COPD
Conditions
Keywords
COPD, Roflumilast, FEV1, China
Brief summary
The aim of this trial is to determine the efficacy, safety and tolerability of 500 µg Roflumilast tablets once daily in patients with COPD in China, Hong Kong, and Singapore.
Interventions
DRUGRoflumilast
Roflumilast tablets
DRUGPlacebo
Placebo tablets
DRUGSalbutamol
Salbutamol (given by MDI and spacer) used as rescue medication on an ass needed basis throughout the trial, and was used for post-bronchodilator spirometry tests at all study visits.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Willingness to sign a written informed consent * Chronic obstructive pulmonary disease (COPD) according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines 2009 * Chinese or Malay or Indian ethnicity * History of chronic obstructive pulmonary disease symptoms for at least 12 months prior to baseline visit V0 * Forced expiratory volume in the first second/ Forced vital capacity (FEV1/FVC) ratio (post-bronchodilator) \< 70% * Forced expiratory volume in the first second (FEV1) (post-bronchodilator) \< 50 % of predicted * Former smoker (defined as: smoking cessation at least one year ago) or current smoker both with a smoking history of at least 10 pack years Main
Exclusion criteria
* Moderate or severe COPD exacerbation and/or COPD exacerbations treated with antibiotics not stopped at V0 * Lower respiratory tract infection not resolved 4 weeks prior to the baseline visit V0 * History of asthma diagnosis in patients \< 40 years of age or relevant lung disease other than COPD * Current participation in a pulmonary rehabilitation program or completion of a pulmonary rehabilitation program within 3 months preceding the baseline visit V0 * Known alpha-1-antitrypsin deficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) | Baseline to Week 24 | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV1, time and a treatment-by-time interaction as independent variables. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) | Baseline to Week 24 | Vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Post-bronchodilator Forced Vital Capacity (FVC) | Baseline to Week 24 | Vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Pre-bronchodilator Forced Expiratory Flow 25-75% | Baseline to Week 24 | Forced expiratory flow 25-75% (FEF25-75%) is the flow (or speed) of air coming out of the lung during the middle half of a forced expiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Post-bronchodilator Forced Expiratory Flow 25-75% | Baseline to Week 24 | Forced expiratory flow 25-75% (FEF25-75%) is the flow (or speed) of air coming out of the lung during the middle half of a forced expiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3) | Baseline to Week 24 | FEV3 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV3, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Post-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3) | Baseline to Week 24 | FEV3 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV3, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6) | Baseline to Week 24 | FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first six seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV6, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Post-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6) | Baseline to Week 24 | FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV6, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Pre-bronchodilator Peak Expiratory Flow Rate (PEF) | Baseline to Week 24 | PEF is the maximal flow (or speed) achieved during the maximally forced expiration initiated at full inspiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Post-bronchodilator Peak Expiratory Flow Rate (PEF) | Baseline to Week 24 | PEF is the maximal flow (or speed) achieved during the maximally forced expiration initiated at full inspiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Pre-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Vital Capacity | Baseline and Week 24 | The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. |
| Change From Baseline in Post-bronchodilator FEV1 | Baseline to Week 24 | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV1, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Pre-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Expiratory Volume After 6 Seconds | Baseline and Week 24 | The FEV1/FEV6 ratio represents the percentage of the volume of air expired in the first six seconds that is expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. |
