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 203 investigative sites in Australia, Austria, Belgium, Brazil, Canada, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Korea (Republic of), Netherlands, Poland, Russia, Slovak Republic, South Africa, Spain, Turkey and United Kingdom from 28 May 2011 to 27 May 2014.

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) entered a 4 week baseline period during which all patients received placebo then were enrolled equally in 1 of 2 treatment groups, once a day placebo or roflumilast 500 µg.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Participant Flow: Overall Study

	Roflumilast 500 µg	Placebo
STARTED	973	972
Full Analysis Set (FAS)	969	966
Safety Population	968	967
COMPLETED	704	780
NOT COMPLETED	269	192
Withdrawal by Subject	117	87
Adverse Event	82	29
Death	16	19
Other	14	20
COPD Exacerbation	11	18
Physician Decision	16	13
Lost to Follow-up	8	5
Met Pre-defined Discontinuation Criteria	5	1

Baseline Characteristics

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

Full Analysis Set (FAS) includes all randomised participants who took at least 1 dose of investigational medicinal product (IMP) after randomisation.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Baseline Measures

	Roflumilast 500 µg	Placebo	Total
Number of Participants [units: Participants]	969	966	1935
Age Continuous [units: years] Mean ± Standard Deviation	64.7 ± 8.38	64.7 ± 8.37	64.7 ± 8.37
Age, Customized [units: participants]
≤ 65 years	527	542	1069
> 65 years	442	424	866
Gender, Male/Female [units: participants]
Female	251	241	492
Male	718	725	1443
Race/Ethnicity, Customized [units: participants]
Asian	20	16	36
Black or African American	6	5	11
White	940	943	1883
Other	3	2	5
Region of Enrollment [units: participants]
Australia	9	16	25
Austria	11	3	14
Belgium	19	18	37
Brazil	42	38	80
Canada	14	12	26
Denmark	15	19	34
France	16	13	29
Germany	70	63	133
Greece	38	30	68
Hungary	111	125	236
Israel	114	126	240
Italy	64	51	115
Korea, Republic Of	11	7	18
Netherlands	11	8	19
Poland	88	88	176
Russian Federation	177	181	358
Slovakia	25	33	58
South Africa	23	30	53
Spain	37	33	70
Turkey	52	44	96
United Kingdom	22	28	50
Height [units: cm] Mean ± Standard Deviation	168.20 ± 8.652	168.33 ± 8.198	168.26 ± 8.427
Weight [units: kg] Mean ± Standard Deviation	75.07 ± 17.275	75.60 ± 17.238	75.33 ± 17.254
Body Mass Index (BMI) [units: kg/m^2] Mean ± Standard Deviation	26.45 ± 5.474	26.58 ± 5.359	26.52 ± 5.416
Chronic Obstructive Pulmonary Disease (COPD) Severity ^[1] [units: participants]
Mild	2	0	2
Moderate	18	16	34
Severe	658	677	1335
Very Severe	291	273	564
COPD Disease Characteristics [units: participants]
Pure emphysema	4	2	6
Predominantly chronic bronchitis	338	330	668
Combined emphysema and chronic bronchitis	626	634	1260
Missing	1	0	1
Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group [units: participants]
A : low risk, less symptoms	0	0	0
B: low risk, more symptoms	0	0	0
C: high risk, less symptoms	62	57	119
D: high risk, more symptoms	905	907	1812
Missing	2	2	4
Smoking Status [units: participants]
Current smoker	411	432	843
Former smoker	558	534	1092
Nonsmoker	0	0	0
Cigarette Pack Years ^[2] [units: pack years] Mean ± Standard Deviation	47.6 ± 24.55	47.6 ± 23.56	47.6 ± 24.6
Pre-bronchodilator Forced Expiratory Volume in the First Second (FEV1) ^[3] [units: Liters] Mean ± Standard Deviation	0.999 ± 0.3149	1.016 ± 0.3209	1.008 ± 0.3180
Post-bronchodilator FEV1 [units: Liters] Mean ± Standard Deviation	1.066 ± 0.3317	1.078 ± 0.3244	1.072 ± 0.3280
Pre-bronchodilator FEV1 Predicted ^[4] [units: percent of predicted] Mean ± Standard Deviation	33.259 ± 9.0781	33.562 ± 9.0043	33.411 ± 9.0402
Post-bronchodilator FEV1 Predicted [units: percent predicted] Mean ± Standard Deviation	35.392 ± 9.2484	35.532 ± 8.7573	35.462 ± 9.0045
FEV1 Reversibility % Increase ^[5] [units: percent reversibility] Mean ± Standard Deviation	7.465 ± 11.2559	7.383 ± 12.0752	7.424 ± 11.6703
FEV1 Reversibility Increase ^[6] [units: mL] Mean ± Standard Deviation	65.2 ± 108.72	65.4 ± 121.55	65.3 ± 115.29
Post-bronchodilator FEV1/Forced Vital Capacity (FVC) ^[7] [units: FEV1/FVC percent] Mean ± Standard Deviation	40.2 ± 10.81	40.1 ± 10.26	40.1 ± 10.54

Outcome Measures

1. Primary Outcome Measure: Rate of Moderate or Severe COPD Exacerbations per Patient per Year [ Time Frame: 52 weeks ]

Measure Type	Primary
Measure Name	Rate of Moderate or Severe COPD Exacerbations per Patient per Year
Measure Description	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient’s baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as follows: Severe=Requiring hospitalization and/or leading to death; Moderate=Requiring oral or parenteral glucocorticosteroid therapy. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Rate of Moderate or Severe COPD Exacerbations per Patient per Year [units: exacerbations per patient per year] Mean (95% Confidence Interval)	0.805 (0.724 to 0.895)	0.927 (0.843 to 1.020)

Statistical Analysis 1 for Rate of Moderate or Severe COPD Exacerbations per Patient per Year

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Generalized Linear Regression]
P-Value^[4]	0.0529
Other^[5]	0.868
Standard Error of the mean	± 0.0633
95% Confidence Interval	( 0.753 to 1.002 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Poisson regression model (estimates of exacerbation rates using time in trial as model offset).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided
[5]	Other relevant estimation information:
	A rate ratio of < 1 represents a favourable outcome for the test treatment.

