Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to evaluate discontinuation rates of roflumilast using an up-titration regimen for the first 4 weeks of treatment compared with continuous treatment of 500 μg one daily (OD) during the entire 12-week main period, and to evaluate if participants who do not tolerate roflumilast 500 μg OD have a drug exposure with 250 μg roflumilast OD similar to that observed in other participants with the 500 μg OD dose.
Detailed description
Roflumilast is a product which has been approved for the treatment of severe chronic obstructive lung disease (COPD) and its approved dose is 500μg once daily. This study is primarily designed to see whether alternation in this dose can improve tolerability of Roflumilast in COPD patients. Therefore one in three patients will start roflumilast therapy at a lower dose of 250μg once daily, another one in three will only take the 500μg tablet every other day (and one placebo every other day). Rest of them will start the regular dose of 500μg once daily right away and see whether starting with a lower dose of Roflumilast will lead to better tolerability. Furthermore, the study will see if patients who do not tolerate roflumilast should be given a lower dose of 250μg once daily. Lastly, the study will investigate what the body does to roflumilast. Patients with a history of COPD for at least last 12 months and a former smoker or current smoker with history of at least 10 pack years will be invited to participate. The main study period lasts for a maximum of 15 weeks and patients will have to visit the study site up to 6 times. If patients are not tolerating roflumilast, the investigators may switch them to the down titration period where they may be on a lower dose for rest of the study. Then patients will remain in the down titration period for additional 8 weeks and will have to visit the study site 4 times. Most of the visits will take approximately 1 to 2 hours. However, one visit in the main period and 1 or 2 visits in the down titration period will take approximately 6 to 7 hours. These visits are longer to allow time to conduct blood taking. The Randomization visit is considered the Baseline visit and for participants that discontinue the Main Period and continue into the Down-Titration Period Day 1 of Down Titration is considered BaselineDT.
Interventions
DRUGRoflumilast
Roflumilast tablets
Roflumilast placebo-matching tablets
DRUGStandard of Care COPD Treatment
The participant is on standard of care COPD maintenance treatment including LABAs, long-acting anticholinergics, or any combination thereof taken on a constant daily dose within 12 weeks prior to Screening (Visit V0) Examples of LABA containing products are: Formoterol, Salmeterol, Indacaterol, Formoterol/Budesonide, Salmeterol/Fluticasone, Treatment including lon-acting anticholinergics: Tiotropium, Aclidinium.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3. Has a history of chronic obstructive pulmonary disease (COPD) (according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2013) for at least 12 months prior to Screening (Visit V0) associated with chronic productive cough for 3 months in each of the 2 years prior to Screening (Visit V0, with other causes of productive cough excluded). 4. Shows a post-bronchodilator forced expiratory volume in 1 second (FEV1) of ≤50% of predicted. 5. Shows an FEV1/forced vital capacity (FVC) ratio (post-bronchodilator) \<70%. 6. Has at least one documented COPD exacerbation within one year prior to Screening (Visit V0). 7. Is on standard of care COPD maintenance treatment including Long Acting β2-Agonist (LABAs), long-acting anticholinergics, or any combination thereof taken on a constant daily dose within 12 weeks prior to Screening (Visit V0). 8. Must be a 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.11 9. Is male or female and aged 40 or older. 10. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study.
Exclusion criteria
Criteria affecting the read-out parameters of the study 1. Has a COPD exacerbation ongoing at the Screening (Visit V0), or has a COPD exacerbation between V0 and V1. 2. Has a lower respiratory tract infection not resolved 4 weeks prior to Screening (Visit V0). 3. Has a diagnosis of asthma and/or other relevant lung disease (eg, history of primary bronchiectases, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease \[eg, fibrosis, silicosis, sarcoidosis\], or active tuberculosis). 4. Has a known α1-antitrypsin deficiency. 5. Has taken roflumilast within 6 months of Screening (Visit V0). Criteria within ethical considerations in terms of general health 6. Has clinically relevant abnormal laboratory values suggesting an undiagnosed disease requiring further clinical evaluation (as assessed by the investigator). 7. Has a history of severe psychiatric or neurological disorders. 8. Has a history of depression associated with suicidal ideation or behavior. 9. Has congestive heart failure severity grade IV according to New York Heart Association (NYHA) Functional Classification. 10. Has hemodynamically significant cardiac arrhythmias or heart valve deformations. 11. Has computed tomography (CT) or chest x-ray findings indicating an acute pulmonary disease other than COPD (eg, tuberculosis, severe bronchiectasis, tumors). 12. Has severe immunological diseases (eg, known human immune deficiency virus (HIV) infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy). 13. Has liver impairment Child-Pugh B or C and/or active viral hepatitis. 14. Has severe acute infectious diseases (eg, tuberculosis, or acute hepatitis). 15. Has a history of malignant disease (except basal cell carcinoma) within 5 years before Screening (Visit V0). 16. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within one year before Screening (Visit V0). 17. Has a history of hypersensitivity or allergies to roflumilast or rescue medication or ingredients thereof, or any other contraindication for the use thereof. 18. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 12 weeks after participating in this study; or intending to donate ova during such time period. 19. Intends to donate blood, organs, or bone marrow during the course of the study. 20. Has received any investigational compound within 30 days prior to Screening (Visit V0), is currently participating in another interventional clinical study, or has been previously enrolled in this study. 21. Is suspected to be unable or unwilling to comply with study procedures (eg, language problems, psychological disorders, number and timing of visits at the center). 22. Suffers from any concomitant disease that might interfere with study procedures or evaluations. 23. Is required to take excluded medications. 24. Is an immediate family member, study center employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling), or may consent under duress.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason | Baseline to Week 12 (Main Period) | The primary endpoint is the percentage of participants prematurely discontinuing study treatment for any reason during the Main Period from Visit 1 (V1) to Last Visit (Vend). Discontinuation is defined as permanently stopping randomized treatment; participants who resume randomized treatment after an interval will not be counted as having discontinued. The analysis used discontinuations occurring during the Main Period, irrespective of whether a participant subsequently entered into the Down-Titration Period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (V0DT) in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) to Final Visit of the Down-Titration Period | Baseline (V0DT) [assessment at end of main period] and Final Visit of Down-Titration Period (Up to Day 56) | 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 spirometry prior to taking study medication A positive change from Baseline indicates improvement. |
| Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason During Down-Titration Period | Baseline DT (Day 1 of Down-Titration Period) to Week 8 (Down-Titration Period) | — |
| Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period | Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period) | 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 spirometry prior to taking study medication. A positive change from Baseline indicates improvement. |
| Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period) | 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 spirometry prior to taking study medication. A positive change from Baseline indicates improvement. |
| Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period) | Forced 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 spirometry prior to taking study medication. A positive change from Baseline indicates improvement. |
| Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period | Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period) | Forced 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 spirometry prior to taking study medication. A positive change from Baseline indicates improvement. |
| Change From Baseline in Treatment Satisfaction Scores During the Main Period | Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period) | Participants will be asked to assess their satisfaction with their COPD therapy at each visit. The participants will rate their treatment satisfaction on a 7-point scale where 0=very satisfied, 1=satisfied, 2=somewhat satisfied, 3=neither satisfied nor dissatisfied, 4=somewhat dissatisfied, 5=dissatisfied and 6=very dissatisfied. A negative change from Baseline indicates improvement. |
| Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period | Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period) | Participants will be asked to assess their satisfaction with their COPD therapy at each visit. The participants will rate their treatment satisfaction on a 7-point scale where 0=very satisfied, 1=satisfied, 2=somewhat satisfied, 3=neither satisfied nor dissatisfied, 4=somewhat dissatisfied, 5=dissatisfied and 6=very dissatisfied. A negative change from Baseline indicates improvement. |
| Percentage of Participants With Adverse Events of Interest | Baseline to Week 12 (Main Period) | Adverse events of interest to evaluate tolerability are defined as diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain. |
| Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8 | PK model point estimates for CL/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model. |
| Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8 | PK model point estimates for Vc/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model. |
| Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8 | PK model point estimates for Vp/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model. |
| Total PDE4 Inhibitory Activity (tPDE4i) | Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. Down-titration: Pre-dose and 1,2,3,4,6 hours post-dose at Days 1 and 14 and pre-dose at Days 28 and 56. | tPDE4i was derived using in-vitro constants for protein binding and biochemical activity (IC50). tPDE4i is reported for a set of reference participants defined according to the covariates included in the final model. |
| Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. Down-titration: Pre-dose and 1,2,3,4,6 hours post-dose at Days 1 and 14 and pre-dose at Days 28 and 56. | tPDE4i was derived using in-vitro constants for protein binding and biochemical activity (IC50). 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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. Adverse Events of Interest (AEI) for PK analyses included: headache, diarrhea, nausea, vomiting, abdominal pain, appetite disorders, sleep disorders, angioedema, psychiatric disorders (anxiety, nervousness), psychiatric disorders (depression,suicidal ideation,behaviour) and weight loss. |
| Median Simulated Percentage of Participants With Adverse Events of Interest | Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. AEIs: 12 Weeks | The PK model predicted the total PDE4 inhibitory activity and the median simulated percentage of participants with Adverse Events of Interest during 12 weeks of treatment based on 1000 participants simulated. Results are reported for the set of reference participants defined according to the covariates \[weight, smoking status, sex, age and long acting muscarinic antagonist (LAMA)\] included in the final model and tPDE4i. Adverse Events of Interest (AEI) for PK analyses included: headache, diarrhea, nausea, vomiting, abdominal pain, appetite disorders, sleep disorders, angioedema, psychiatric disorders (anxiety, nervousness), psychiatric disorders (depression, suicidal ideation, behaviour) and weight loss. |
| Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. FEV-1: Pre-dose and Weeks 4 and 12 | The PK model predicted the total PDE4 inhibitory activity and the median simulated Change from Baseline (CFB) in FEV1 at Week 4 and the Change from Baseline in FEV1 at Week 12 during 12 weeks of treatment with roflumilast 500 μg OD based on 1000 participants simulated. Results are reported for the set of reference participants defined according to the covariates \[weight, smoking status, sex, age, race, COPD severity, concomitant long acting muscarinic antagonist (LAMA) and Percent FEV1 reversibility\] included in the final model and tPDE4i. 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 spirometry prior to taking study medication. A positive change from Baseline indicates improvement. |
| Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8 | PK model point estimates for Ka are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model. |
Countries
Slovakia
Participant flow
Recruitment details
Participants took part in the study at 161 investigative sites in Bulgaria, Germany, Greece, Hungary, Korea, Philippines, Poland, Romania, Russia, Slovakia, South Africa, Spain, Thailand, Ukraine and the United Kingdom from 30 April 2014 to 21 October 2015.
Pre-assignment details
Participants with a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) were enrolled equally in 1 of 3 treatment groups in the Main Treatment Period: roflumilast 250 μg then 500 μg once daily (OD), 500 μg every other day (EOD) then 500 μg OD and 500 μg OD. Participants who discontinued received 250 μg in the Down-Titration Period.