| Change From Baseline in Post-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Expiratory Volume After 6 Seconds | Baseline and Week 24 | The FEV1/FEV6 ratio represents the percentage of the volume of air expired in the first six seconds that is expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. |
| Change From Baseline in COPD Symptom Scores | Baseline to Week 24 | Symptoms of chronic bronchitis with respect to cough and sputum production were assessed daily by the patient and recorded in a diary. Symptoms were assessed on a 4-point scale as follows: Cough: 0: no cough; 1: mild cough (at some time during the day); 2: moderate cough (regularly during the day); 3: severe cough (never free of cough or feeling free of need to cough). Sputum production: 0: no sputum production (unnoticeable); 1: mild sputum production (noticeable as a problem); 2: moderate sputum production (frequent inconvenience); 3: severe sputum production (constant problem). Change from Baseline is reported for cough and sputum separately, and for the sum of the 2 scores (range 0 - 6). Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables. |
| Change From Baseline in Use of Rescue Medication | Baseline to Week 24 | Salbutamol (given by metered dose inhaler and spacer) was used as rescue medication according to the individual needs of a patient. Each use was documented in the patient's paper diary. Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables. |
| Transition Dyspnoea Index (TDI) Total Score at Week 24 | Baseline to Week 24 | The TDI is a recognized questionnaire to measure dyspnoea (shortness of breath) in patients with COPD. Questions from the TDI were used to assess the 3 components: change in functional impairment, change in magnitude of task and change in magnitude of effort. Transitions or changes from baseline are rated from -3 (major deterioration) to +3 (major improvement), and summed to give a total score ranging from -9 to +9. Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables. |
| Percentage of Participants With Moderate or Severe COPD Exacerbations | 24 weeks | A COPD exacerbation is an event characterised by a worsening in the patient's baseline dyspnoea, or cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management, and may be accompanied by increased wheeze, chest tightness, purulent sputum and symptoms of cold and/or fatigue. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy. |
| Mean Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year | 24 weeks | The mean rate of COPD exacerbations per patient per year rate = (number of exacerbations per treatment group/time to study withdrawal per treatment group) \* 365. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy. |
| Time to Onset of First Moderate or Severe COPD Exacerbation | 24 weeks | Time to onset of a COPD exacerbation is defined as onset date of COPD exacerbation - date of first intake of study drug + 1 day. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy. |
| Time to Onset of Second Moderate or Severe COPD Exacerbation | 24 weeks | Time to onset of a COPD exacerbation is defined as onset date of COPD exacerbation - date of first intake of study drug + 1 day. At least 10 days between the stop date of an exacerbation and the start date of the following exacerbation was required for these to be be considered as two separate COPD exacerbations. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy. |
| Number of Participants With Adverse Events | 24 weeks | An adverse event (AE) is any untoward medical occurrence in a clinical trial participant regardless of causal relationship to study drug and regardless whether study drug has been administered. A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. A non-serious AE is any AE that does not meet the criteria above. Each AE was assessed by the Investigator as either 'related' or 'not related' to study drug. |
| Change From Baseline in Post-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Vital Capacity | Baseline and Week 24 | The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. |
Countries
China, Hong Kong, Singapore
Participant flow
Recruitment details
Participants took part in the study at 43 investigative sites in mainland China, Hong Kong and Singapore from 04 Mar 2011 to 16 May 2012.
Pre-assignment details
Participants with a diagnosis of chronic obstructive pulmonary disease (COPD) were randomized in 1 of 2 treatment groups (placebo and roflumilast 500 μg once daily).
Participants by arm
| Arm | Count |
|---|---|
| Roflumilast Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks. | 313 |
| Placebo Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks. | 313 |
| Total | 626 |
Baseline characteristics
