%)

Respiratory, thoracic and mediastinal disorders

Acute respiratory failure¹,^†

# participants affected / at risk

0/315 (0.00%)

1/311 (0.32%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

44/315 (13.97%)

39/311 (12.54%)

Respiratory, thoracic and mediastinal disorders

Pneumothorax¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Respiratory, thoracic and mediastinal disorders

Respiratory failure¹,^†

# participants affected / at risk

0/315 (0.00%)

1/311 (0.32%)

Respiratory, thoracic and mediastinal disorders

Vocal cord polyp¹,^†

# participants affected / at risk

1/315 (0.32%)

0/311 (0.00%)

Vascular disorders

Varicose vein¹,^†

# participants affected / at risk

0/315 (0.00%)

1/311 (0.32%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 15.0

Other Adverse Events

Time Frame	24 weeks.
Additional Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Roflumilast	Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.
Placebo	Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

Other Adverse Events

Roflumilast

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

143/315 (45.40%)

133/311 (42.77%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

90/315 (28.57%)

89/311 (28.62%)

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

28/315 (8.89%)

45/311 (14.47%)

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

17/315 (5.40%)

18/311 (5.79%)

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

21/315 (6.67%)

3/311 (0.96%)

Metabolism and nutrition disorders

Decreased appetite¹,^†

# participants affected / at risk

19/315 (6.03%)

2/311 (0.64%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 15.0

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	AstraZeneca Clinical Study Information Center
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

AstraZeneca AstraZeneca

AstraZeneca

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Trial Results Summaries