Participants by arm
| Arm | Count |
|---|---|
| Roflumilast 250 μg OD Then 500 μg OD Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period. | 441 |
| Roflumilast 500 μg EOD Then 500 μg OD Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period. | 437 |
| Roflumilast 500 μg OD Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period. | 443 |
| Total | 1,321 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Down-Titration Period | Pre-treatment Event/Adverse Event | 4 | 10 | 3 |
| Down-Titration Period | Reason Not Specified | 1 | 0 | 2 |
| Down-Titration Period | Voluntary Withdrawal | 2 | 1 | 2 |
| Main Treatment Period | Did Not Receive Study Drug | 0 | 2 | 0 |
| Main Treatment Period | Lack of Efficacy | 2 | 0 | 0 |
| Main Treatment Period | Lost to Follow-up | 4 | 2 | 1 |
| Main Treatment Period | Major/Significant Protocol Deviation | 0 | 1 | 3 |
| Main Treatment Period | Pre-treatment Event/Adverse Event | 44 | 57 | 68 |
| Main Treatment Period | Reason Not Specified | 8 | 5 | 16 |
| Main Treatment Period | Voluntary Withdrawal | 23 | 23 | 21 |
Baseline characteristics
| Characteristic | Total | Roflumilast 250 μg OD Then 500 μg OD | Roflumilast 500 μg OD | Roflumilast 500 μg EOD Then 500 μg OD |
|---|---|---|---|---|
| Age, Continuous | 64.6 years STANDARD_DEVIATION 8.13 | 64.2 years STANDARD_DEVIATION 7.81 | 64.6 years STANDARD_DEVIATION 8.36 | 65.0 years STANDARD_DEVIATION 8.21 |
| Age, Customized 40-64 years | 668 participants | 242 participants | 224 participants | 202 participants |
| Age, Customized 65-84 years | 651 participants | 199 participants | 217 participants | 235 participants |
| Age, Customized 85 years and over | 2 participants | 0 participants | 2 participants | 0 participants |
| Body Mass Index (BMI) | 26.26 kg/m^2 STANDARD_DEVIATION 5.822 | 26.36 kg/m^2 STANDARD_DEVIATION 5.957 | 26.44 kg/m^2 STANDARD_DEVIATION 5.888 | 25.98 kg/m^2 STANDARD_DEVIATION 5.614 |
| Height | 169.0 cm STANDARD_DEVIATION 8.64 | 169.1 cm STANDARD_DEVIATION 8.73 | 169.1 cm STANDARD_DEVIATION 8.55 | 168.8 cm STANDARD_DEVIATION 8.66 |
| Number of Cigarette Pack-Years | 38.6 pack-years STANDARD_DEVIATION 18.17 | 38.1 pack-years STANDARD_DEVIATION 17.49 | 37.6 pack-years STANDARD_DEVIATION 17.7 | 40.2 pack-years STANDARD_DEVIATION 19.22 |
| Pre-bronchodilator Forced Expiratory Volume in the First Second (FEV1) | 1.023 liters STANDARD_DEVIATION 0.3211 | 1.022 liters STANDARD_DEVIATION 0.3177 | 1.018 liters STANDARD_DEVIATION 0.3289 | 1.028 liters STANDARD_DEVIATION 0.3173 |
| Pre-Bronchodilator Forced Vital Capacity (FVC) | 2.307 liters STANDARD_DEVIATION 0.7109 | 2.304 liters STANDARD_DEVIATION 0.7418 | 2.314 liters STANDARD_DEVIATION 0.6822 | 2.303 liters STANDARD_DEVIATION 0.7091 |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 94 participants | 32 participants | 32 participants | 30 participants |
| Race/Ethnicity, Customized Black or African American | 9 participants | 3 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 8 participants | 1 participants | 5 participants | 2 participants |
| Race/Ethnicity, Customized Missing | 36 participants | 12 participants | 12 participants | 12 participants |
| Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander | 8 participants | 1 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 1277 participants | 428 participants | 426 participants | 423 participants |
| Race/Ethnicity, Customized White | 1209 participants | 405 participants | 405 participants | 399 participants |
| Region of Enrollment Bulgaria | 84 participants | 36 participants | 30 participants | 18 participants |
| Region of Enrollment Germany | 52 participants | 12 participants | 16 participants | 24 participants |
| Region of Enrollment Greece | 20 participants | 8 participants | 6 participants | 6 participants |
| Region of Enrollment Hungary | 235 participants | 82 participants | 79 participants | 74 participants |
| Region of Enrollment Korea, Republic Of | 46 participants | 22 participants | 13 participants | 11 participants |
| Region of Enrollment Philippines | 30 participants | 7 participants | 10 participants | 13 participants |
| Region of Enrollment Poland | 199 participants | 60 participants | 71 participants | 68 participants |
| Region of Enrollment Romania | 144 participants | 54 participants | 44 participants | 46 participants |
| Region of Enrollment Russia | 140 participants | 37 participants | 55 participants | 48 participants |
| Region of Enrollment Slovakia | 105 participants | 40 participants | 27 participants | 38 participants |
| Region of Enrollment South Africa | 61 participants | 17 participants | 26 participants | 18 participants |
| Region of Enrollment Spain | 5 participants | 2 participants | 1 participants | 2 participants |
| Region of Enrollment Thailand | 17 participants | 2 participants | 9 participants | 6 participants |
| Region of Enrollment Ukraine | 168 participants | 56 participants | 54 participants | 58 participants |
| Region of Enrollment United Kingdom | 15 participants | 6 participants | 2 participants | 7 participants |
| Sex: Female, Male Female | 338 Participants | 121 Participants | 105 Participants | 112 Participants |
| Sex: Female, Male Male | 983 Participants | 320 Participants | 338 Participants | 325 Participants |
| Smoking Classification Current Smoker | 607 participants | 213 participants | 196 participants | 198 participants |
| Smoking Classification Ex-smoker | 714 participants | 228 participants | 247 participants | 239 participants |
| Weight | 75.20 kg STANDARD_DEVIATION 17.804 | 75.59 kg STANDARD_DEVIATION 18.627 | 75.68 kg STANDARD_DEVIATION 16.949 | 74.31 kg STANDARD_DEVIATION 17.808 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 239 / 441 | 248 / 437 | 272 / 443 | 13 / 27 | 21 / 39 | 25 / 38 |
| serious Total, serious adverse events | 19 / 441 | 22 / 437 | 20 / 443 | 1 / 27 | 0 / 39 | 0 / 38 |
Outcome results
Primary
Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason
The primary endpoint is the percentage of participants prematurely discontinuing study treatment for any reason during the Main Period from Visit 1 (V1) to Last Visit (Vend). Discontinuation is defined as permanently stopping randomized treatment; participants who resume randomized treatment after an interval will not be counted as having discontinued. The analysis used discontinuations occurring during the Main Period, irrespective of whether a participant subsequently entered into the Down-Titration Period.