| Characteristic | Roflumilast | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 64.2 Years STANDARD_DEVIATION 8.76 | 64.1 Years STANDARD_DEVIATION 8.51 | 64.0 Years STANDARD_DEVIATION 8.27 |
| Body Mass Index (BMI) | 21.8 kg/m^2 STANDARD_DEVIATION 3.42 | 22.1 kg/m^2 STANDARD_DEVIATION 3.44 | 22.4 kg/m^2 STANDARD_DEVIATION 3.43 |
| Chronic obstructive pulmonary disease (COPD) severity Mild | 1 Participants | 2 Participants | 1 Participants |
| Chronic obstructive pulmonary disease (COPD) severity Moderate | 28 Participants | 44 Participants | 16 Participants |
| Chronic obstructive pulmonary disease (COPD) severity Severe | 196 Participants | 400 Participants | 204 Participants |
| Chronic obstructive pulmonary disease (COPD) severity Very severe | 88 Participants | 180 Participants | 92 Participants |
| Cigarette pack years | 37.2 pack years STANDARD_DEVIATION 21.18 | 37.4 pack years STANDARD_DEVIATION 22.09 | 37.5 pack years STANDARD_DEVIATION 23 |
| COPD disease characteristics Combined emphysema and chronic bronchitis | 217 Participants | 433 Participants | 216 Participants |
| COPD disease characteristics Predominantly chronic bronchitis | 56 Participants | 117 Participants | 61 Participants |
| COPD disease characteristics Predominantly emphysema | 40 Participants | 76 Participants | 36 Participants |
| FEV1 reversibility increase | 108.4 mL STANDARD_DEVIATION 110.83 | 101.6 mL STANDARD_DEVIATION 107.94 | 94.8 mL STANDARD_DEVIATION 104.71 |
| FEV1 reversibility % increase | 13.6 Percent reversibility STANDARD_DEVIATION 15.29 | 12.7 Percent reversibility STANDARD_DEVIATION 14.27 | 11.8 Percent reversibility STANDARD_DEVIATION 13.15 |
| Gender Female | 30 Participants | 57 Participants | 27 Participants |
| Gender Male | 283 Participants | 569 Participants | 286 Participants |
| Height | 166.2 cm STANDARD_DEVIATION 7.27 | 166.1 cm STANDARD_DEVIATION 7.2 | 165.9 cm STANDARD_DEVIATION 7.12 |
| Post-bronchodilator FEV1 | 1.0 Liters STANDARD_DEVIATION 0.35 | 0.9 Liters STANDARD_DEVIATION 0.31 | 0.9 Liters STANDARD_DEVIATION 0.27 |
| Post-bronchodilator FEV1/forced vital capacity (FVC) | 35.8 FEV1/FVC percent STANDARD_DEVIATION 9.69 | 35.5 FEV1/FVC percent STANDARD_DEVIATION 9.31 | 35.3 FEV1/FVC percent STANDARD_DEVIATION 8.92 |
| Post-bronchodilator FEV1 predicted | 36.8 Percent of predicted STANDARD_DEVIATION 11.42 | 36.6 Percent of predicted STANDARD_DEVIATION 10.79 | 36.4 Percent of predicted STANDARD_DEVIATION 10.13 |
| Pre-bronchodilator FEV1 predicted | 32.7 Percent of predicted STANDARD_DEVIATION 10.23 | 32.7 Percent of predicted STANDARD_DEVIATION 9.63 | 32.7 Percent of predicted STANDARD_DEVIATION 9 |
| Pre-bronchodilator forced expiratory volume in the first second (FEV1) | 0.8 Liters STANDARD_DEVIATION 0.31 | 0.8 Liters STANDARD_DEVIATION 0.28 | 0.8 Liters STANDARD_DEVIATION 0.24 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 313 Participants | 626 Participants | 313 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Smoking status Current smoker | 75 Participants | 167 Participants | 92 Participants |
| Smoking status Former smoker | 238 Participants | 459 Participants | 221 Participants |
| Weight | 60.4 kg STANDARD_DEVIATION 11 | 61.1 kg STANDARD_DEVIATION 10.78 | 61.8 kg STANDARD_DEVIATION 10.54 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 143 / 315 | 133 / 311 |
| serious Total, serious adverse events | 62 / 315 | 48 / 311 |
Outcome results
Primary
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)
FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV1, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population included all randomly assigned patients who took at least 1 dose of trial treatment after randomization. Patients were assigned to the treatment group based on the treatment to which they were randomly assigned. Only patients with available data at Baseline and with at least 1 post-baseline measurement are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) | 0.049 liters | Standard Error 0.009 |
| Placebo | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) | -0.022 liters | Standard Error 0.009 |
Comparison: The primary endpoint was tested in a confirmatory manner with a 2-sided significance level of 5%.p-value: <0.000195% CI: [0.046, 0.095]Repeated measures ANCOVA
Secondary
Change From Baseline in COPD Symptom Scores