2. Secondary Outcome Measure: Change from Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1) [ Time Frame: Baseline and Week 52 ]

Measure Type	Secondary
Measure Name	Change from Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1)
Measure Description	Pulmonary function testing was performed using centralised spirometry. FEV1 is the maximum amount of air that can be forcefully exhaled in one second. Least-squares means is from Analysis of Covariance (ANCOVA) including treatment by time interaction. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Week 52
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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	928	941
Change from Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1) [units: liters] Least Squares Mean (Standard Error)	0.052 (0.0064)	-0.004 (0.0062)

Statistical Analysis 1 for Change from Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.056
Standard Error of the mean	± 0.0089
95% Confidence Interval	( 0.038 to 0.073 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis of Covariance (ANCOVA) including 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.

3. Secondary Outcome Measure: Rate of Severe COPD Exacerbations per Patient per Year [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Name	Rate of Severe COPD Exacerbations per Patient per Year
Measure Description	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient’s baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. Severe COPD exacerbations were categorized as requiring hospitalization and/or leading to death. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Rate of Severe COPD Exacerbations per Patient per Year [units: exacerbations per patient per year] Mean (95% Confidence Interval)	0.239 (0.201 to 0.283)	0.315 (0.270 to 0.368)

Statistical Analysis 1 for Rate of Severe COPD Exacerbations per Patient per Year

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Generalized Linear Regression]
P-Value^[4]	0.0175
Other^[5]	0.757
Standard Error of the mean	± 0.0889
95% Confidence Interval	( 0.601 to 0.952 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analyzed using a negative binomial regression model excluding a correction for overdispersion.
[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:
	A rate ratio of < 1 represents a favourable outcome for the test treatment.

4. Secondary Outcome Measure: Rate of COPD Exacerbations per Patient per Year All Categories [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Name	Rate of COPD Exacerbations per Patient per Year All Categories
Measure Description	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient’s baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as follows: Severe=Requiring hospitalization and/or leading to death; Moderate=Requiring oral or parenteral glucocorticosteroid therapy. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Rate of COPD Exacerbations per Patient per Year All Categories [units: exacerbations per patient per year] Mean (95% Confidence Interval)
Moderate	0.574 (0.508 to 0.648)	0.627 (0.561 to 0.702)
Mild, Moderate or Severe	3.078 (2.723 to 3.479)	3.879 (3.492 to 4.310)
Leading to Hospitalisation	0.238 (0.200 to 0.283)	0.313 (0.268 to 0.365)
Glucocorticosteroids and/or Antibiotics treatment	0.794 (0.716 to 0.88)	0.929 (0.847 to 1.019)
Moderate or Severe and/or treated with Antibiotics	1.012 (0.922 to 1.110)	1.210 (1.115 to 1.313)

Statistical Analysis 1 for Rate of COPD Exacerbations per Patient per Year All Categories

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Generalized Linear Regression]
P-Value^[4]	0.2875
Other^[5]	0.914
Standard Error of the mean	± 0.0771
95% Confidence Interval	( 0.775 to 1.078 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Moderate COPD Exacerbations
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Poisson regression model (estimates of exacerbation rates using time in trial as model offset).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided
[5]	Other relevant estimation information:
	A rate ratio of < 1 represents a favourable outcome for the test treatment.

Statistical Analysis 2 for Rate of COPD Exacerbations per Patient per Year All Categories

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Generalized Linear Regression]
P-Value^[4]	0.0050
Other^[5]	0.794
Standard Error of the mean	± 0.0654
95% Confidence Interval	( 0.675 to 0.933 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Mild, Moderate or Severe COPD Exacerbations
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Poisson regression model (estimates of exacerbation rates using time in trial as model offset).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided
[5]	Other relevant estimation information:
	A rate ratio of < 1 represents a favourable outcome for the test treatment.

Statistical Analysis 3 for Rate of COPD Exacerbations per Patient per Year All Categories

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Generalized Linear Regression]
P-Value^[4]	0.0262
Other^[5]	0.854
Standard Error of the mean	± 0.0605
95% Confidence Interval	( 0.744 to 0.982 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	COPD Exacerbations treated with Glucocorticosteroids and/or Antibiotics
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Poisson regression model (estimates of exacerbation rates using time in trial as model offset).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided
[5]	Other relevant estimation information:
	A rate ratio of < 1 represents a favourable outcome for the test treatment.

Statistical Analysis 4 for Rate of COPD Exacerbations per Patient per Year All Categories

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Generalized Linear Regression]
P-Value^[4]	0.0047
Other^[5]	0.837
Standard Error of the mean	± 0.0528
95% Confidence Interval	( 0.739 to 0.947 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Moderate or Severe COPD Exacerbations and/or treated with Antibiotics
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Poisson regression model (estimates of exacerbation rates using time in trial as model offset).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided
[5]	Other relevant estimation information:
	A rate ratio of < 1 represents a favourable outcome for the test treatment.

Statistical Analysis 5 for Rate of COPD Exacerbations per Patient per Year All Categories

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Generalized Linear Regression]
P-Value^[4]	0.0209
Other^[5]	0.761
Standard Error of the mean	± 0.0899
95% Confidence Interval	( 0.604 to 0.960 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Leading to Hospitalisation
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Negative binomial regression model (estimates of exacerbation rates)
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	A rate ratio of < 1 represents a favourable outcome for the test treatment.

5. Secondary Outcome Measure: Percentage of Participants Experiencing at Least 1 COPD Exacerbation [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Name	Percentage of Participants Experiencing at Least 1 COPD Exacerbation
Measure Description	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient’s baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Percentage of Participants Experiencing at Least 1 COPD Exacerbation [units: percentage of participants]	55.2	60.5

No statistical analysis provided for Percentage of Participants Experiencing at Least 1 COPD Exacerbation

6. Secondary Outcome Measure: Time to First COPD Exacerbation All Categories [ Time Frame: 52 Weeks ]

Measure Type	Secondary
Measure Name	Time to First COPD Exacerbation All Categories
Measure Description	Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day for all events: mild, moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient’s baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Time to First COPD Exacerbation All Categories [units: days] Median (95% Confidence Interval)	218.0 (189.0 to 259.0)	180.0 (147.0 to 200.0)

Statistical Analysis 1 for Time to First COPD Exacerbation All Categories

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Cox proportional hazards model]
P-Value^[4]	0.1461
Hazard Ratio (HR)^[5]	0.917
Standard Error of the mean	± 0.0549
95% Confidence Interval	( 0.815 to 1.031 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	A hazards ratio of < 1 represents a lower hazard for the test treatment.

