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

Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1)

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

Rate of Severe COPD Exacerbations Per Patient Per Year

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

Rate of COPD Exacerbations Per Patient Per Year All Categories

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

Percentage of Participants Experiencing at Least 1 COPD Exacerbation

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

Time to First COPD Exacerbation All Categories

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

Time to Second Moderate or Severe COPD Exacerbation

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)

Time to Third Moderate or Severe COPD Exacerbation

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

Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation Derived From Exacerbation Per Patient Per Year

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

Number of Moderate or Severe COPD Exacerbation Days

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

Duration of Moderate or Severe COPD Exacerbations Per Participant

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

Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC)

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

Change From Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%)

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

Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6)

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

Change From Baseline in Post-Bronchodilator FEV1/FVC

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

Change From Baseline in Use of Rescue Medication From Daily Diary

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

Change From Baseline in COPD Symptom Score From Daily Diary

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

Percentage of Symptom-Free Days

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

Time frame: 52 Weeks

Percentage of Rescue Medication-Free Days

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

Time frame: 52 Weeks

Change From Baseline in COPD Assessment Test (CAT) Total Score

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

Percentage of Participants With Improvement in CAT

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

Time to Mortality Due to Any Reason During the Treatment Period Score

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)

Time to Mortality Due to COPD Exacerbation During the Treatment Period

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

Time to Withdrawal During the Treatment Period

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)

Time to Withdrawal Due to COPD Exacerbation During the Treatment Period

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)

Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period

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

Time frame: 52 Weeks

Time to First Major Adverse Cardiovascular Event (MACE) During the Treatment Period

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)

Percentage of Participant With All-Cause Hospitalisation During the Treatment Period

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

Time frame: 52 Weeks

Time to First Hospitalisation Due to Any Cause During the Treatment Period

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)

Time to Trial Withdrawal Due to an Adverse Event

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)

Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE)

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

Change From Baseline in Body Weight

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

Time frame: Baseline and Week 52

Change From Baseline in Body Mass Index (BMI)

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