Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD, Roflumilast, Daxas
Brief summary
The objective of the REACT trial is to investigate the effect of roflumilast 500 μg tablets once daily versus placebo on exacerbation rate and pulmonary function in COPD patients who are concomitantly treated with a fixed combination of long-acting β2-agonists (LABA) and inhaled glucocorticosteroids (ICS). In addition, data on safety and tolerability of roflumilast will be obtained. An additional objective is to further characterize the population pharmacokinetic profile of roflumilast and roflumilast N oxide and to further characterize their pharmacokinetics/pharmacodynamics (PK/PD) relationship in terms of efficacy and relevant safety aspects. Patients to be included are required to have severe COPD associated with chronic bronchitis and a history of frequent exacerbations and must be concomitantly treated with a fixed combination of LABA and ICS. Two parallel treatment arms (roflumilast 500 μg once daily and placebo) are included.
Detailed description
The drug tested in this study is called Roflumilast. Roflumilast is being developed to treat people who have chronic obstructive pulmonary disease (COPD). This study investigated the effect of roflumilast 500 μg tablets once daily versus placebo on exacerbation rate, pulmonary function, and major adverse cardiovascular events (MACE) in COPD patients who were concomitantly treated with a fixed combination of long-acting beta-agonists (LABA) and inhaled glucocorticosteroids. The study was targeted to enroll approximately 1934 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need): * Roflumilast 500 μg once daily * Placebo (dummy inactive pill) - this was a tablet that looked like the study drug but had no active ingredient Trial treatment was taken in the morning by mouth after breakfast with some water. The trial consisted of the following periods: * Single-blind baseline period (4 weeks) during which all patients received placebo. * Double-blind treatment period (52 weeks) during which patients received either roflumilast or matching placebo. * Safety follow-up (30 days after end of treatment (Vend) or premature discontinuation date) in case of ongoing Adverse Events at Vend, if necessary. * Follow-up visit 12 weeks after end of treatment, at Week 64 (VFU), only for patients who completed the trial as scheduled. This multi-center trial was conducted worldwide. The overall time to participate in this study was up to 64 weeks. Participants made multiple visits to the clinic which included a follow-up visit at week 64.
Interventions
DRUGRoflumilast
500 µg, once daily
DRUGPlacebo
once daily
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Giving written informed consent * History of COPD (according to GOLD 2009) for at least 12 months prior to baseline Visit V0 associated with chronic productive cough for 3 months in each of the 2 years prior to baseline visit (with other causes of productive cough excluded) * Age ≥ 40 years * Forced expiratory volume after one second (FEV1)/forced vital capacity (FVC) ratio (post-bronchodilator) \< 70% * FEV1 (post-bronchodilator) ≤ 50% of predicted * At least two documented moderate or severe COPD exacerbations within one year prior to baseline visit * Patients must be pre-treated with LABA and ICS for at least 12 months before baseline Visit V0. Up to 3 months before baseline Visit V0 free or fixed combinations of LABA and ICS are allowed, including changes in dose, active substances, and brands. In the last 3 months before baseline Visit V0 patients must be pre-treated with fixed combinations of LABA and ICS at a constant dose (maximum approved dosage strength of the combination). * Former smoker (defined as smoking cessation at least one year ago) or current smoker both with a smoking history of at least 20 pack years Main
Exclusion criteria
* Exacerbations not resolved at first baseline visit * Diagnosis of asthma and/or other relevant lung disease * Known alpha-1-antitrypsin deficiency * Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year | 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. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Severe COPD Exacerbations Per Patient Per Year | 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. |
| Rate of COPD Exacerbations Per Patient Per Year All Categories | 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. 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. |
| Percentage of Participants Experiencing at Least 1 COPD Exacerbation | 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. |
| Time to First COPD Exacerbation All Categories | 52 Weeks | 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 to Second Moderate or Severe COPD Exacerbation | 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) | 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 to Third Moderate or Severe COPD Exacerbation | 52 Weeks | 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. |
| Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation Derived From Exacerbation Per Patient Per Year | 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. |
| Number of Moderate or Severe COPD Exacerbation Days | 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. |
| Duration of Moderate or Severe COPD Exacerbations Per Participant | 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. |
| Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC) | 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. |
| Change From Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%) | 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. |
| Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6) | 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. |
| Change From Baseline in Post-Bronchodilator FEV1/FVC | 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. |
| Change From Baseline in Use of Rescue Medication From Daily Diary | 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. |
| Change From Baseline in COPD Symptom Score From Daily Diary | 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). |
| Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1) | 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. |
| Percentage of Rescue Medication-Free Days | 52 Weeks | Participants recorded their use of rescue medication in a daily diary. The percentage of days without rescue medication use. |
| Change From Baseline in COPD Assessment Test (CAT) Total Score | 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. |
| Percentage of Participants With Improvement in CAT | 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. |
| Time to Mortality Due to Any Reason During the Treatment Period Score | 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. |
| Time to Mortality Due to COPD Exacerbation During the Treatment Period | 52 Weeks | Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day. |
| Time to Withdrawal During the Treatment Period | 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. |
| Time to Withdrawal Due to COPD Exacerbation During the Treatment Period | 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. |
| Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period | 52 Weeks | Composite MACE is a combined endpoint (cardiovascular death \[including death due to undetermined cause\], nonfatal myocardial infarction, and nonfatal stroke). |
| Time to First Major Adverse Cardiovascular Event (MACE) During the Treatment Period | 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) | 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. |
| Percentage of Participant With All-Cause Hospitalisation During the Treatment Period | 52 Weeks | Percentage of patients with at least one hospital admission due to any cause. |
| Time to First Hospitalisation Due to Any Cause During the Treatment Period | 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. |
| Time to Trial Withdrawal Due to an Adverse Event | 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. |
| Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE) | 52 Weeks | 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. |
| Change From Baseline in Body Weight | Baseline and Week 52 | Least Square Means was from an ANCOVA model including Last Observation Carried Forward (LOCF). |
| Change From Baseline in Body Mass Index (BMI) | Baseline and Week 52 | 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. |
| Percentage of Symptom-Free Days | 52 Weeks | Symptoms of COPD (cough, sputum) were recorded in a daily diary. The percentage of days without symptoms is reported. |
Countries
Australia, Austria, Belgium, Brazil, Canada, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Netherlands, Poland, Russia, Slovakia, South Africa, South Korea, Spain, Turkey (Türkiye), United Kingdom
Participant flow
Recruitment details
Participants took part in the study at 203 investigative sites in Australia, Austria, Belgium, Brazil, Canada, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Korea (Republic of), Netherlands, Poland, Russia, Slovak Republic, South Africa, Spain, Turkey and United Kingdom from 28 May 2011 to 27 May 2014.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 969 |
| 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. | 966 |
| Total | 1,935 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 82 | 29 |
| Overall Study | COPD Exacerbation | 11 | 18 |
| Overall Study | Death | 16 | 19 |
| Overall Study | Lost to Follow-up | 8 | 5 |
| Overall Study | Met Pre-defined Discontinuation Criteria | 5 | 1 |
| Overall Study | Other | 14 | 20 |
| Overall Study | Physician Decision | 16 | 13 |
| Overall Study | Withdrawal by Subject | 117 | 87 |
Baseline characteristics
| Characteristic | Total | Placebo | Roflumilast 500 µg |
|---|---|---|---|
| Age, Continuous | 64.7 years STANDARD_DEVIATION 8.37 | 64.7 years STANDARD_DEVIATION 8.37 | 64.7 years STANDARD_DEVIATION 8.38 |
| Age, Customized ≤ 65 years | 1069 participants | 542 participants | 527 participants |
