Trial Outcomes & Findings for Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Fixed Combinations of Long-acting β2-agonists (LABA) and Inhaled Glucocorticosteroid (ICS) (NCT NCT01329029)

Last Updated: 2016-12-13

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

1945 participants

Primary outcome timeframe

52 weeks

Results posted on

2016-12-13

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.
Overall Study STARTED	973	972
Overall Study Full Analysis Set (FAS)	969	966
Overall Study Safety Population	968	967
Overall Study COMPLETED	704	780
Overall Study NOT COMPLETED	269	192

Reasons for withdrawal

Reasons for withdrawal
Measure	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.
Overall Study Withdrawal by Subject	117	87
Overall Study Adverse Event	82	29
Overall Study Death	16	19
Overall Study Other	14	20
Overall Study COPD Exacerbation	11	18
Overall Study Physician Decision	16	13
Overall Study Lost to Follow-up	8	5
Overall Study Met Pre-defined Discontinuation Criteria	5	1

Baseline Characteristics

Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Fixed Combinations of Long-acting β2-agonists (LABA) and Inhaled Glucocorticosteroid (ICS)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.	Total n=1935 Participants Total of all reporting groups
Age, Continuous	64.7 years STANDARD_DEVIATION 8.38 • n=5 Participants	64.7 years STANDARD_DEVIATION 8.37 • n=7 Participants	64.7 years STANDARD_DEVIATION 8.37 • n=5 Participants
Age, Customized ≤ 65 years	527 participants n=5 Participants	542 participants n=7 Participants	1069 participants n=5 Participants
Age, Customized > 65 years	442 participants n=5 Participants	424 participants n=7 Participants	866 participants n=5 Participants
Gender Female	251 Participants n=5 Participants	241 Participants n=7 Participants	492 Participants n=5 Participants
Gender Male	718 Participants n=5 Participants	725 Participants n=7 Participants	1443 Participants n=5 Participants
Race/Ethnicity, Customized Asian	20 participants n=5 Participants	16 participants n=7 Participants	36 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	6 participants n=5 Participants	5 participants n=7 Participants	11 participants n=5 Participants
Race/Ethnicity, Customized White	940 participants n=5 Participants	943 participants n=7 Participants	1883 participants n=5 Participants
Race/Ethnicity, Customized Other	3 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants
Region of Enrollment Australia	9 participants n=5 Participants	16 participants n=7 Participants	25 participants n=5 Participants
Region of Enrollment Austria	11 participants n=5 Participants	3 participants n=7 Participants	14 participants n=5 Participants
Region of Enrollment Belgium	19 participants n=5 Participants	18 participants n=7 Participants	37 participants n=5 Participants
Region of Enrollment Brazil	42 participants n=5 Participants	38 participants n=7 Participants	80 participants n=5 Participants
Region of Enrollment Canada	14 participants n=5 Participants	12 participants n=7 Participants	26 participants n=5 Participants
Region of Enrollment Denmark	15 participants n=5 Participants	19 participants n=7 Participants	34 participants n=5 Participants
Region of Enrollment France	16 participants n=5 Participants	13 participants n=7 Participants	29 participants n=5 Participants
Region of Enrollment Germany	70 participants n=5 Participants	63 participants n=7 Participants	133 participants n=5 Participants
Region of Enrollment Greece	38 participants n=5 Participants	30 participants n=7 Participants	68 participants n=5 Participants
Region of Enrollment Hungary	111 participants n=5 Participants	125 participants n=7 Participants	236 participants n=5 Participants
Region of Enrollment Israel	114 participants n=5 Participants	126 participants n=7 Participants	240 participants n=5 Participants
Region of Enrollment Italy	64 participants n=5 Participants	51 participants n=7 Participants	115 participants n=5 Participants
Region of Enrollment Korea, Republic Of	11 participants n=5 Participants	7 participants n=7 Participants	18 participants n=5 Participants
Region of Enrollment Netherlands	11 participants n=5 Participants	8 participants n=7 Participants	19 participants n=5 Participants
Region of Enrollment Poland	88 participants n=5 Participants	88 participants n=7 Participants	176 participants n=5 Participants
Region of Enrollment Russian Federation	177 participants n=5 Participants	181 participants n=7 Participants	358 participants n=5 Participants
Region of Enrollment Slovakia	25 participants n=5 Participants	33 participants n=7 Participants	58 participants n=5 Participants
Region of Enrollment South Africa	23 participants n=5 Participants	30 participants n=7 Participants	53 participants n=5 Participants