Time frame: Baseline to Week 12 (Main Period)
Population: Safety Analysis Set (SAS) included all randomized participants who took at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason | 18.4 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason | 20.1 percentage of participants |
| Roflumilast 500 μg OD | Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason | 24.6 percentage of participants |
Comparison: Analyses were performed using a hierarchical testing procedure.p-value: 0.01795% CI: [0.47, 0.93]Regression, Logistic
Comparison: Analyses were performed using a hierarchical testing procedure.95% CI: [0.51, 0.92]
Comparison: Analyses were performed using a hierarchical testing procedure.p-value: 0.11495% CI: [0.55, 1.07]Regression, Logistic
Comparison: Analyses were performed using a hierarchical testing procedure.95% CI: [0.58, 1.02]
Secondary
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period
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 spirometry prior to taking study medication. A positive change from Baseline indicates improvement.
Time frame: Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period)
Population: Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication. n in each category is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period | Day 28 (n=20, 29, 31) | 0.162 Liters | Standard Deviation 0.4274 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period | Day 14 (n=20, 32, 34) | 0.128 Liters | Standard Deviation 0.3708 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period | Day 56 (n=26, 39, 38) | 0.162 Liters | Standard Deviation 0.3311 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period | Day 28 (n=20, 29, 31) | 0.218 Liters | Standard Deviation 0.4443 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period | Day 14 (n=20, 32, 34) | 0.223 Liters | Standard Deviation 0.4101 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period | Day 56 (n=26, 39, 38) | 0.261 Liters | Standard Deviation 0.4616 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period | Day 14 (n=20, 32, 34) | 0.097 Liters | Standard Deviation 0.2532 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period | Day 56 (n=26, 39, 38) | 0.127 Liters | Standard Deviation 0.3334 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period | Day 28 (n=20, 29, 31) | 0.070 Liters | Standard Deviation 0.2067 |
Secondary
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period
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 spirometry prior to taking study medication. A positive change from Baseline indicates improvement.
Time frame: Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period)
Population: Main Period FAS included all randomized participants, regardless of whether they took study medication. n in each of the categories is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 15 (n=409, 406, 386) | 0.067 Liters | Standard Deviation 0.2299 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 29 (n=402, 389, 365) | 0.099 Liters | Standard Deviation 0.2605 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 57 (n=376, 367, 352) | 0.104 Liters | Standard Deviation 0.2659 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 84 (n=402, 411, 409) | 0.117 Liters | Standard Deviation 0.269 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 84 (n=402, 411, 409) | 0.141 Liters | Standard Deviation 0.2882 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 15 (n=409, 406, 386) | 0.094 Liters | Standard Deviation 0.2573 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 57 (n=376, 367, 352) | 0.161 Liters | Standard Deviation 0.2765 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 29 (n=402, 389, 365) | 0.115 Liters | Standard Deviation 0.2629 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 84 (n=402, 411, 409) | 0.122 Liters | Standard Deviation 0.2705 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 29 (n=402, 389, 365) | 0.116 Liters | Standard Deviation 0.244 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 57 (n=376, 367, 352) | 0.133 Liters | Standard Deviation 0.2705 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period | Day 15 (n=409, 406, 386) | 0.094 Liters | Standard Deviation 0.2566 |
Secondary
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period
Forced 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 spirometry prior to taking study medication. A positive change from Baseline indicates improvement.
Time frame: Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period)
Population: Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period | Day 28 (n=20, 29, 31) | 0.125 Liters | Standard Deviation 0.6151 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period | Day 14 (n=20, 32, 34) | 0.087 Liters | Standard Deviation 0.5392 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period | Day 56 (n=26, 39, 38) | 0.167 Liters | Standard Deviation 0.5492 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period | Day 28 (n=20, 29, 31) | 0.191 Liters | Standard Deviation 0.478 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period | Day 14 (n=20, 32, 34) | 0.303 Liters | Standard Deviation 0.5103 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period | Day 56 (n=26, 39, 38) | 0.113 Liters | Standard Deviation 0.51 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period | Day 14 (n=20, 32, 34) | 0.104 Liters | Standard Deviation 0.4568 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period | Day 56 (n=26, 39, 38) | 0.029 Liters | Standard Deviation 0.4628 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period | Day 28 (n=20, 29, 31) | 0.067 Liters | Standard Deviation 0.3522 |
Secondary
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period
Forced 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 spirometry prior to taking study medication. A positive change from Baseline indicates improvement.
Time frame: Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period)
Population: Main Period FAS included all randomized participants, regardless of whether they took study medication. n in each of the categories is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 15 (n=409, 406, 386) | 0.096 Liters | Standard Deviation 0.4053 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 29 (n=402, 389, 365) | 0.139 Liters | Standard Deviation 0.3826 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 57 (n=376, 367, 352) | 0.156 Liters | Standard Deviation 0.4346 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 84 (n=402, 411, 409) | 0.157 Liters | Standard Deviation 0.4746 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 84 (n=402, 411, 409) | 0.207 Liters | Standard Deviation 0.4925 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 15 (n=409, 406, 386) | 0.112 Liters | Standard Deviation 0.4168 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 57 (n=376, 367, 352) | 0.194 Liters | Standard Deviation 0.4974 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 29 (n=402, 389, 365) | 0.143 Liters | Standard Deviation 0.4172 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 84 (n=402, 411, 409) | 0.147 Liters | Standard Deviation 0.4555 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 29 (n=402, 389, 365) | 0.149 Liters | Standard Deviation 0.4173 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 57 (n=376, 367, 352) | 0.162 Liters | Standard Deviation 0.4341 |
| Roflumilast 500 μg OD | Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period | Day 15 (n=409, 406, 386) | 0.104 Liters | Standard Deviation 0.4166 |
Secondary
Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period
Participants will be asked to assess their satisfaction with their COPD therapy at each visit. The participants will rate their treatment satisfaction on a 7-point scale where 0=very satisfied, 1=satisfied, 2=somewhat satisfied, 3=neither satisfied nor dissatisfied, 4=somewhat dissatisfied, 5=dissatisfied and 6=very dissatisfied. A negative change from Baseline indicates improvement.