| Age, Customized > 65 years | 866 participants | 424 participants | 442 participants |
| Body Mass Index (BMI) | 26.52 kg/m^2 STANDARD_DEVIATION 5.416 | 26.58 kg/m^2 STANDARD_DEVIATION 5.359 | 26.45 kg/m^2 STANDARD_DEVIATION 5.474 |
| Chronic Obstructive Pulmonary Disease (COPD) Severity Mild | 2 participants | 0 participants | 2 participants |
| Chronic Obstructive Pulmonary Disease (COPD) Severity Moderate | 34 participants | 16 participants | 18 participants |
| Chronic Obstructive Pulmonary Disease (COPD) Severity Severe | 1335 participants | 677 participants | 658 participants |
| Chronic Obstructive Pulmonary Disease (COPD) Severity Very Severe | 564 participants | 273 participants | 291 participants |
| Cigarette Pack Years | 47.6 pack years STANDARD_DEVIATION 24.6 | 47.6 pack years STANDARD_DEVIATION 23.56 | 47.6 pack years STANDARD_DEVIATION 24.55 |
| COPD Disease Characteristics Combined emphysema and chronic bronchitis | 1260 participants | 634 participants | 626 participants |
| COPD Disease Characteristics Missing | 1 participants | 0 participants | 1 participants |
| COPD Disease Characteristics Predominantly chronic bronchitis | 668 participants | 330 participants | 338 participants |
| COPD Disease Characteristics Pure emphysema | 6 participants | 2 participants | 4 participants |
| FEV1 Reversibility Increase | 65.3 mL STANDARD_DEVIATION 115.29 | 65.4 mL STANDARD_DEVIATION 121.55 | 65.2 mL STANDARD_DEVIATION 108.72 |
| FEV1 Reversibility % Increase | 7.424 percent reversibility STANDARD_DEVIATION 11.6703 | 7.383 percent reversibility STANDARD_DEVIATION 12.0752 | 7.465 percent reversibility STANDARD_DEVIATION 11.2559 |
| Gender Female | 492 Participants | 241 Participants | 251 Participants |
| Gender Male | 1443 Participants | 725 Participants | 718 Participants |
| Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group A : low risk, less symptoms | 0 participants | 0 participants | 0 participants |
| Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group B: low risk, more symptoms | 0 participants | 0 participants | 0 participants |
| Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group C: high risk, less symptoms | 119 participants | 57 participants | 62 participants |
| Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group D: high risk, more symptoms | 1812 participants | 907 participants | 905 participants |
| Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group Missing | 4 participants | 2 participants | 2 participants |
| Height | 168.26 cm STANDARD_DEVIATION 8.427 | 168.33 cm STANDARD_DEVIATION 8.198 | 168.20 cm STANDARD_DEVIATION 8.652 |
| Post-bronchodilator FEV1 | 1.072 Liters STANDARD_DEVIATION 0.328 | 1.078 Liters STANDARD_DEVIATION 0.3244 | 1.066 Liters STANDARD_DEVIATION 0.3317 |
| Post-bronchodilator FEV1/Forced Vital Capacity (FVC) | 40.1 FEV1/FVC percent STANDARD_DEVIATION 10.54 | 40.1 FEV1/FVC percent STANDARD_DEVIATION 10.26 | 40.2 FEV1/FVC percent STANDARD_DEVIATION 10.81 |
| Post-bronchodilator FEV1 Predicted | 35.462 percent predicted STANDARD_DEVIATION 9.0045 | 35.532 percent predicted STANDARD_DEVIATION 8.7573 | 35.392 percent predicted STANDARD_DEVIATION 9.2484 |
| Pre-bronchodilator FEV1 Predicted | 33.411 percent of predicted STANDARD_DEVIATION 9.0402 | 33.562 percent of predicted STANDARD_DEVIATION 9.0043 | 33.259 percent of predicted STANDARD_DEVIATION 9.0781 |
| Pre-bronchodilator Forced Expiratory Volume in the First Second (FEV1) | 1.008 Liters STANDARD_DEVIATION 0.318 | 1.016 Liters STANDARD_DEVIATION 0.3209 | 0.999 Liters STANDARD_DEVIATION 0.3149 |
| Race/Ethnicity, Customized Asian | 36 participants | 16 participants | 20 participants |
| Race/Ethnicity, Customized Black or African American | 11 participants | 5 participants | 6 participants |
| Race/Ethnicity, Customized Other | 5 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized White | 1883 participants | 943 participants | 940 participants |
| Region of Enrollment Australia | 25 participants | 16 participants | 9 participants |
| Region of Enrollment Austria | 14 participants | 3 participants | 11 participants |
| Region of Enrollment Belgium | 37 participants | 18 participants | 19 participants |
| Region of Enrollment Brazil | 80 participants | 38 participants | 42 participants |
| Region of Enrollment Canada | 26 participants | 12 participants | 14 participants |
| Region of Enrollment Denmark | 34 participants | 19 participants | 15 participants |
| Region of Enrollment France | 29 participants | 13 participants | 16 participants |
| Region of Enrollment Germany | 133 participants | 63 participants | 70 participants |
| Region of Enrollment Greece | 68 participants | 30 participants | 38 participants |
| Region of Enrollment Hungary | 236 participants | 125 participants | 111 participants |
| Region of Enrollment Israel | 240 participants | 126 participants | 114 participants |
| Region of Enrollment Italy | 115 participants | 51 participants | 64 participants |