Region of Enrollment Spain	37 participants n=5 Participants	33 participants n=7 Participants	70 participants n=5 Participants
Region of Enrollment Turkey	52 participants n=5 Participants	44 participants n=7 Participants	96 participants n=5 Participants
Region of Enrollment United Kingdom	22 participants n=5 Participants	28 participants n=7 Participants	50 participants n=5 Participants
Height	168.20 cm STANDARD_DEVIATION 8.652 • n=5 Participants	168.33 cm STANDARD_DEVIATION 8.198 • n=7 Participants	168.26 cm STANDARD_DEVIATION 8.427 • n=5 Participants
Weight	75.07 kg STANDARD_DEVIATION 17.275 • n=5 Participants	75.60 kg STANDARD_DEVIATION 17.238 • n=7 Participants	75.33 kg STANDARD_DEVIATION 17.254 • n=5 Participants
Body Mass Index (BMI)	26.45 kg/m^2 STANDARD_DEVIATION 5.474 • n=5 Participants	26.58 kg/m^2 STANDARD_DEVIATION 5.359 • n=7 Participants	26.52 kg/m^2 STANDARD_DEVIATION 5.416 • n=5 Participants
Chronic Obstructive Pulmonary Disease (COPD) Severity Mild	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Chronic Obstructive Pulmonary Disease (COPD) Severity Moderate	18 participants n=5 Participants	16 participants n=7 Participants	34 participants n=5 Participants
Chronic Obstructive Pulmonary Disease (COPD) Severity Severe	658 participants n=5 Participants	677 participants n=7 Participants	1335 participants n=5 Participants
Chronic Obstructive Pulmonary Disease (COPD) Severity Very Severe	291 participants n=5 Participants	273 participants n=7 Participants	564 participants n=5 Participants
COPD Disease Characteristics Pure emphysema	4 participants n=5 Participants	2 participants n=7 Participants	6 participants n=5 Participants
COPD Disease Characteristics Predominantly chronic bronchitis	338 participants n=5 Participants	330 participants n=7 Participants	668 participants n=5 Participants
COPD Disease Characteristics Combined emphysema and chronic bronchitis	626 participants n=5 Participants	634 participants n=7 Participants	1260 participants n=5 Participants
COPD Disease Characteristics Missing	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group A : low risk, less symptoms	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group B: low risk, more symptoms	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group C: high risk, less symptoms	62 participants n=5 Participants	57 participants n=7 Participants	119 participants n=5 Participants
Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group D: high risk, more symptoms	905 participants n=5 Participants	907 participants n=7 Participants	1812 participants n=5 Participants
Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group Missing	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Smoking Status Current smoker	411 participants n=5 Participants	432 participants n=7 Participants	843 participants n=5 Participants
Smoking Status Former smoker	558 participants n=5 Participants	534 participants n=7 Participants	1092 participants n=5 Participants
Smoking Status Nonsmoker	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Cigarette Pack Years	47.6 pack years STANDARD_DEVIATION 24.55 • n=5 Participants	47.6 pack years STANDARD_DEVIATION 23.56 • n=7 Participants	47.6 pack years STANDARD_DEVIATION 24.6 • n=5 Participants
Pre-bronchodilator Forced Expiratory Volume in the First Second (FEV1)	0.999 Liters STANDARD_DEVIATION 0.3149 • n=5 Participants	1.016 Liters STANDARD_DEVIATION 0.3209 • n=7 Participants	1.008 Liters STANDARD_DEVIATION 0.3180 • n=5 Participants
Post-bronchodilator FEV1	1.066 Liters STANDARD_DEVIATION 0.3317 • n=5 Participants	1.078 Liters STANDARD_DEVIATION 0.3244 • n=7 Participants	1.072 Liters STANDARD_DEVIATION 0.3280 • n=5 Participants
Pre-bronchodilator FEV1 Predicted	33.259 percent of predicted STANDARD_DEVIATION 9.0781 • n=5 Participants	33.562 percent of predicted STANDARD_DEVIATION 9.0043 • n=7 Participants	33.411 percent of predicted STANDARD_DEVIATION 9.0402 • n=5 Participants
Post-bronchodilator FEV1 Predicted	35.392 percent predicted STANDARD_DEVIATION 9.2484 • n=5 Participants	35.532 percent predicted STANDARD_DEVIATION 8.7573 • n=7 Participants	35.462 percent predicted STANDARD_DEVIATION 9.0045 • n=5 Participants
FEV1 Reversibility % Increase	7.465 percent reversibility STANDARD_DEVIATION 11.2559 • n=5 Participants	7.383 percent reversibility STANDARD_DEVIATION 12.0752 • n=7 Participants	7.424 percent reversibility STANDARD_DEVIATION 11.6703 • n=5 Participants
FEV1 Reversibility Increase	65.2 mL STANDARD_DEVIATION 108.72 • n=5 Participants	65.4 mL STANDARD_DEVIATION 121.55 • n=7 Participants	65.3 mL STANDARD_DEVIATION 115.29 • n=5 Participants
Post-bronchodilator FEV1/Forced Vital Capacity (FVC)	40.2 FEV1/FVC percent STANDARD_DEVIATION 10.81 • n=5 Participants	40.1 FEV1/FVC percent STANDARD_DEVIATION 10.26 • n=7 Participants	40.1 FEV1/FVC percent STANDARD_DEVIATION 10.54 • n=5 Participants