7. Secondary Outcome Measure: Time to Second Moderate or Severe COPD Exacerbation [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ]

Measure Type	Secondary
Measure Name	Time to Second Moderate or Severe COPD Exacerbation
Measure Description	Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day for events: moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient’s baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
Time Frame	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Time to Second Moderate or Severe COPD Exacerbation [units: days] Median (95% Confidence Interval)	421.0 (413.0 to NA) ^[1]	NA (NA to NA) ^[2]

[1]	95% confidence interval upper limit not estimated.
[2]	Parameters not estimated-data did not reach the median.

Statistical Analysis 1 for Time to Second Moderate or Severe COPD Exacerbation

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Wei-Lin-Weissfeld Method]
P-Value^[4]	0.0270
Hazard Ratio (HR)^[5]	0.790
Standard Error of the mean	± 0.0842
95% Confidence Interval	( 0.641 to 0.974 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided
[5]	Other relevant estimation information:
	A hazard ratio of <1 represents a favourable outcome for the test treatment

8. Secondary Outcome Measure: Time to Third Moderate or Severe COPD Exacerbation [ Time Frame: 52 Weeks ]

Measure Type	Secondary
Measure Name	Time to Third Moderate or Severe COPD Exacerbation
Measure Description	Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day for events: moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient’s baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Time to Third Moderate or Severe COPD Exacerbation [units: days] Median (Full Range)	NA (NA to NA) ^[1]	NA (NA to NA) ^[2]

[1]	Parameters not estimated-data did not reach the median.
[2]	Parameters not estimated-data did not reach the median.

Statistical Analysis 1 for Time to Third Moderate or Severe COPD Exacerbation

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Wei-Lin-Weissfeld Method]
P-Value^[4]	0.0731
Hazard Ratio (HR)^[5]	0.749
Standard Error of the mean	± 0.1209
95% Confidence Interval	( 0.546 to 1.027 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided
[5]	Other relevant estimation information:
	A hazard ratio of <1 represents a favourable outcome for the test treatment.

9. Secondary Outcome Measure: Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation derived from Exacerbation Per Patient Per Year [ Time Frame: 52 Weeks ]

Measure Type	Secondary
Measure Name	Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation derived from Exacerbation Per Patient Per Year
Measure Description	The number needed to treat (NNT) analysis is a simple, concise method to quantify directly the benefits that alternative treatment options have on disease outcomes in terms of the number of patients who need to be treated before a benefit is observed. Risk reduction: Rate(Placebo)— Rate (Roflumilast 500 μg), Number needed to treat for benefit (NNTB): 1/(Risk reduction). A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation derived from Exacerbation Per Patient Per Year [units: participants]	0.805	0.927

Statistical Analysis 1 for Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation derived from Exacerbation Per Patient Per Year

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	9
95% Confidence Interval	( 4 to 31 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

10. Secondary Outcome Measure: Number of Moderate or Severe COPD Exacerbation Days [ Time Frame: 52 Weeks ]

Measure Type	Secondary
Measure Name	Number of Moderate or Severe COPD Exacerbation Days
Measure Description	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient’s baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. The number of exacerbation days per patient is the sum of durations (stop date of exacerbation — start date of exacerbation + 1) of all exacerbations within the category.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	380	432
Number of Moderate or Severe COPD Exacerbation Days [units: days] Mean (Standard Deviation)	26.9 (23.09)	30.9 (29.49)

No statistical analysis provided for Number of Moderate or Severe COPD Exacerbation Days

11. Secondary Outcome Measure: Duration of Moderate or Severe COPD Exacerbations per Participant [ Time Frame: 52 Weeks ]

Measure Type	Secondary
Measure Name	Duration of Moderate or Severe COPD Exacerbations per Participant
Measure Description	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient’s baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis. n in each of the categories is the number of participants with exacerbations.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	380	432
Duration of Moderate or Severe COPD Exacerbations per Participant [units: days] Mean (Standard Deviation)	15.9 (10.59)	16.6 (14.49)

No statistical analysis provided for Duration of Moderate or Severe COPD Exacerbations per Participant

12. Secondary Outcome Measure: Change from Baseline in Post-Bronchodilator Forced Vital Capacity (FVC) [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Name	Change from Baseline in Post-Bronchodilator Forced Vital Capacity (FVC)
Measure Description	Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Least-squares means was from ANCOVA including treatment by time interaction. A positive change from Baseline indicates improvement.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	928	941
Change from Baseline in Post-Bronchodilator Forced Vital Capacity (FVC) [units: liters] Least Squares Mean (Standard Error)	0.036 (0.0114)	-0.057 (0.0111)

Statistical Analysis 1 for Change from Baseline in Post-Bronchodilator Forced Vital Capacity (FVC)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Repeated measurement model]
P-Value^[4]	<0.0001
Other^[5]	0.092
Standard Error of the mean	± 0.0159
95% Confidence Interval	( 0.061 to 0.124 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Unstructured covariance structure and restricted maximum likelihood (REML).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	No text entered.

13. Secondary Outcome Measure: Change from Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%) [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Name	Change from Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%)
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. Least-squares means was from ANCOVA including treatment by time interaction. A positive change from Baseline indicates improvement.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	928	941
Change from Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%) [units: liters/second] Least Squares Mean (Standard Error)	0.035 (0.0044)	0.009 (0.0043)

Statistical Analysis 1 for Change from Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Repeated measurement model]
P-Value^[4]	<0.0001
Other^[5]	0.025
Standard Error of the mean	± 0.0062
95% Confidence Interval	( 0.013 to 0.038 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Unstructured covariance structure and REML.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	No text entered.