Symptoms of chronic bronchitis with respect to cough and sputum production were assessed daily by the patient and recorded in a diary. Symptoms were assessed on a 4-point scale as follows: Cough: 0: no cough; 1: mild cough (at some time during the day); 2: moderate cough (regularly during the day); 3: severe cough (never free of cough or feeling free of need to cough). Sputum production: 0: no sputum production (unnoticeable); 1: mild sputum production (noticeable as a problem); 2: moderate sputum production (frequent inconvenience); 3: severe sputum production (constant problem). Change from Baseline is reported for cough and sputum separately, and for the sum of the 2 scores (range 0 - 6). Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Roflumilast | Change From Baseline in COPD Symptom Scores | Score Sum (n=282, 296) | 0.013 units on a scale | Standard Error 0.054 |
| Roflumilast | Change From Baseline in COPD Symptom Scores | Cough (n=284, 299) | -0.019 units on a scale | Standard Error 0.029 |
| Roflumilast | Change From Baseline in COPD Symptom Scores | Sputum (n=284, 296) | 0.035 units on a scale | Standard Error 0.03 |
| Placebo | Change From Baseline in COPD Symptom Scores | Score Sum (n=282, 296) | 0.064 units on a scale | Standard Error 0.053 |
| Placebo | Change From Baseline in COPD Symptom Scores | Cough (n=284, 299) | 0.036 units on a scale | Standard Error 0.028 |
| Placebo | Change From Baseline in COPD Symptom Scores | Sputum (n=284, 296) | 0.037 units on a scale | Standard Error 0.029 |
Secondary
Change From Baseline in Post-bronchodilator FEV1
FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV1, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Post-bronchodilator FEV1 | 0.045 liters | Standard Error 0.009 |
| Placebo | Change From Baseline in Post-bronchodilator FEV1 | -0.023 liters | Standard Error 0.009 |
Secondary
Change From Baseline in Post-bronchodilator Forced Expiratory Flow 25-75%
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 prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Post-bronchodilator Forced Expiratory Flow 25-75% | 0.022 liters/second | Standard Error 0.005 |
| Placebo | Change From Baseline in Post-bronchodilator Forced Expiratory Flow 25-75% | -0.008 liters/second | Standard Error 0.005 |
Secondary
Change From Baseline in Post-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6)
FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV6, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Post-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6) | 0.078 liters | Standard Error 0.013 |
| Placebo | Change From Baseline in Post-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6) | -0.032 liters | Standard Error 0.013 |
Secondary
Change From Baseline in Post-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3)
FEV3 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV3, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Post-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3) | 0.064 liters | Standard Error 0.012 |
| Placebo | Change From Baseline in Post-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3) | -0.030 liters | Standard Error 0.011 |
Secondary
Change From Baseline in Post-bronchodilator Forced Vital Capacity (FVC)
Vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Post-bronchodilator Forced Vital Capacity (FVC) | 0.094 liters | Standard Error 0.017 |
| Placebo | Change From Baseline in Post-bronchodilator Forced Vital Capacity (FVC) | -0.007 liters | Standard Error 0.016 |
Secondary
Change From Baseline in Post-bronchodilator Peak Expiratory Flow Rate (PEF)
PEF is the maximal flow (or speed) achieved during the maximally forced expiration initiated at full inspiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Post-bronchodilator Peak Expiratory Flow Rate (PEF) | 0.099 liters/minute | Standard Error 0.027 |
| Placebo | Change From Baseline in Post-bronchodilator Peak Expiratory Flow Rate (PEF) | -0.030 liters/minute | Standard Error 0.027 |
Secondary
Change From Baseline in Post-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Expiratory Volume After 6 Seconds
The FEV1/FEV6 ratio represents the percentage of the volume of air expired in the first six seconds that is expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol.
Time frame: Baseline and Week 24
Population: Intent-to-treat population with available data; last observation carried forward (LOCF) was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Post-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Expiratory Volume After 6 Seconds | -0.340 percentage of FEV1/FEV6 | Full Range 3.724 |
| Placebo | Change From Baseline in Post-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Expiratory Volume After 6 Seconds | -0.420 percentage of FEV1/FEV6 | Full Range 4.1957 |
Secondary
Change From Baseline in Post-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Vital Capacity
The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol.