Time frame: Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period)
Population: Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication. n in each of the categories is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period | Day 28 (n=20, 29, 31) | -1.2 score on a scale | Standard Deviation 2.01 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period | Day 14 (n=20, 32, 34) | -1.1 score on a scale | Standard Deviation 1.85 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period | Day 56 (n=26, 39, 38) | -0.8 score on a scale | Standard Deviation 2.23 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period | Day 28 (n=20, 29, 31) | -0.8 score on a scale | Standard Deviation 1.75 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period | Day 14 (n=20, 32, 34) | -0.8 score on a scale | Standard Deviation 1.57 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period | Day 56 (n=26, 39, 38) | -0.3 score on a scale | Standard Deviation 2.15 |
| Roflumilast 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period | Day 14 (n=20, 32, 34) | -0.8 score on a scale | Standard Deviation 1.84 |
| Roflumilast 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period | Day 56 (n=26, 39, 38) | -0.4 score on a scale | Standard Deviation 2.26 |
| Roflumilast 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period | Day 28 (n=20, 29, 31) | -0.9 score on a scale | Standard Deviation 1.81 |
Secondary
Change From Baseline in Treatment Satisfaction Scores During the Main Period
Participants will be asked to assess their satisfaction with their COPD therapy at each visit. The participants will rate their treatment satisfaction on a 7-point scale where 0=very satisfied, 1=satisfied, 2=somewhat satisfied, 3=neither satisfied nor dissatisfied, 4=somewhat dissatisfied, 5=dissatisfied and 6=very dissatisfied. A negative change from Baseline indicates improvement.
Time frame: Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period)
Population: Main Period FAS included all randomized participants, regardless of whether they took study medication. n in each of the categories is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 15 (n=410, 408, 386) | -0.4 score on a scale | Standard Deviation 1.12 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 29 (n=403, 390, 366) | -0.5 score on a scale | Standard Deviation 1.23 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 57 (n=375, 369, 351) | -0.6 score on a scale | Standard Deviation 1.24 |
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 84 (n=407, 416, 412) | -0.5 score on a scale | Standard Deviation 1.43 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 84 (n=407, 416, 412) | -0.5 score on a scale | Standard Deviation 1.51 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 15 (n=410, 408, 386) | -0.3 score on a scale | Standard Deviation 1.15 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 57 (n=375, 369, 351) | -0.6 score on a scale | Standard Deviation 1.26 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 29 (n=403, 390, 366) | -0.5 score on a scale | Standard Deviation 1.16 |
| Roflumilast 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 84 (n=407, 416, 412) | -0.3 score on a scale | Standard Deviation 1.52 |
| Roflumilast 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 29 (n=403, 390, 366) | -0.5 score on a scale | Standard Deviation 1.22 |
| Roflumilast 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 57 (n=375, 369, 351) | -0.5 score on a scale | Standard Deviation 1.29 |
| Roflumilast 500 μg OD | Change From Baseline in Treatment Satisfaction Scores During the Main Period | Day 15 (n=410, 408, 386) | -0.3 score on a scale | Standard Deviation 1.07 |
Secondary
Change From Baseline (V0DT) in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) to Final Visit of the Down-Titration Period
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 spirometry prior to taking study medication A positive change from Baseline indicates improvement.
Time frame: Baseline (V0DT) [assessment at end of main period] and Final Visit of Down-Titration Period (Up to Day 56)
Population: Participants from the Down-Titration Period Full Analysis Set (FAS), all randomized participants who entered this period, regardless of whether they took study medication, with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Change From Baseline (V0DT) in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) to Final Visit of the Down-Titration Period | 0.030 Liters | Standard Deviation 0.2294 |
| Roflumilast 500 μg EOD Then 500 μg OD | Change From Baseline (V0DT) in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) to Final Visit of the Down-Titration Period | 0.055 Liters | Standard Deviation 0.417 |
| Roflumilast 500 μg OD | Change From Baseline (V0DT) in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) to Final Visit of the Down-Titration Period | 0.007 Liters | Standard Deviation 0.3555 |
Secondary
Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12
The PK model predicted the total PDE4 inhibitory activity and the median simulated Change from Baseline (CFB) in FEV1 at Week 4 and the Change from Baseline in FEV1 at Week 12 during 12 weeks of treatment with roflumilast 500 μg OD based on 1000 participants simulated. Results are reported for the set of reference participants defined according to the covariates \[weight, smoking status, sex, age, race, COPD severity, concomitant long acting muscarinic antagonist (LAMA) and Percent FEV1 reversibility\] included in the final model and tPDE4i. 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 spirometry prior to taking study medication. A positive change from Baseline indicates improvement.