14. Secondary Outcome Measure: Change from Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6) [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Name	Change from Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 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. A positive change from Baseline indicates improvement.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	924	937
Change from Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6) [units: liters] Least Squares Mean (Standard Error)	0.061 (0.0093)	-0.033 (0.0091)

Statistical Analysis 1 for Change from Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Repeated measurement model]
P-Value^[4]	<0.0001
Other^[5]	0.094
Standard Error of the mean	± 0.0131
95% Confidence Interval	( 0.069 to 0.120 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Unstructured covariance structure and REML.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	No text entered.

15. Secondary Outcome Measure: Change from Baseline in Post-Bronchodilator FEV1/FVC [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Name	Change from Baseline in Post-Bronchodilator FEV1/FVC
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. A positive change from Baseline indicates improvement.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	701	780
Change from Baseline in Post-Bronchodilator FEV1/FVC [units: percent] Mean (Standard Deviation)	1.170 (7.0339)	0.580 (6.8405)

No statistical analysis provided for Change from Baseline in Post-Bronchodilator FEV1/FVC

16. Secondary Outcome Measure: Change from Baseline in Use of Rescue Medication from Daily Diary [ Time Frame: Baseline and Week 52 ]

Measure Type	Secondary
Measure Name	Change from Baseline in Use of Rescue Medication from Daily Diary
Measure Description	Salbutamol metered dose inhaler was available as rescue medication during the study. The participant recorded the use of rescue medication in a daily diary. A negative change from Baseline indicates an improvement.
Time Frame	Baseline and Week 52
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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data included in the repeated measurements analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	848	896
Change from Baseline in Use of Rescue Medication from Daily Diary [units: puffs per day] Least Squares Mean (Standard Error)	-0.109 (0.0676)	0.173 (0.0654)

Statistical Analysis 1 for Change from Baseline in Use of Rescue Medication from Daily Diary

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Repeated measurement model]
P-Value^[4]	0.0027
Other^[5]	-0.283
Standard Error of the mean	± 0.0941
95% Confidence Interval	( -0.467 to -0.098 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Compound symmetry covariance structure and REML.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	No text entered.

17. Secondary Outcome Measure: Change from Baseline in COPD Symptom Score from Daily Diary [ Time Frame: 52 weeks ]

Measure Type	Secondary
Measure Name	Change from Baseline in COPD Symptom Score from Daily Diary
Measure Description	Participants recorded COPD symptoms cough and sputum production in a daily diary. Cough was assessed using a 4-point scale where 0=No cough to 3=severe cough and sputum was assessed using a 4-point scale where 0=no sputum production to 3=severe sputum production. Least-squares means from ANCOVA including treatment by time interaction. A negative change from Baseline indicates improvement. Total symptom score is the sum of cough and sputum scores, ranging from 0 (best possible outcome) to 6 (worst possible outcome).
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	897	932
Change from Baseline in COPD Symptom Score from Daily Diary [units: score on a scale] Least Squares Mean (Standard Error)	-0.412 (0.0315)	-0.398 (0.0306)

Statistical Analysis 1 for Change from Baseline in COPD Symptom Score from Daily Diary

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Repeated measurement model]
P-Value^[4]	0.7392
Other^[5]	-0.015
Standard Error of the mean	± 0.0439
95% Confidence Interval	( -0.101 to 0.071 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Compound symmetry covariance structure and REML.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	No text entered.

18. Secondary Outcome Measure: Percentage of Symptom-Free Days [ Time Frame: 52 Weeks ]

Measure Type	Secondary
Measure Name	Percentage of Symptom-Free Days
Measure Description	Symptoms of COPD (cough, sputum) were recorded in a daily diary. The percentage of days without symptoms is reported.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Percentage of Symptom-Free Days [units: percentage of days] Mean (Standard Deviation)	7.09 (17.119)	6.88 (16.185)

No statistical analysis provided for Percentage of Symptom-Free Days

19. Secondary Outcome Measure: Percentage of Rescue Medication-Free Days [ Time Frame: 52 Weeks ]

Measure Type	Secondary
Measure Name	Percentage of Rescue Medication-Free Days
Measure Description	Participants recorded their use of rescue medication in a daily diary. The percentage of days without rescue medication use.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Percentage of Rescue Medication-Free Days [units: percentage of days] Mean (Standard Deviation)	23.25 (33.734)	22.77 (33.141)

No statistical analysis provided for Percentage of Rescue Medication-Free Days

20. Secondary Outcome Measure: Change from Baseline in COPD Assessment Test (CAT) Total Score [ Time Frame: Baseline and Week 52 ]

Measure Type	Secondary
Measure Name	Change from Baseline in COPD Assessment Test (CAT) Total Score
Measure Description	Participants completed the CAT questionnaire at Baseline and after 52 Weeks of Treatment. The CAT questionnaire measures the impact of COPD on wellbeing and daily life. Participants answer 8 questions on a scale from 0 (best) to 5 (worst). The total score ranges from 0 to 40 with higher scores indicating more impact. A negative change from Baseline indicates improvement. Least-squares means from ANCOVA including treatment by time interaction.
Time Frame	Baseline and Week 52
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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	924	940
Change from Baseline in COPD Assessment Test (CAT) Total Score [units: score on a scale] Mean (Standard Error)	-1.270 (0.1556)	-0.985 (0.1518)

Statistical Analysis 1 for Change from Baseline in COPD Assessment Test (CAT) Total Score

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Repeated measurement model]
P-Value^[4]	0.1909
Other^[5]	-0.285
Standard Error of the mean	± 0.2175
95% Confidence Interval	( -0.711 to 0.142 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Unstructured covariance structure and REML.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	No text entered.

21. Secondary Outcome Measure: Percentage of Participants with Improvement in CAT [ Time Frame: Baseline and Week 52 ]

Measure Type	Secondary
Measure Name	Percentage of Participants with Improvement in CAT
Measure Description	Participants completed the CAT questionnaire at Baseline and after 52 Weeks of treatment. The CAT questionnaire measures the impact of COPD on wellbeing and daily life. Participants answer 8 questions on a scale from 0 (best) to 5 (worst). The total score ranges from 0 to 40 with higher scores indicating more impact. Improvement was defined as a CAT Total Score reduction from Baseline > 1.6.
Time Frame	Baseline and Week 52
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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Percentage of Participants with Improvement in CAT [units: percentage of participants]	71.2	72.5

No statistical analysis provided for Percentage of Participants with Improvement in CAT

22. Secondary Outcome Measure: Time to Mortality Due to Any Reason During the Treatment Period Score [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ]

Measure Type	Secondary
Measure Name	Time to Mortality Due to Any Reason During the Treatment Period Score
Measure Description	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.
Time Frame	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Time to Mortality Due to Any Reason During the Treatment Period Score [units: days] Median (Full Range)	NA (44 to 381) ^[1]	NA (21 to 293) ^[2]

[1]	Data did not reach the median.
[2]	Data did not reach the median.