Time frame: Baseline and Week 24
Population: Intent-to-treat population with available data; last observation carried forward (LOCF) was used.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Post-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Vital Capacity | -0.320 percent FEV1/FVC | Full Range 4.54 |
| Placebo | Change From Baseline in Post-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Vital Capacity | -0.940 percent FEV1/FVC | Full Range 5.1677 |
Secondary
Change From Baseline in Pre-bronchodilator Forced Expiratory Flow 25-75%
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 prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Pre-bronchodilator Forced Expiratory Flow 25-75% | 0.023 liters/second | Standard Error 0.005 |
| Placebo | Change From Baseline in Pre-bronchodilator Forced Expiratory Flow 25-75% | -0.010 liters/second | Standard Error 0.005 |
Secondary
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Six 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 prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV6, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6) | 0.084 liters | Standard Error 0.014 |
| Placebo | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6) | -0.031 liters | Standard Error 0.014 |
Secondary
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3)
FEV3 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV3, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3) | 0.072 liters | Standard Error 0.012 |
| Placebo | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3) | -0.030 liters | Standard Error 0.012 |
Secondary
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC)
Vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) | 0.100 liters | Standard Error 0.017 |
| Placebo | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) | -0.009 liters | Standard Error 0.017 |
Secondary
Change From Baseline in Pre-bronchodilator Peak Expiratory Flow Rate (PEF)
PEF is the maximal flow (or speed) achieved during the maximally forced expiration initiated at full inspiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Pre-bronchodilator Peak Expiratory Flow Rate (PEF) | 0.096 liters/minute | Standard Error 0.027 |
| Placebo | Change From Baseline in Pre-bronchodilator Peak Expiratory Flow Rate (PEF) | -0.036 liters/minute | Standard Error 0.026 |
Secondary
Change From Baseline in Pre-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Expiratory Volume After 6 Seconds
The FEV1/FEV6 ratio represents the percentage of the volume of air expired in the first six seconds that is expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication.
Time frame: Baseline and Week 24
Population: Intent-to-treat population with available data; last observation carried forward (LOCF) was used.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Pre-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Expiratory Volume After 6 Seconds | -0.210 percentage of FEV1/FEV6 | Full Range 3.9213 |
| Placebo | Change From Baseline in Pre-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Expiratory Volume After 6 Seconds | -0.950 percentage of FEV1/FEV6 | Full Range 3.9173 |
Secondary
Change From Baseline in Pre-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Vital Capacity
The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication.
Time frame: Baseline and Week 24
Population: Intent-to-treat population with available data; last observation carried forward (LOCF) was used.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Pre-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Vital Capacity | -0.570 percent FEV1/FVC | Full Range 4.5667 |
| Placebo | Change From Baseline in Pre-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Vital Capacity | -1.370 percent FEV1/FVC | Full Range 4.9968 |
Secondary
Change From Baseline in Use of Rescue Medication
Salbutamol (given by metered dose inhaler and spacer) was used as rescue medication according to the individual needs of a patient. Each use was documented in the patient's paper diary. Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Change From Baseline in Use of Rescue Medication | -0.485 puffs/day | Standard Error 0.134 |
| Placebo | Change From Baseline in Use of Rescue Medication | -0.518 puffs/day | Standard Error 0.131 |
Secondary
Mean Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year
The mean rate of COPD exacerbations per patient per year rate = (number of exacerbations per treatment group/time to study withdrawal per treatment group) \* 365. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
Time frame: 24 weeks
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roflumilast | Mean Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year | 0.55 exacerbations per patient per year |
| Placebo | Mean Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year | 0.44 exacerbations per patient per year |
Secondary
Number of Participants With Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical trial participant regardless of causal relationship to study drug and regardless whether study drug has been administered. A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. A non-serious AE is any AE that does not meet the criteria above. Each AE was assessed by the Investigator as either 'related' or 'not related' to study drug.