Time frame: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. FEV-1: Pre-dose and Weeks 4 and 12
Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration. The number of participants analyzed is the number of participants simulated. Measured values are predicted values.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Male (tPDE4i=0.839,0.839) | 60.5 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Asian (tPDE4i=0.839,0.839) | 56.1 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Current Smoker (tPDE4i=0.729,0.729) | 99.5 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | non-Asian (tPDE4i=0.839,0.839) | 60.5 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Female (tPDE4i=0.937,0.937) | 53.2 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | COPD_Not Very Severe (tPDE4i=0.839,0.839) | 60.5 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Weight=160 kg (tPDE4i=0.681,0.681) | 108 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | COPD_Very Severe (tPDE4i=0.839,0.839) | 42.2 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Age=40 years (tPDE4i=0.675,0.675) | 57.6 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | LAMA=Yes (tPDE4i=0.839,0.839) | 60.5 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Former/Never Smoker (tPDE4i=0.839,0.839) | 60.5 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | LAMA=No (tPDE4i=0.839,0.839) | 63.5 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Age=60 years (tPDE4i=0.839,0.839) | 60.5 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | %FEV1 Reversibility=-28% (tPDE4i=0.839,0.839) | 68.1 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Weight=70 kg (tPDE4i=0.839,0.839) | 60.5 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | %FEV1 Reversibility=10% (tPDE4i=0.839,0.839) | 60.5 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Age=92 years (tPDE4i=1.06,1.06) | 56.4 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | %FEV1 Reversibility=147% (tPDE4i=0.839,0.839) | 32.9 milliliters (mL) |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Weight=33.5 kg (tPDE4i=1.012,1.012) | 50 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | %FEV1 Reversibility=147% (tPDE4i=0.839,0.839) | 30.5 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Weight=33.5 kg (tPDE4i=1.012,1.012) | 32 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Weight=70 kg (tPDE4i=0.839,0.839) | 56 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Weight=160 kg (tPDE4i=0.681,0.681) | 157 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Current Smoker (tPDE4i=0.729,0.729) | 96.5 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Former/Never Smoker (tPDE4i=0.839,0.839) | 56 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Male (tPDE4i=0.839,0.839) | 56 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Female (tPDE4i=0.937,0.937) | 49.8 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Age=40 years (tPDE4i=0.675,0.675) | 52.2 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Age=60 years (tPDE4i=0.839,0.839) | 56 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Age=92 years (tPDE4i=1.06,1.06) | 53.3 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | Asian (tPDE4i=0.839,0.839) | 52 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | non-Asian (tPDE4i=0.839,0.839) | 56 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | COPD_Not Very Severe (tPDE4i=0.839,0.839) | 56 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | COPD_Very Severe (tPDE4i=0.839,0.839) | 39.1 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | LAMA=Yes (tPDE4i=0.839,0.839) | 56 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | LAMA=No (tPDE4i=0.839,0.839) | 58.8 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | %FEV1 Reversibility=-28% (tPDE4i=0.839,0.839) | 63.1 milliliters (mL) |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12 | %FEV1 Reversibility=10% (tPDE4i=0.839,0.839) | 56 milliliters (mL) |
Secondary
Median Simulated Percentage of Participants With Adverse Events of Interest
The PK model predicted the total PDE4 inhibitory activity and the median simulated percentage of participants with Adverse Events of Interest during 12 weeks of treatment based on 1000 participants simulated. Results are reported for the set of reference participants defined according to the covariates \[weight, smoking status, sex, age and long acting muscarinic antagonist (LAMA)\] included in the final model and tPDE4i. Adverse Events of Interest (AEI) for PK analyses included: headache, diarrhea, nausea, vomiting, abdominal pain, appetite disorders, sleep disorders, angioedema, psychiatric disorders (anxiety, nervousness), psychiatric disorders (depression, suicidal ideation, behaviour) and weight loss.
Time frame: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. AEIs: 12 Weeks
Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration. Number of participants analyzed is the number of participants simulated. Measured values are predicted values.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Weight=48 kg (tPDE4i=0.72,0.72,1.45) | 53.2 percentage of participants |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Weight=74 kg (tPDE4i=0.65,0.65,1.30) | 52.3 percentage of participants |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Weight=105 kg (tPDE4i=0.60.0.60,1.19) | 51.7 percentage of participants |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Former Smoker (tPDE4i=0.65,0.65,1.30) | 52.3 percentage of participants |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Current Smoker (tPDE4i=0.56,0.56,1.13) | 42.5 percentage of participants |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Male (tPDE4i=0.65,0.65,1.30) | 52.3 percentage of participants |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Female (tPDE4i=0.72,0.72,1.45) | 53.2 percentage of participants |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Age=51 (tPDE4i=0.58,0.58,1.15) | 51.4 percentage of participants |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Age=64 (tPDE4i=0.65,0.65,1.30) | 52.3 percentage of participants |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Age=77 (tPDE4i=0.72,0.72,1.44) | 53.2 percentage of participants |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | With LAMA (tPDE4i=0.65,0.65,1.30) | 52.3 percentage of participants |
| Roflumilast 250 μg OD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Without LAMA (tPDE4i=0.65,0.65,1.30) | 43.5 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Without LAMA (tPDE4i=0.65,0.65,1.30) | 43.5 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Weight=48 kg (tPDE4i=0.72,0.72,1.45) | 53.2 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Female (tPDE4i=0.72,0.72,1.45) | 53.2 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Age=64 (tPDE4i=0.65,0.65,1.30) | 52.3 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Weight=74 kg (tPDE4i=0.65,0.65,1.30) | 52.3 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Male (tPDE4i=0.65,0.65,1.30) | 52.3 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | With LAMA (tPDE4i=0.65,0.65,1.30) | 52.3 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Weight=105 kg (tPDE4i=0.60.0.60,1.19) | 51.7 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Age=51 (tPDE4i=0.58,0.58,1.15) | 51.4 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Current Smoker (tPDE4i=0.56,0.56,1.13) | 42.5 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Former Smoker (tPDE4i=0.65,0.65,1.30) | 52.3 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Age=77 (tPDE4i=0.72,0.72,1.44) | 53.2 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Former Smoker (tPDE4i=0.65,0.65,1.30) | 60.1 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Current Smoker (tPDE4i=0.56,0.56,1.13) | 49.2 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Age=77 (tPDE4i=0.72,0.72,1.44) | 61.7 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Male (tPDE4i=0.65,0.65,1.30) | 60.1 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Female (tPDE4i=0.72,0.72,1.45) | 61.8 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Age=51 (tPDE4i=0.58,0.58,1.15) | 58.4 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | With LAMA (tPDE4i=0.65,0.65,1.30) | 60.1 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Weight=48 kg (tPDE4i=0.72,0.72,1.45) | 61.8 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Weight=74 kg (tPDE4i=0.65,0.65,1.30) | 60.1 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Age=64 (tPDE4i=0.65,0.65,1.30) | 60.1 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Weight=105 kg (tPDE4i=0.60.0.60,1.19) | 58.8 percentage of participants |
| Roflumilast 500 μg OD | Median Simulated Percentage of Participants With Adverse Events of Interest | Without LAMA (tPDE4i=0.65,0.65,1.30) | 51.4 percentage of participants |
Secondary
Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason During Down-Titration Period
Time frame: Baseline DT (Day 1 of Down-Titration Period) to Week 8 (Down-Titration Period)
Population: Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason During Down-Titration Period | 25.9 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason During Down-Titration Period | 28.2 percentage of participants |
| Roflumilast 500 μg OD | Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason During Down-Titration Period | 18.4 percentage of participants |
Secondary
Percentage of Participants With Adverse Events of Interest
Adverse events of interest to evaluate tolerability are defined as diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain.