Statistical Analysis 1 for Time to Mortality Due to Any Reason During the Treatment Period Score

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Cox-proportional hazards model]
P-Value^[4]	0.9414
Hazard Ratio (HR)^[5]	1.025
Standard Error of the mean	± 0.3468
95% Confidence Interval	( 0.528 to 1.990 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	A hazards ratio of < 1 represents a lower hazard for the test treatment.

23. Secondary Outcome Measure: Time to Mortality Due to COPD Exacerbation During the Treatment Period [ Time Frame: 52 Weeks ]

Measure Type	Secondary
Measure Name	Time to Mortality Due to COPD Exacerbation During the Treatment Period
Measure Description	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Time to Mortality Due to COPD Exacerbation During the Treatment Period [units: days] Median (Full Range)	NA (44 to 322) ^[1]	NA (25 to 293) ^[2]

[1]	Data did not reach the median.
[2]	Data did not reach the median.

Statistical Analysis 1 for Time to Mortality Due to COPD Exacerbation During the Treatment Period

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Cox-proportional hazards model]
P-Value^[4]	0.8876
Hazard Ratio (HR)^[5]	1.078
Standard Error of the mean	± 0.5765
95% Confidence Interval	( 0.378 to 3.075 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Level of significance: 5% 2-sided.
[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:
	A hazards ratio of < 1 represents a lower hazard for the test treatment.

24. Secondary Outcome Measure: Time to Withdrawal During the Treatment Period [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ]

Measure Type	Secondary
Measure Name	Time to Withdrawal During the Treatment Period
Measure Description	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.
Time Frame	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Time to Withdrawal During the Treatment Period [units: days] Median (Full Range)	420.0 (5 to 428)	444.0 (1 to 444)

Statistical Analysis 1 for Time to Withdrawal During the Treatment Period

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Cox-proportional hazards model]
P-Value^[4]	<0.0001
Hazard Ratio (HR)^[5]	1.529
Standard Error of the mean	± 0.1463
95% Confidence Interval	( 1.268 to 1.845 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Level of significance: 5% 2-sided.
[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:
	A hazards ratio of < 1 represents a lower hazard for the test treatment.

25. Secondary Outcome Measure: Time to Withdrawal due to COPD Exacerbation During the Treatment Period [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ]

Measure Type	Secondary
Measure Name	Time to Withdrawal due to COPD Exacerbation During the Treatment Period
Measure Description	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.
Time Frame	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Time to Withdrawal due to COPD Exacerbation During the Treatment Period [units: days] Median (Full Range)	NA (25 to 371) ^[1]	NA (12 to 319) ^[2]

[1]	Data did not reach the median.
[2]	Data did not reach the median.

Statistical Analysis 1 for Time to Withdrawal due to COPD Exacerbation During the Treatment Period

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Cox-proportional hazards model]
P-Value^[4]	0.3477
Hazard Ratio (HR)^[5]	0.695
Standard Error of the mean	± 0.2691
95% Confidence Interval	( 0.326 to 1.484 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	A hazards ratio of < 1 represents a lower hazard for the test treatment.

26. Secondary Outcome Measure: Percentage of Participants with Major Adverse Cardiovascular Event (MACE) during the Treatment Period [ Time Frame: 52 Weeks ]

Measure Type	Secondary
Measure Name	Percentage of Participants with Major Adverse Cardiovascular Event (MACE) during the Treatment Period
Measure Description	Composite MACE is a combined endpoint (cardiovascular death [including death due to undetermined cause], nonfatal myocardial infarction, and nonfatal stroke).
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Percentage of Participants with Major Adverse Cardiovascular Event (MACE) during the Treatment Period [units: percentage of participants]	1.7	1.7

No statistical analysis provided for Percentage of Participants with Major Adverse Cardiovascular Event (MACE) during the Treatment Period

27. Secondary Outcome Measure: Time to First Major Adverse Cardiovascular Event (MACE) during the Treatment Period [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ]

Measure Type	Secondary
Measure Name	Time to First Major Adverse Cardiovascular Event (MACE) during the Treatment Period
Measure Description	Composite MACE is a combined endpoint(cardiovascular death [including death due to undetermined cause], nonfatal myocardial infarction, and nonfatal stroke). Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.
Time Frame	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Time to First Major Adverse Cardiovascular Event (MACE) during the Treatment Period [units: days] Median (Full Range)	NA (52 to 415) ^[1]	NA (50 to 365) ^[2]

[1]	Data did not reach the median.
[2]	Data did not reach the median.

Statistical Analysis 1 for Time to First Major Adverse Cardiovascular Event (MACE) during the Treatment Period

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Cox-proportional hazards model]
P-Value^[4]	0.8208
Hazard Ratio (HR)^[5]	1.083
Standard Error of the mean	± 0.3832
95% Confidence Interval	( 0.542 to 2.167 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	A hazards ratio of < 1 represents a lower hazard for the test treatment.

28. Secondary Outcome Measure: Percentage of Participant with All-Cause Hospitalisation during the Treatment Period [ Time Frame: 52 Weeks ]

Measure Type	Secondary
Measure Name	Percentage of Participant with All-Cause Hospitalisation during the Treatment Period
Measure Description	Percentage of patients with at least one hospital admission due to any cause.
Time Frame	52 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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Percentage of Participant with All-Cause Hospitalisation during the Treatment Period [units: percentage of participants]	24.9	29.3

No statistical analysis provided for Percentage of Participant with All-Cause Hospitalisation during the Treatment Period

29. Secondary Outcome Measure: Time to First Hospitalisation due to Any Cause during the Treatment Period [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ]

Measure Type	Secondary
Measure Name	Time to First Hospitalisation due to Any Cause during the Treatment Period
Measure Description	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.
Time Frame	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with events.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Time to First Hospitalisation due to Any Cause during the Treatment Period [units: days] Median (95% Confidence Interval)	400.0 (387.0 to 415.0)	408.0 (391.0 to 420.0)

Statistical Analysis 1 for Time to First Hospitalisation due to Any Cause during the Treatment Period

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Cox-proportional hazards model]
P-Value^[4]	0.7943
Hazard Ratio (HR)^[5]	0.977
Standard Error of the mean	± 0.0865
95% Confidence Interval	( 0.821 to 1.162 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Level of significance: 5% 2-sided.
[5]	Other relevant estimation information:
	No text entered.

30. Secondary Outcome Measure: Time to Trial Withdrawal due to an Adverse Event [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ]

Measure Type	Secondary
Measure Name	Time to Trial Withdrawal due to an Adverse Event
Measure Description	Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.
Time Frame	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
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.
Participants from the Intent-to treat population, all randomized participants who received at least 1 dose of study drug analyzed by the treatment for which they were randomized, with events.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	969	966
Time to Trial Withdrawal due to an Adverse Event [units: days] Median (Full Range)	NA (7 to 420) ^[1]	NA (13 to 444) ^[2]

[1]	Data did not reach the median.
[2]	Data did not reach the median.

No statistical analysis provided for Time to Trial Withdrawal due to an Adverse Event

31. Secondary Outcome Measure: Percentage of Participants who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE) [ Time Frame: 52 Weeks ]

Measure Type	Secondary
Measure Name	Percentage of Participants who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE)
Measure Description	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	52 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 included all randomized participants who received at least one dose of study drug.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	968	967
Percentage of Participants who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE) [units: percentage of participants]	66.9	59.2

No statistical analysis provided for Percentage of Participants who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE)

32. Secondary Outcome Measure: Change from Baseline in Body Weight [ Time Frame: Baseline and Week 52 ]

Measure Type	Secondary
Measure Name	Change from Baseline in Body Weight
Measure Description	Least Square Means was from an ANCOVA model including Last Observation Carried Forward (LOCF).
Time Frame	Baseline and Week 52
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.
Participants from the Safety Population, all randomized participants who received at least one dose of study drug, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	938	944
Change from Baseline in Body Weight [units: kilogram (kg)] Least Squares Mean (Standard Error)	-2.66 (0.130)	-0.14 (0.130)

No statistical analysis provided for Change from Baseline in Body Weight

33. Secondary Outcome Measure: Change from Baseline in Body Mass Index (BMI) [ Time Frame: Baseline and Week 52 ]

Measure Type	Secondary
Measure Name	Change from Baseline in Body Mass Index (BMI)
Measure Description	Body mass index (BMI) is a measure of body fat based on height and weight. Least Square Means was from an ANCOVA model including LOCF.
Time Frame	Baseline and Week 52
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.
Participants from the Safety Population, all randomized participants who received at least one dose of study drug, with data available for analysis.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Measured Values

	Roflumilast 500 µg	Placebo
Number of Participants Analyzed [units:participants]	938	944
Change from Baseline in Body Mass Index (BMI) [units: kg/m^2] Least Squares Mean (Standard Error)	-0.94 (0.046)	-0.04 (0.046)

No statistical analysis provided for Change from Baseline in Body Mass Index (BMI)

Serious Adverse Events

Time Frame	52 weeks
Additional Description	Safety Population included all randomized participants who received at least one dose of study drug.

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Serious Adverse Events

Roflumilast 500 µg

Placebo

Total, serious adverse events

# participants affected / at risk

249/968 (25.72%)

285/967 (29.47%)

Blood and lymphatic system disorders

Anaemia¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

Blood and lymphatic system disorders

Iron deficiency anaemia¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Blood and lymphatic system disorders

Polycythaemia¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Cardiac disorders

Acute coronary syndrome¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

Cardiac disorders

Acute myocardial infarction¹,^†

# participants affected / at risk

2/968 (0.21%)

2/967 (0.21%)

Cardiac disorders

Angina pectoris¹,^†

# participants affected / at risk

1/968 (0.10%)

5/967 (0.52%)

Cardiac disorders

Angina unstable¹,^†

# participants affected / at risk

0/968 (0.00%)

2/967 (0.21%)

Cardiac disorders

Aortic valve stenosis¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Cardiac disorders

Arrhythmia¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

Cardiac disorders

Arrhythmia supraventricular¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

6/968 (0.62%)

6/967 (0.62%)

Cardiac disorders

Atrial flutter¹,^†

# participants affected / at risk

2/968 (0.21%)

2/967 (0.21%)

Cardiac disorders

Atrial tachycardia¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Cardiac disorders

Atrial thrombosis¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Cardiac disorders

Bundle branch block right¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Cardiac disorders

Cardiac arrest¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Cardiac disorders

Cardiac failure¹,^†

# participants affected / at risk

3/968 (0.31%)

5/967 (0.52%)

Cardiac disorders

Cardiac failure chronic¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Cardiac disorders

Cardiac failure congestive¹,^†

# participants affected / at risk

4/968 (0.41%)

2/967 (0.21%)

Cardiac disorders

Cardiogenic shock¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

Cardiac disorders

Coronary artery disease¹,^†

# participants affected / at risk

0/968 (0.00%)

2/967 (0.21%)

Cardiac disorders

Coronary artery insufficiency¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Cardiac disorders

Coronary artery occlusion¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Cardiac disorders

Left ventricular failure¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Cardiac disorders

Mitral valve incompetence¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Cardiac disorders

Mitral valve stenosis¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Cardiac disorders

Myocardial infarction¹,^†

# participants affected / at risk

3/968 (0.31%)

5/967 (0.52%)

Cardiac disorders

Myocardial ischaemia¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Cardiac disorders

Palpitations¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Cardiac disorders

Sick sinus syndrome¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Cardiac disorders

Supraventricular tachycardia¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Cardiac disorders

Tachyarrhythmia¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Cardiac disorders

Tachycardia¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Cardiac disorders

Ventricular fibrillation¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Congenital, familial and genetic disorders

Accessory auricle¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Congenital, familial and genetic disorders

Vitello-intestinal duct remnant¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Ear and labyrinth disorders

Acute vestibular syndrome¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Ear and labyrinth disorders

Vertigo¹,^†

# participants affected / at risk

1/968 (0.10%)

2/967 (0.21%)

Endocrine disorders

Thyrotoxic crisis¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Eye disorders

Angle closure glaucoma¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Eye disorders

Cataract¹,^†

# participants affected / at risk

0/968 (0.00%)

2/967 (0.21%)

Eye disorders

Eye haemorrhage¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Eye disorders

Retinal detachment¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Gastrointestinal disorders

Abdominal hernia¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

4/968 (0.41%)

0/967 (0.00%)

Gastrointestinal disorders

Abdominal pain upper¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Gastrointestinal disorders

Colitis¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

2/968 (0.21%)

2/967 (0.21%)

Gastrointestinal disorders

Diverticulum intestinal¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Gastrointestinal disorders

Duodenal ulcer¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Gastrointestinal disorders

Duodenal ulcer haemorrhage¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Gastrointestinal disorders

Faeces discoloured¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Gastrointestinal disorders

Gastric ulcer¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Gastrointestinal disorders

Gastric ulcer haemorrhage¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Gastrointestinal disorders

Gastritis¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Gastrointestinal disorders

Gastritis erosive¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Gastrointestinal disorders

Gastrointestinal angiodysplasia haemorrhagic¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Gastrointestinal disorders

Gastrointestinal haemorrhage¹,^†

# participants affected / at risk

1/968 (0.10%)

3/967 (0.31%)

Gastrointestinal disorders

Haemorrhoids¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Gastrointestinal disorders

Hiatus hernia¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Gastrointestinal disorders

Ileus¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Gastrointestinal disorders

Inguinal hernia, obstructive¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

Gastrointestinal disorders

Large intestine polyp¹,^†

# participants affected / at risk

3/968 (0.31%)

0/967 (0.00%)

Gastrointestinal disorders

Megacolon¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Gastrointestinal disorders

Melaena¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Gastrointestinal disorders

Small intestinal obstruction¹,^†

# participants affected / at risk

0/968 (0.00%)

2/967 (0.21%)

Gastrointestinal disorders

Umbilical hernia¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

General disorders

Chest pain¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

General disorders

Death¹,^†

# participants affected / at risk

3/968 (0.31%)

2/967 (0.21%)

General disorders

Drug ineffective¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

General disorders

General physical health deterioration¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

General disorders

Hernia¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

General disorders

Malaise¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

General disorders

Multi-organ failure¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

General disorders

Non-cardiac chest pain¹,^†

# participants affected / at risk

2/968 (0.21%)

3/967 (0.31%)

General disorders

Pain¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

General disorders

Sudden death¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Hepatobiliary disorders

Bile duct stone¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Hepatobiliary disorders

Cholangitis¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Hepatobiliary disorders

Cholecystitis acute¹,^†

# participants affected / at risk

0/968 (0.00%)

2/967 (0.21%)

Hepatobiliary disorders

Cholelithiasis¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Infections and infestations

Bronchopneumonia¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

Infections and infestations

Cellulitis¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Infections and infestations

Clostridium difficile colitis¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Infections and infestations

Diarrhoea infectious¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Infections and infestations

Erysipelas¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Infections and infestations

Extradural abscess¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Infections and infestations

Gastroenteritis¹,^†

# participants affected / at risk

2/968 (0.21%)

1/967 (0.10%)

Infections and infestations

Gastroenteritis rotavirus¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Infections and infestations

Infective exacerbation of chronic obstructive airways disease¹,^†

# participants affected / at risk

3/968 (0.31%)

7/967 (0.72%)

Infections and infestations

Laryngitis¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Infections and infestations

Lobar pneumonia¹,^†

# participants affected / at risk

0/968 (0.00%)

2/967 (0.21%)

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

2/968 (0.21%)

1/967 (0.10%)

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Infections and infestations

Nosocomial infection¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Infections and infestations

Oesophageal candidiasis¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Infections and infestations

Parotid abscess¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Infections and infestations

Peritonitis¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

33/968 (3.41%)

37/967 (3.83%)

Infections and infestations

Pneumonia moraxella¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Infections and infestations

Pulmonary tuberculosis¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Infections and infestations

Respiratory tract infection¹,^†

# participants affected / at risk

1/968 (0.10%)

2/967 (0.21%)

Infections and infestations

Sepsis¹,^†

# participants affected / at risk

2/968 (0.21%)

2/967 (0.21%)

Infections and infestations

Septic shock¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Infections and infestations

Tracheobronchitis¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

Infections and infestations

Upper respiratory tract infection bacterial¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Infections and infestations

Urinary tract infection viral¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Injury, poisoning and procedural complications

Burns second degree¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Injury, poisoning and procedural complications

Cartilage injury¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Injury, poisoning and procedural complications

Clavicle fracture¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Injury, poisoning and procedural complications

Contusion¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

Injury, poisoning and procedural complications

Femur fracture¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Injury, poisoning and procedural complications

Incisional hernia¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Injury, poisoning and procedural complications

Multiple fractures¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Injury, poisoning and procedural complications

Pneumothorax traumatic¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Injury, poisoning and procedural complications

Rib fracture¹,^†

# participants affected / at risk

0/968 (0.00%)

2/967 (0.21%)

Injury, poisoning and procedural complications

Road traffic accident¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Injury, poisoning and procedural complications

Spinal fracture¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Investigations

Blood creatine phosphokinase increased¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Investigations

International normalised ratio increased¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Investigations

Transplant evaluation¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Investigations

Weight decreased¹,^†

# participants affected / at risk

4/968 (0.41%)

0/967 (0.00%)

Metabolism and nutrition disorders

Dehydration¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

Metabolism and nutrition disorders

Diabetes mellitus¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

Metabolism and nutrition disorders

Diabetic ketoacidosis¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Metabolism and nutrition disorders

Glucose tolerance impaired¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Metabolism and nutrition disorders

Hyponatraemia¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

0/968 (0.00%)

2/967 (0.21%)

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Musculoskeletal and connective tissue disorders