Time frame: 24 weeks
Population: Safety population, all randomized patients who took at least 1 dose of the trial treatment after randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Roflumilast | Number of Participants With Adverse Events | Non-serious AEs | 189 participants |
| Roflumilast | Number of Participants With Adverse Events | AEs with suggested relationship to trial treatment | 65 participants |
| Roflumilast | Number of Participants With Adverse Events | Death | 2 participants |
| Roflumilast | Number of Participants With Adverse Events | AEs leading to withdrawal from the trial | 15 participants |
| Roflumilast | Number of Participants With Adverse Events | Serious AEs (including death) | 62 participants |
| Roflumilast | Number of Participants With Adverse Events | AEs not recovered at trial termination | 54 participants |
| Roflumilast | Number of Participants With Adverse Events | Serious AEs not including death | 60 participants |
| Roflumilast | Number of Participants With Adverse Events | AEs with changes in concomitant medication | 164 participants |
| Roflumilast | Number of Participants With Adverse Events | All AEs | 213 participants |
| Placebo | Number of Participants With Adverse Events | AEs with changes in concomitant medication | 155 participants |
| Placebo | Number of Participants With Adverse Events | All AEs | 196 participants |
| Placebo | Number of Participants With Adverse Events | Non-serious AEs | 172 participants |
| Placebo | Number of Participants With Adverse Events | Serious AEs (including death) | 48 participants |
| Placebo | Number of Participants With Adverse Events | Death | 2 participants |
| Placebo | Number of Participants With Adverse Events | Serious AEs not including death | 46 participants |
| Placebo | Number of Participants With Adverse Events | AEs with suggested relationship to trial treatment | 18 participants |
| Placebo | Number of Participants With Adverse Events | AEs leading to withdrawal from the trial | 2 participants |
| Placebo | Number of Participants With Adverse Events | AEs not recovered at trial termination | 45 participants |
Secondary
Percentage of Participants With Moderate or Severe COPD Exacerbations
A COPD exacerbation is an event characterised by a worsening in the patient's baseline dyspnoea, or cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management, and may be accompanied by increased wheeze, chest tightness, purulent sputum and symptoms of cold and/or fatigue. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
Time frame: 24 weeks
Population: Intent-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Roflumilast | Percentage of Participants With Moderate or Severe COPD Exacerbations | No exacerbations | 81.8 percentage of participants |
| Roflumilast | Percentage of Participants With Moderate or Severe COPD Exacerbations | One exacerbation | 15.0 percentage of participants |
| Roflumilast | Percentage of Participants With Moderate or Severe COPD Exacerbations | Two exacerbations | 2.6 percentage of participants |
| Roflumilast | Percentage of Participants With Moderate or Severe COPD Exacerbations | Three exacerbations | 0.6 percentage of participants |
| Placebo | Percentage of Participants With Moderate or Severe COPD Exacerbations | Three exacerbations | 0.6 percentage of participants |
| Placebo | Percentage of Participants With Moderate or Severe COPD Exacerbations | No exacerbations | 84.7 percentage of participants |
| Placebo | Percentage of Participants With Moderate or Severe COPD Exacerbations | Two exacerbations | 1.9 percentage of participants |
| Placebo | Percentage of Participants With Moderate or Severe COPD Exacerbations | One exacerbation | 12.8 percentage of participants |
Secondary
Time to Onset of First Moderate or Severe COPD Exacerbation
Time to onset of a COPD exacerbation is defined as onset date of COPD exacerbation - date of first intake of study drug + 1 day. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
Time frame: 24 weeks
Population: Intent-to-treat population with at least one moderate or severe exacerbation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast | Time to Onset of First Moderate or Severe COPD Exacerbation | 67.0 days |
| Placebo | Time to Onset of First Moderate or Severe COPD Exacerbation | 86.0 days |
Secondary
Time to Onset of Second Moderate or Severe COPD Exacerbation
Time to onset of a COPD exacerbation is defined as onset date of COPD exacerbation - date of first intake of study drug + 1 day. At least 10 days between the stop date of an exacerbation and the start date of the following exacerbation was required for these to be be considered as two separate COPD exacerbations. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
Time frame: 24 weeks
Population: Intent-to-treat population who experienced a second moderate to severe COPD exacerbation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast | Time to Onset of Second Moderate or Severe COPD Exacerbation | 119.5 days |
| Placebo | Time to Onset of Second Moderate or Severe COPD Exacerbation | 117.0 days |
Secondary
Transition Dyspnoea Index (TDI) Total Score at Week 24
The TDI is a recognized questionnaire to measure dyspnoea (shortness of breath) in patients with COPD. Questions from the TDI were used to assess the 3 components: change in functional impairment, change in magnitude of task and change in magnitude of effort. Transitions or changes from baseline are rated from -3 (major deterioration) to +3 (major improvement), and summed to give a total score ranging from -9 to +9. Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.
Time frame: Baseline to Week 24
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast | Transition Dyspnoea Index (TDI) Total Score at Week 24 | 1.335 units on a scale | Standard Error 0.124 |
| Placebo | Transition Dyspnoea Index (TDI) Total Score at Week 24 | 1.396 units on a scale | Standard Error 0.122 |