Time frame: Baseline to Week 12 (Main Period)
Population: SAS included all randomized participants who took at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Percentage of Participants With Adverse Events of Interest | 45.4 percentage of participants |
| Roflumilast 500 μg EOD Then 500 μg OD | Percentage of Participants With Adverse Events of Interest | 48.3 percentage of participants |
| Roflumilast 500 μg OD | Percentage of Participants With Adverse Events of Interest | 54.2 percentage of participants |
Comparison: Analyses were performed using a hierarchical testing procedure.p-value: 0.00195% CI: [0.47, 0.83]Regression, Logistic
Comparison: Analyses were performed using a hierarchical testing procedure.p-value: 0.09195% CI: [0.59, 1.04]Regression, Logistic
Secondary
Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide
PK model point estimates for Ka are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model.
Time frame: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8
Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Weight=33.5 kg | 0.90 units per hour (1/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Weight=70 kg | 0.90 units per hour (1/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Weight=160 kg | 0.90 units per hour (1/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Age=40 | 0.90 units per hour (1/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Age=60 | 0.90 units per hour (1/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Age=92 | 0.90 units per hour (1/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Smoking=former | 0.90 units per hour (1/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Smoking=current | 0.90 units per hour (1/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Sex=female | 0.90 units per hour (1/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Sex=male | 0.90 units per hour (1/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Smoking=current | 0.57 units per hour (1/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Weight=33.5 kg | 0.57 units per hour (1/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Age=92 | 0.57 units per hour (1/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Weight=70 kg | 0.57 units per hour (1/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Sex=male | 0.57 units per hour (1/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Weight=160 kg | 0.57 units per hour (1/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Smoking=former | 0.57 units per hour (1/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Age=40 | 0.57 units per hour (1/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Sex=female | 0.57 units per hour (1/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide | Age=60 | 0.57 units per hour (1/h) |
Secondary
Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide
PK model point estimates for Vc/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model.
Time frame: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8
Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Weight=33.5 kg | 26.0 liters (L) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Weight=70 kg | 63.9 liters (L) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Weight=160 kg | 175.2 liters (L) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Age=40 | 63.9 liters (L) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Age=60 | 63.9 liters (L) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Age=92 | 63.9 liters (L) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Smoking=former | 63.9 liters (L) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Smoking=current | 63.9 liters (L) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Sex=female | 63.9 liters (L) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Sex=male | 63.9 liters (L) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Smoking=current | 11.0 liters (L) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Weight=33.5 kg | 4.5 liters (L) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Age=92 | 11.0 liters (L) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Weight=70 kg | 11.0 liters (L) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Sex=male | 11.0 liters (L) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Weight=160 kg | 30.2 liters (L) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Smoking=former | 11.0 liters (L) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Age=40 | 11.0 liters (L) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Sex=female | 11.0 liters (L) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide | Age=60 | 11.0 liters (L) |
Secondary
Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide
PK model point estimates for CL/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model.
Time frame: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8
Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Weight=33.5 kg | 5.64 liters per hour (L/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Weight=70 kg | 5.64 liters per hour (L/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Weight=160 kg | 5.64 liters per hour (L/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Age=40 | 7.23 liters per hour (L/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Age=60 | 5.64 liters per hour (L/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Age=92 | 4.35 liters per hour (L/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Smoking=former | 5.64 liters per hour (L/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Smoking=current | 6.50 liters per hour (L/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Sex=female | 5.64 liters per hour (L/h) |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Sex=male | 5.64 liters per hour (L/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Smoking=current | 1.03 liters per hour (L/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Weight=33.5 kg | 0.73 liters per hour (L/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Age=92 | 0.71 liters per hour (L/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Weight=70 kg | 0.89 liters per hour (L/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Sex=male | 0.79 liters per hour (L/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Weight=160 kg | 1.12 liters per hour (L/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Smoking=former | 0.89 liters per hour (L/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Age=40 | 1.11 liters per hour (L/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Sex=female | 0.89 liters per hour (L/h) |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide | Age=60 | 0.89 liters per hour (L/h) |
Secondary
Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide
PK model point estimates for Vp/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model.
Time frame: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8
Population: Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Weight=33.5 kg | 69.6 L |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Weight=70 kg | 171.0 L |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Weight=160 kg | 468.8 L |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Age=40 | 171.0 L |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Age=60 | 171.0 L |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Age=92 | 171.0 L |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Smoking=former | 171.0 L |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Smoking=current | 171.0 L |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Sex=female | 171.0 L |
| Roflumilast 250 μg OD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Sex=male | 171.0 L |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Smoking=current | 12.4 L |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Weight=33.5 kg | 5.0 L |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Age=92 | 12.4 L |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Weight=70 kg | 12.4 L |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Sex=male | 12.4 L |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Weight=160 kg | 34.0 L |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Smoking=former | 12.4 L |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Age=40 | 12.4 L |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Sex=female | 12.4 L |
| Roflumilast 500 μg EOD Then 500 μg OD | Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide | Age=60 | 12.4 L |
Secondary
Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i)
tPDE4i was derived using in-vitro constants for protein binding and biochemical activity (IC50). 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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. Adverse Events of Interest (AEI) for PK analyses included: headache, diarrhea, nausea, vomiting, abdominal pain, appetite disorders, sleep disorders, angioedema, psychiatric disorders (anxiety, nervousness), psychiatric disorders (depression,suicidal ideation,behaviour) and weight loss.
Time frame: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. Down-titration: Pre-dose and 1,2,3,4,6 hours post-dose at Days 1 and 14 and pre-dose at Days 28 and 56.