Intervertebral disc disorder¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Musculoskeletal and connective tissue disorders

Intervertebral disc protrusion¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Musculoskeletal and connective tissue disorders

Musculoskeletal pain¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Musculoskeletal and connective tissue disorders

Osteoarthritis¹,^†

# participants affected / at risk

1/968 (0.10%)

2/967 (0.21%)

Musculoskeletal and connective tissue disorders

Osteonecrosis¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Musculoskeletal and connective tissue disorders

Psoriatic arthropathy¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

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

Adenocarcinoma of colon¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Basal cell carcinoma¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

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

Benign lung neoplasm¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Bile duct cancer¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Bladder adenocarcinoma stage unspecified¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Bladder cancer¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

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

Bladder neoplasm¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

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

Colon cancer¹,^†

# participants affected / at risk

1/968 (0.10%)

2/967 (0.21%)

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

Colon cancer metastatic¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

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

Colon neoplasm¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Eyelid tumour¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Gastric neoplasm¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Haemangioma¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Kaposi's sarcoma¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Laryngeal cancer¹,^†

# participants affected / at risk

0/968 (0.00%)

2/967 (0.21%)

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

Lung neoplasm¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

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

Lung neoplasm malignant¹,^†

# participants affected / at risk

1/968 (0.10%)

4/967 (0.41%)

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

Malignant melanoma¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

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

Metastatic gastric cancer¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

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

Metastatic squamous cell carcinoma¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

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

Oesophageal carcinoma¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Pancreatic carcinoma¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

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

Prostate cancer¹,^†

# participants affected / at risk

4/968 (0.41%)

4/967 (0.41%)

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

Rectal cancer¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

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

Renal neoplasm¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

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

Small cell lung cancer metastatic¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Squamous cell carcinoma of lung¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

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

Tonsil cancer¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Nervous system disorders

Carotid sinus syndrome¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Nervous system disorders

Cerebral haemorrhage¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Nervous system disorders

Cerebrovascular accident¹,^†

# participants affected / at risk

3/968 (0.31%)

1/967 (0.10%)

Nervous system disorders

Depressed level of consciousness¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Nervous system disorders

Epilepsy¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Nervous system disorders

Facial nerve disorder¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Nervous system disorders

Grand mal convulsion¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Nervous system disorders

Ischaemic stroke¹,^†

# participants affected / at risk

0/968 (0.00%)

2/967 (0.21%)

Nervous system disorders

Radiculopathy¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Nervous system disorders

Sciatica¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Nervous system disorders

Syncope¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Nervous system disorders

Transient ischaemic attack¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Nervous system disorders

Tremor¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Nervous system disorders

Trigeminal nerve disorder¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Psychiatric disorders

Depression¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Psychiatric disorders

Psychotic disorder due to a general medical condition¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Psychiatric disorders

Suicidal ideation¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Renal and urinary disorders

Calculus ureteric¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Renal and urinary disorders

Haematuria¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Renal and urinary disorders

Nephrolithiasis¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Renal and urinary disorders

Renal colic¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Renal and urinary disorders

Renal failure¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Renal and urinary disorders

Renal failure acute¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Renal and urinary disorders

Renal mass¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Renal and urinary disorders

Urinary retention¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Reproductive system and breast disorders

Benign prostatic hyperplasia¹,^†

# participants affected / at risk

2/968 (0.21%)

0/967 (0.00%)

Reproductive system and breast disorders

Prostatitis¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Acute pulmonary oedema¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Respiratory, thoracic and mediastinal disorders

Acute respiratory distress syndrome¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Acute respiratory failure¹,^†

# participants affected / at risk

2/968 (0.21%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

144/968 (14.88%)

184/967 (19.03%)

Respiratory, thoracic and mediastinal disorders

Chronic respiratory failure¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

3/968 (0.31%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Epistaxis¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Haemoptysis¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Lung infiltration¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Nasal obstruction¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Nasal septum disorder¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Pleurisy¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Pneumothorax¹,^†

# participants affected / at risk

5/968 (0.52%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Pulmonary hypertension¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Respiratory, thoracic and mediastinal disorders

Pulmonary mass¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Respiratory, thoracic and mediastinal disorders

Respiratory failure¹,^†

# participants affected / at risk

1/968 (0.10%)

3/967 (0.31%)

Respiratory, thoracic and mediastinal disorders

Sleep apnoea syndrome¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Skin and subcutaneous tissue disorders

Decubitus ulcer¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Skin and subcutaneous tissue disorders

Henoch-Schonlein purpura¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Skin and subcutaneous tissue disorders

Perivascular dermatitis¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Skin and subcutaneous tissue disorders

Purpura¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Surgical and medical procedures

Alcohol detoxification¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Vascular disorders

Aortic aneurysm¹,^†

# participants affected / at risk

0/968 (0.00%)

2/967 (0.21%)

Vascular disorders

Aortic aneurysm rupture¹,^†

# participants affected / at risk

1/968 (0.10%)

0/967 (0.00%)

Vascular disorders

Aortic occlusion¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Vascular disorders

Aortic stenosis¹,^†

# participants affected / at risk

3/968 (0.31%)

0/967 (0.00%)

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

2/968 (0.21%)

1/967 (0.10%)

Vascular disorders

Hypertensive crisis¹,^†

# participants affected / at risk

1/968 (0.10%)

1/967 (0.10%)

Vascular disorders

Leriche syndrome¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Vascular disorders

Peripheral ischaemia¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

Vascular disorders

Varicose vein¹,^†

# participants affected / at risk

0/968 (0.00%)

1/967 (0.10%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 16.0

Other Adverse Events

Time Frame	52 weeks
Additional Description	Safety Population included all randomized participants who received at least one dose of study drug.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Roflumilast 500 µg	Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo	Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Other Adverse Events

Roflumilast 500 µg

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

228/968 (23.55%)

114/967 (11.79%)

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

97/968 (10.02%)

33/967 (3.41%)

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

55/968 (5.68%)

15/967 (1.55%)

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

52/968 (5.37%)

52/967 (5.38%)

Investigations

Weight decreased¹,^†

# participants affected / at risk

84/968 (8.68%)

27/967 (2.79%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 16.0

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
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Results Point of Contact

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