PRIMARY outcome

Timeframe: 52 weeks

Population: 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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year	0.805 exacerbations per patient per year Interval 0.724 to 0.895	0.927 exacerbations per patient per year Interval 0.843 to 1.02

SECONDARY outcome

Timeframe: Baseline and Week 52

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=928 Participants 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 n=941 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1)	0.052 liters Standard Error 0.0064	-0.004 liters Standard Error 0.0062

SECONDARY outcome

Timeframe: 52 weeks

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Rate of Severe COPD Exacerbations Per Patient Per Year	0.239 exacerbations per patient per year Interval 0.201 to 0.283	0.315 exacerbations per patient per year Interval 0.27 to 0.368

SECONDARY outcome

Timeframe: 52 weeks

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Rate of COPD Exacerbations Per Patient Per Year All Categories Moderate	0.574 exacerbations per patient per year Interval 0.508 to 0.648	0.627 exacerbations per patient per year Interval 0.561 to 0.702
Rate of COPD Exacerbations Per Patient Per Year All Categories Mild, Moderate or Severe	3.078 exacerbations per patient per year Interval 2.723 to 3.479	3.879 exacerbations per patient per year Interval 3.492 to 4.31
Rate of COPD Exacerbations Per Patient Per Year All Categories Leading to Hospitalisation	0.238 exacerbations per patient per year Interval 0.2 to 0.283	0.313 exacerbations per patient per year Interval 0.268 to 0.365
Rate of COPD Exacerbations Per Patient Per Year All Categories Glucocorticosteroids and/or Antibiotics treatment	0.794 exacerbations per patient per year Interval 0.716 to 0.88	0.929 exacerbations per patient per year Interval 0.847 to 1.019
Rate of COPD Exacerbations Per Patient Per Year All Categories Moderate or Severe and/or treated with Antibiotics	1.012 exacerbations per patient per year Interval 0.922 to 1.11	1.210 exacerbations per patient per year Interval 1.115 to 1.313

SECONDARY outcome

Timeframe: 52 weeks

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Percentage of Participants Experiencing at Least 1 COPD Exacerbation	55.2 percentage of participants	60.5 percentage of participants

SECONDARY outcome

Timeframe: 52 Weeks

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Time to First COPD Exacerbation All Categories	218.0 days Interval 189.0 to 259.0	180.0 days Interval 147.0 to 200.0

SECONDARY outcome

Timeframe: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Time to Second Moderate or Severe COPD Exacerbation	421.0 days Interval 413.0 to 95% confidence interval upper limit not estimated.	NA days Parameters not estimated-data did not reach the median.