| Region of Enrollment Korea, Republic Of | 18 participants | 7 participants | 11 participants |
| Region of Enrollment Netherlands | 19 participants | 8 participants | 11 participants |
| Region of Enrollment Poland | 176 participants | 88 participants | 88 participants |
| Region of Enrollment Russian Federation | 358 participants | 181 participants | 177 participants |
| Region of Enrollment Slovakia | 58 participants | 33 participants | 25 participants |
| Region of Enrollment South Africa | 53 participants | 30 participants | 23 participants |
| Region of Enrollment Spain | 70 participants | 33 participants | 37 participants |
| Region of Enrollment Turkey | 96 participants | 44 participants | 52 participants |
| Region of Enrollment United Kingdom | 50 participants | 28 participants | 22 participants |
| Smoking Status Current smoker | 843 participants | 432 participants | 411 participants |
| Smoking Status Former smoker | 1092 participants | 534 participants | 558 participants |
| Smoking Status Nonsmoker | 0 participants | 0 participants | 0 participants |
| Weight | 75.33 kg STANDARD_DEVIATION 17.254 | 75.60 kg STANDARD_DEVIATION 17.238 | 75.07 kg STANDARD_DEVIATION 17.275 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 228 / 968 | 114 / 967 |
| serious Total, serious adverse events | 249 / 968 | 285 / 967 |
Outcome results
Primary
Rate of Moderate or 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. 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
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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Roflumilast 500 µg | Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year | 0.805 exacerbations per patient per year |
| Placebo | Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year | 0.927 exacerbations per patient per year |
p-value: 0.052995% CI: [0.753, 1.002]Generalized Linear Regression
Secondary
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
Population: Participants from the Safety Population, all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Change From Baseline in Body Mass Index (BMI) | -0.94 kg/m^2 | Standard Error 0.046 |
| Placebo | Change From Baseline in Body Mass Index (BMI) | -0.04 kg/m^2 | Standard Error 0.046 |
Secondary
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
Population: Participants from the Safety Population, all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Change From Baseline in Body Weight | -2.66 kilogram (kg) | Standard Error 0.13 |
| Placebo | Change From Baseline in Body Weight | -0.14 kilogram (kg) | Standard Error 0.13 |
Secondary
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Change From Baseline in COPD Assessment Test (CAT) Total Score | -1.270 score on a scale | Standard Error 0.1556 |
| Placebo | Change From Baseline in COPD Assessment Test (CAT) Total Score | -0.985 score on a scale | Standard Error 0.1518 |
p-value: 0.190995% CI: [-0.711, 0.142]Repeated measurement model
Secondary
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
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Change From Baseline in COPD Symptom Score From Daily Diary | -0.412 score on a scale | Standard Error 0.0315 |
| Placebo | Change From Baseline in COPD Symptom Score From Daily Diary | -0.398 score on a scale | Standard Error 0.0306 |
p-value: 0.739295% CI: [-0.101, 0.071]Repeated measurement model
Secondary
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Change From Baseline in Post-Bronchodilator FEV1/FVC | 1.170 percent | Standard Deviation 7.0339 |
| Placebo | Change From Baseline in Post-Bronchodilator FEV1/FVC | 0.580 percent | Standard Deviation 6.8405 |
Secondary
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
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | 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 |
| Placebo | Change From Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%) | 0.009 liters/second | Standard Error 0.0043 |
p-value: <0.000195% CI: [0.013, 0.038]Repeated measurement model
Secondary
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
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6) | 0.061 liters | Standard Error 0.0093 |
| Placebo | Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6) | -0.033 liters | Standard Error 0.0091 |
p-value: <0.000195% CI: [0.069, 0.12]Repeated measurement model
Secondary
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
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1) | 0.052 liters | Standard Error 0.0064 |
| Placebo | Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1) | -0.004 liters | Standard Error 0.0062 |
p-value: <0.000195% CI: [0.038, 0.073]ANCOVA
Secondary
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
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC) | 0.036 liters | Standard Error 0.0114 |
| Placebo | Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC) | -0.057 liters | Standard Error 0.0111 |
p-value: <0.000195% CI: [0.061, 0.124]Repeated measurement model
Secondary