Population: PK Set included all participants who had at least 1 quantifiable PK concentration. n in the category is the number of participants with available data. Study design only includes the 250 µg OD and 500 µg OD arms for analyses of this outcome measure. Measured values are predicted values reported as median and 90% prediction interval.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation due to Any AE=Yes (n=77,64) | 1.29 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation Due to Any Reason=No (n=1008,1) | 1.16 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation due to Any AEI=No (n=1047,14) | 1.16 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | At Least 1 AEI=Yes (n=536,75) | 1.23 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation due to Any AE=No (n=1037,12) | 1.16 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | At Least 1 AEI=No (578,1) | 1.12 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation due to Any AEI=Yes (n=67,62) | 1.28 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | At Least 1 AE=Yes (n=693,76) | 1.22 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation Due to Any Reason=Yes (n=106,75) | 1.23 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | At Least 1 AE=No (n=421,0) | 1.08 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | All Participants (n=1114,76) | 1.17 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | At Least 1 AE=No (n=421,0) | NA unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | All Participants (n=1114,76) | 0.611 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation due to Any AEI=Yes (n=67,62) | 0.647 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation due to Any AEI=No (n=1047,14) | 0.436 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation due to Any AE=Yes (n=77,64) | 0.647 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation due to Any AE=No (n=1037,12) | 0.408 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation Due to Any Reason=Yes (n=106,75) | 0.600 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | Discontinuation Due to Any Reason=No (n=1008,1) | 0.626 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | At Least 1 AEI=Yes (n=536,75) | 0.600 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | At Least 1 AEI=No (578,1) | 0.929 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i) | At Least 1 AE=Yes (n=693,76) | 0.611 unitless |
Secondary
Total PDE4 Inhibitory Activity (tPDE4i)
tPDE4i was derived using in-vitro constants for protein binding and biochemical activity (IC50). tPDE4i is reported for a set of reference participants defined according to the covariates included in the final model.
Time frame: Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. Down-titration: Pre-dose and 1,2,3,4,6 hours post-dose at Days 1 and 14 and pre-dose at Days 28 and 56.
Population: Participants from the PK Set, all participants who had at least 1 quantifiable PK concentration, with data available. Study design only includes the 250 µg arm for analyses of this outcome measure in the Down-Titration period. Measured values are predicted values reported as median and 90% prediction interval.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Roflumilast 250 μg OD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Age ≥ 65 to < 75 (n=146,159,136,39) | 1.24 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Weight ≥ 60 kg (n=336,321,331,84) | 1.12 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Overall | 1.17 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Males (n=300,297,290,66) | 1.12 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Age ≥ 75 (n=48,53,39,17) | 1.24 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Females (n=92,102,114,35) | 1.29 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Age < 65 (n=198,187,229,45) | 1.06 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Current Smoker (n=179,183,200,45) | 1.04 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Weight < 60 kg (n=56,78,73,17) | 1.34 unitless |
| Roflumilast 250 μg OD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Former Smoker (n=213,216,204,56) | 1.25 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Weight < 60 kg (n=56,78,73,17) | 0.755 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Weight ≥ 60 kg (n=336,321,331,84) | 0.592 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Males (n=300,297,290,66) | 0.585 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Age < 65 (n=198,187,229,45) | 0.559 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Overall | 0.608 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Age ≥ 65 to < 75 (n=146,159,136,39) | 0.660 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Current Smoker (n=179,183,200,45) | 0.568 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Age ≥ 75 (n=48,53,39,17) | 0.676 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Former Smoker (n=213,216,204,56) | 0.632 unitless |
| Roflumilast 500 μg EOD Then 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Females (n=92,102,114,35) | 0.696 unitless |
| Roflumilast 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Weight < 60 kg (n=56,78,73,17) | 0.653 unitless |
| Roflumilast 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Females (n=92,102,114,35) | 0.618 unitless |
| Roflumilast 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Overall | 0.563 unitless |
| Roflumilast 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Age < 65 (n=198,187,229,45) | 0.518 unitless |
| Roflumilast 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Age ≥ 65 to < 75 (n=146,159,136,39) | 0.614 unitless |
| Roflumilast 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Age ≥ 75 (n=48,53,39,17) | 0.616 unitless |
| Roflumilast 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Weight ≥ 60 kg (n=336,321,331,84) | 0.552 unitless |
| Roflumilast 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Males (n=300,297,290,66) | 0.558 unitless |
| Roflumilast 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Current Smoker (n=179,183,200,45) | 0.514 unitless |
| Roflumilast 500 μg OD | Total PDE4 Inhibitory Activity (tPDE4i) | Former Smoker (n=213,216,204,56) | 0.626 unitless |
| Roflumilast 250 µg Down-Titration | Total PDE4 Inhibitory Activity (tPDE4i) | Weight < 60 kg (n=56,78,73,17) | 0.934 unitless |
| Roflumilast 250 µg Down-Titration | Total PDE4 Inhibitory Activity (tPDE4i) | Females (n=92,102,114,35) | 0.626 unitless |
| Roflumilast 250 µg Down-Titration | Total PDE4 Inhibitory Activity (tPDE4i) | Age ≥ 75 (n=48,53,39,17) | 0.712 unitless |
| Roflumilast 250 µg Down-Titration | Total PDE4 Inhibitory Activity (tPDE4i) | Age ≥ 65 to < 75 (n=146,159,136,39) | 0.683 unitless |
| Roflumilast 250 µg Down-Titration | Total PDE4 Inhibitory Activity (tPDE4i) | Former Smoker (n=213,216,204,56) | 0.624 unitless |
| Roflumilast 250 µg Down-Titration | Total PDE4 Inhibitory Activity (tPDE4i) | Current Smoker (n=179,183,200,45) | 0.554 unitless |
| Roflumilast 250 µg Down-Titration | Total PDE4 Inhibitory Activity (tPDE4i) | Age < 65 (n=198,187,229,45) | 0.511 unitless |
| Roflumilast 250 µg Down-Titration | Total PDE4 Inhibitory Activity (tPDE4i) | Weight ≥ 60 kg (n=336,321,331,84) | 0.538 unitless |
| Roflumilast 250 µg Down-Titration | Total PDE4 Inhibitory Activity (tPDE4i) | Overall | 0.583 unitless |
| Roflumilast 250 µg Down-Titration | Total PDE4 Inhibitory Activity (tPDE4i) | Males (n=300,297,290,66) | 0.575 unitless |