SECONDARY outcome

Timeframe: 52 Weeks

Population: 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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Time to Third Moderate or Severe COPD Exacerbation	NA days Parameters not estimated-data did not reach the median.	NA days Parameters not estimated-data did not reach the median.

SECONDARY outcome

Timeframe: 52 Weeks

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation Derived From Exacerbation Per Patient Per Year	0.805 participants	0.927 participants

SECONDARY outcome

Timeframe: 52 Weeks

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=380 Participants 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 n=432 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Number of Moderate or Severe COPD Exacerbation Days	26.9 days Standard Deviation 23.09	30.9 days Standard Deviation 29.49

SECONDARY outcome

Timeframe: 52 Weeks

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=380 Participants 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 n=432 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Duration of Moderate or Severe COPD Exacerbations Per Participant	15.9 days Standard Deviation 10.59	16.6 days Standard Deviation 14.49

SECONDARY outcome

Timeframe: 52 weeks

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=928 Participants 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 n=941 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC)	0.036 liters Standard Error 0.0114	-0.057 liters Standard Error 0.0111

SECONDARY outcome

Timeframe: 52 weeks

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=928 Participants 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 n=941 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Change From Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%)	0.035 liters/second Standard Error 0.0044	0.009 liters/second Standard Error 0.0043

SECONDARY outcome

Timeframe: 52 weeks

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=924 Participants 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 n=937 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6)	0.061 liters Standard Error 0.0093	-0.033 liters Standard Error 0.0091

SECONDARY outcome

Timeframe: 52 weeks

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=701 Participants 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 n=780 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Change From Baseline in Post-Bronchodilator FEV1/FVC	1.170 percent Standard Deviation 7.0339	0.580 percent Standard Deviation 6.8405

SECONDARY outcome

Timeframe: Baseline and Week 52

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=848 Participants 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 n=896 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Change From Baseline in Use of Rescue Medication From Daily Diary	-0.109 puffs per day Standard Error 0.0676	0.173 puffs per day Standard Error 0.0654

SECONDARY outcome

Timeframe: 52 weeks

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).

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=897 Participants 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 n=932 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Change From Baseline in COPD Symptom Score From Daily Diary	-0.412 score on a scale Standard Error 0.0315	-0.398 score on a scale Standard Error 0.0306

SECONDARY outcome

Timeframe: 52 Weeks

Symptoms of COPD (cough, sputum) were recorded in a daily diary. The percentage of days without symptoms is reported.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Percentage of Symptom-Free Days	7.09 percentage of days Standard Deviation 17.119	6.88 percentage of days Standard Deviation 16.185

SECONDARY outcome

Timeframe: 52 Weeks

Participants recorded their use of rescue medication in a daily diary. The percentage of days without rescue medication use.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Percentage of Rescue Medication-Free Days	23.25 percentage of days Standard Deviation 33.734	22.77 percentage of days Standard Deviation 33.141

SECONDARY outcome

Timeframe: Baseline and Week 52

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=924 Participants 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 n=940 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Change From Baseline in COPD Assessment Test (CAT) Total Score	-1.270 score on a scale Standard Error 0.1556	-0.985 score on a scale Standard Error 0.1518

SECONDARY outcome

Timeframe: Baseline and Week 52

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Percentage of Participants With Improvement in CAT	71.2 percentage of participants	72.5 percentage of participants

SECONDARY outcome

Timeframe: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)

Population: 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.

Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Time to Mortality Due to Any Reason During the Treatment Period Score	NA days Interval 44.0 to 381.0 Data did not reach the median.	NA days Interval 21.0 to 293.0 Data did not reach the median.

SECONDARY outcome

Timeframe: 52 Weeks

Population: 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.

Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Time to Mortality Due to COPD Exacerbation During the Treatment Period	NA days Interval 44.0 to 322.0 Data did not reach the median.	NA days Interval 25.0 to 293.0 Data did not reach the median.