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
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 included in the repeated measurements analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Change From Baseline in Use of Rescue Medication From Daily Diary | -0.109 puffs per day | Standard Error 0.0676 |
| Placebo | Change From Baseline in Use of Rescue Medication From Daily Diary | 0.173 puffs per day | Standard Error 0.0654 |
p-value: 0.002795% CI: [-0.467, -0.098]Repeated measurement model
Secondary
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
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. n in each of the categories is the number of participants with exacerbations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Duration of Moderate or Severe COPD Exacerbations Per Participant | 15.9 days | Standard Deviation 10.59 |
| Placebo | Duration of Moderate or Severe COPD Exacerbations Per Participant | 16.6 days | Standard Deviation 14.49 |
Secondary
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Number of Moderate or Severe COPD Exacerbation Days | 26.9 days | Standard Deviation 23.09 |
| Placebo | Number of Moderate or Severe COPD Exacerbation Days | 30.9 days | Standard Deviation 29.49 |
Secondary
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roflumilast 500 µg | Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation Derived From Exacerbation Per Patient Per Year | 0.805 participants |
| Placebo | Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation Derived From Exacerbation Per Patient Per Year | 0.927 participants |
95% CI: [4, 31]
Secondary
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roflumilast 500 µg | Percentage of Participants Experiencing at Least 1 COPD Exacerbation | 55.2 percentage of participants |
| Placebo | Percentage of Participants Experiencing at Least 1 COPD Exacerbation | 60.5 percentage of participants |
Secondary
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
Population: Safety Population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roflumilast 500 µg | Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE) | 66.9 percentage of participants |
| Placebo | Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE) | 59.2 percentage of participants |
Secondary
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roflumilast 500 µg | Percentage of Participants With Improvement in CAT | 71.2 percentage of participants |
| Placebo | Percentage of Participants With Improvement in CAT | 72.5 percentage of participants |
Secondary
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roflumilast 500 µg | Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period | 1.7 percentage of participants |
| Placebo | Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period | 1.7 percentage of participants |
Secondary
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roflumilast 500 µg | Percentage of Participant With All-Cause Hospitalisation During the Treatment Period | 24.9 percentage of participants |
| Placebo | Percentage of Participant With All-Cause Hospitalisation During the Treatment Period | 29.3 percentage of participants |
Secondary
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Percentage of Rescue Medication-Free Days | 23.25 percentage of days | Standard Deviation 33.734 |
| Placebo | Percentage of Rescue Medication-Free Days | 22.77 percentage of days | Standard Deviation 33.141 |
Secondary
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 500 µg | Percentage of Symptom-Free Days | 7.09 percentage of days | Standard Deviation 17.119 |
| Placebo | Percentage of Symptom-Free Days | 6.88 percentage of days | Standard Deviation 16.185 |
Secondary
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
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Roflumilast 500 µg | Rate of COPD Exacerbations Per Patient Per Year All Categories | Mild, Moderate or Severe | 3.078 exacerbations per patient per year |
| Roflumilast 500 µg | Rate of COPD Exacerbations Per Patient Per Year All Categories | Glucocorticosteroids and/or Antibiotics treatment | 0.794 exacerbations per patient per year |
| Roflumilast 500 µg | Rate of COPD Exacerbations Per Patient Per Year All Categories | Leading to Hospitalisation | 0.238 exacerbations per patient per year |
| Roflumilast 500 µg | 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 |
| Roflumilast 500 µg | Rate of COPD Exacerbations Per Patient Per Year All Categories | Moderate | 0.574 exacerbations per patient per year |
| Placebo | Rate of COPD Exacerbations Per Patient Per Year All Categories | Moderate or Severe and/or treated with Antibiotics | 1.210 exacerbations per patient per year |
| Placebo | Rate of COPD Exacerbations Per Patient Per Year All Categories | Moderate | 0.627 exacerbations per patient per year |
| Placebo | Rate of COPD Exacerbations Per Patient Per Year All Categories | Mild, Moderate or Severe | 3.879 exacerbations per patient per year |
| Placebo | Rate of COPD Exacerbations Per Patient Per Year All Categories | Leading to Hospitalisation | 0.313 exacerbations per patient per year |
| Placebo | Rate of COPD Exacerbations Per Patient Per Year All Categories | Glucocorticosteroids and/or Antibiotics treatment | 0.929 exacerbations per patient per year |
Comparison: Moderate COPD Exacerbationsp-value: 0.287595% CI: [0.775, 1.078]Generalized Linear Regression
Comparison: Mild, Moderate or Severe COPD Exacerbationsp-value: 0.00595% CI: [0.675, 0.933]Generalized Linear Regression
Comparison: COPD Exacerbations treated with Glucocorticosteroids and/or Antibioticsp-value: 0.026295% CI: [0.744, 0.982]Generalized Linear Regression
Comparison: Moderate or Severe COPD Exacerbations and/or treated with Antibioticsp-value: 0.004795% CI: [0.739, 0.947]Generalized Linear Regression
Comparison: Leading to Hospitalisationp-value: 0.020995% CI: [0.604, 0.96]Generalized Linear Regression
Secondary
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
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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Roflumilast 500 µg | Rate of Severe COPD Exacerbations Per Patient Per Year | 0.239 exacerbations per patient per year |
| Placebo | Rate of Severe COPD Exacerbations Per Patient Per Year | 0.315 exacerbations per patient per year |
p-value: 0.017595% CI: [0.601, 0.952]Generalized Linear Regression
Secondary
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
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast 500 µg | Time to First COPD Exacerbation All Categories | 218.0 days |
| Placebo | Time to First COPD Exacerbation All Categories | 180.0 days |
p-value: 0.146195% CI: [0.815, 1.031]Cox proportional hazards model
Secondary
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)
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 events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast 500 µg | Time to First Hospitalisation Due to Any Cause During the Treatment Period | 400.0 days |
| Placebo | Time to First Hospitalisation Due to Any Cause During the Treatment Period | 408.0 days |
p-value: 0.794395% CI: [0.821, 1.162]Cox-proportional hazards model
Secondary
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)
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast 500 µg | Time to First Major Adverse Cardiovascular Event (MACE) During the Treatment Period | NA days |
| Placebo | Time to First Major Adverse Cardiovascular Event (MACE) During the Treatment Period | NA days |
p-value: 0.820895% CI: [0.542, 2.167]Cox-proportional hazards model
Secondary
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)
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast 500 µg | Time to Mortality Due to Any Reason During the Treatment Period Score | NA days |
| Placebo | Time to Mortality Due to Any Reason During the Treatment Period Score | NA days |
p-value: 0.941495% CI: [0.528, 1.99]Cox-proportional hazards model
Secondary
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
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast 500 µg | Time to Mortality Due to COPD Exacerbation During the Treatment Period | NA days |
| Placebo | Time to Mortality Due to COPD Exacerbation During the Treatment Period | NA days |
p-value: 0.887695% CI: [0.378, 3.075]Cox-proportional hazards model
Secondary
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)
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast 500 µg | Time to Second Moderate or Severe COPD Exacerbation | 421.0 days |
| Placebo | Time to Second Moderate or Severe COPD Exacerbation | NA days |
p-value: 0.02795% CI: [0.641, 0.974]Wei-Lin-Weissfeld Method
Secondary
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
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast 500 µg | Time to Third Moderate or Severe COPD Exacerbation | NA days |
| Placebo | Time to Third Moderate or Severe COPD Exacerbation | NA days |
p-value: 0.073195% CI: [0.546, 1.027]Wei-Lin-Weissfeld Method
Secondary
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)
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 events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast 500 µg | Time to Trial Withdrawal Due to an Adverse Event | NA days |
| Placebo | Time to Trial Withdrawal Due to an Adverse Event | NA days |
Secondary
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)
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast 500 µg | Time to Withdrawal Due to COPD Exacerbation During the Treatment Period | NA days |
| Placebo | Time to Withdrawal Due to COPD Exacerbation During the Treatment Period | NA days |
p-value: 0.347795% CI: [0.326, 1.484]Cox-proportional hazards model
Secondary
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)
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roflumilast 500 µg | Time to Withdrawal During the Treatment Period | 420.0 days |
| Placebo | Time to Withdrawal During the Treatment Period | 444.0 days |
p-value: <0.000195% CI: [1.268, 1.845]Cox-proportional hazards model