SECONDARY outcome

Timeframe: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)

Population: 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.

Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Time to Withdrawal During the Treatment Period	420.0 days Interval 5.0 to 428.0	444.0 days Interval 1.0 to 444.0

SECONDARY outcome

Timeframe: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)

Population: 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.

Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Time to Withdrawal Due to COPD Exacerbation During the Treatment Period	NA days Interval 25.0 to 371.0 Data did not reach the median.	NA days Interval 12.0 to 319.0 Data did not reach the median.

SECONDARY outcome

Timeframe: 52 Weeks

Composite MACE is a combined endpoint (cardiovascular death \[including death due to undetermined cause\], nonfatal myocardial infarction, and nonfatal stroke).

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period	1.7 percentage of participants	1.7 percentage of participants

SECONDARY outcome

Timeframe: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Time to First Major Adverse Cardiovascular Event (MACE) During the Treatment Period	NA days Interval 52.0 to 415.0 Data did not reach the median.	NA days Interval 50.0 to 365.0 Data did not reach the median.

SECONDARY outcome

Timeframe: 52 Weeks

Percentage of patients with at least one hospital admission due to any cause.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Percentage of Participant With All-Cause Hospitalisation During the Treatment Period	24.9 percentage of participants	29.3 percentage of participants

SECONDARY outcome

Timeframe: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)

Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Time to First Hospitalisation Due to Any Cause During the Treatment Period	400.0 days Interval 387.0 to 415.0	408.0 days Interval 391.0 to 420.0

SECONDARY outcome

Timeframe: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)

Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=969 Participants 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 n=966 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Time to Trial Withdrawal Due to an Adverse Event	NA days Interval 7.0 to 420.0 Data did not reach the median.	NA days Interval 13.0 to 444.0 Data did not reach the median.

SECONDARY outcome

Timeframe: 52 Weeks

Population: Safety Population included all randomized participants who received at least one dose of study drug.

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=968 Participants 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 n=967 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE)	66.9 percentage of participants	59.2 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: Participants from the Safety Population, all randomized participants who received at least one dose of study drug, with data available for analysis.

Least Square Means was from an ANCOVA model including Last Observation Carried Forward (LOCF).

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=938 Participants 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 n=944 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Change From Baseline in Body Weight	-2.66 kilogram (kg) Standard Error 0.130	-0.14 kilogram (kg) Standard Error 0.130

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: Participants from the Safety Population, all randomized participants who received at least one dose of study drug, with data available for analysis.

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.

Outcome measures

Outcome measures
Measure	Roflumilast 500 µg n=938 Participants 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 n=944 Participants Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Change From Baseline in Body Mass Index (BMI)	-0.94 kg/m^2 Standard Error 0.046	-0.04 kg/m^2 Standard Error 0.046

Adverse Events

Roflumilast 500 µg

Serious events: 249 serious events

Other events: 228 other events

Deaths: 0 deaths

Placebo

Serious events: 285 serious events

Other events: 114 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Roflumilast 500 µg n=968 participants at risk 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 n=967 participants at risk Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Gastrointestinal disorders Diarrhoea	10.0% 97/968 • 52 weeks Safety Population included all randomized participants who received at least one dose of study drug.	3.4% 33/967 • 52 weeks Safety Population included all randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Nausea	5.7% 55/968 • 52 weeks Safety Population included all randomized participants who received at least one dose of study drug.	1.6% 15/967 • 52 weeks Safety Population included all randomized participants who received at least one dose of study drug.
Infections and infestations Nasopharyngitis	5.4% 52/968 • 52 weeks Safety Population included all randomized participants who received at least one dose of study drug.	5.4% 52/967 • 52 weeks Safety Population included all randomized participants who received at least one dose of study drug.
Investigations Weight decreased	8.7% 84/968 • 52 weeks Safety Population included all randomized participants who received at least one dose of study drug.	2.8% 27/967 • 52 weeks Safety Population included all randomized participants who received at least one dose of study drug.

Additional Information

AstraZeneca Clinical Study Information Center

AstraZeneca

Phone: 1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER