Chronic Obstructive Airway Disease, Chronic Obstructive Lung Diseases, COPD, COPD Exacerbation, Lung Diseases, Pulmonary Disease, Respiratory Disorders
Conditions
Keywords
COPD, Exacerbations, Roflumilast, Daliresp
Brief summary
To demonstrate the additional benefit of roflumilast when added on to fixed-dose combination (FDC) LABA/ICS in the reduction of exacerbations in subjects with severe to very severe COPD.
Interventions
DRUGRoflumilast
Roflumilast 500 µg, oral administration, once per day
DRUGPlacebo
Dose-matched placebo, oral administration, once per day.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. Male or female patients at least 40 years of age * 2\. History of COPD (according to Global Initiative for Chronic Obstructive Lung Disease \[GOLD\] 2010) for at least 12 months prior to Screening (Visit 1) associated with chronic productive cough for 3 months in each of 2 consecutive years (with other causes of productive cough excluded). Only patients with chronic bronchitis will be included (concomitant emphysema is permitted) * 3\. Forced expiratory volume after 1 second (FEV1)/forced vital capacity (FVC) ratio (postbronchodilator) \< 70% at Screening (Visit 1) * 4\. FEV1 (postbronchodilator) ≤ 50% of predicted at Screening (Visit 1) * 5\. At least two documented moderate or severe COPD exacerbations within 12 months prior to Screening (Visit 1) * 6\. Patients must be on FDC LABA/ICS treatment ≥ 3 months prior to Screening (Visit 1) * 7\. Former smokers (defined as smoking cessation at least 1 year ago) or current smokers (including patients who ceased smoking within the past year) both with a smoking history of at least 20 pack-years
Exclusion criteria
* 1\. Moderate or severe COPD exacerbation and/or COPD exacerbations treated with antibiotics or systemic glucocorticosteroids within 4 weeks of Screening (Visit 1) (ie, patients must be clinically stable) * 2\. Known alpha-1-antitrypsin deficiency * 3\. Current diagnosis of asthma (either controlled or uncontrolled) (Note: History of childhood asthma is not exclusionary.) * 4\. Body mass index (BMI) ≥ 45 kg/m2 * 5\. Patients with a history (within 5 years) or current diagnosis of cancer other than basal or squamous cell skin cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year. | Baseline to Week 52 | Rate of moderate or severe COPD exacerbations, defined as requiring oral or parenteral glucocorticosteroids (moderate) or requiring hospitalization and/or leading to death (severe), during the double-blind treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of COPD Exacerbations That Led to Hospitalization or Death (ie, Severe COPD Exacerbations) | Week 0 (Visit 2) to Week 52 | Rate of moderate or severe COPD exacerbations, defined as requiring hospitalization and/or leading to death (severe), during the double-blind treatment period. |
| Rate of Moderate or Severe COPD Exacerbations or COPD Exacerbations Treated With Antibiotics | Week 0 (Visit 2) to Week 52 | Rate of moderate or severe COPD exacerbations treated with antibiotics during the double-blind treatment period. |
| Mean Change in Predose Forced Expiratory Volume in 1 Second (FEV1) | Week 0 (Visit 2) to Week 52 | Mean change from randomization (Visit 2) over 52 weeks of treatment in predose forced expiratory volume in 1 second (FEV1) |
Countries
Argentina, Canada, Chile, Colombia, Italy, Malaysia, Mexico, Peru, Philippines, Romania, Russia, Serbia, Spain, Taiwan, Thailand, Ukraine, United States
Participant flow
Recruitment details
Recruitment occurred from September 2011 to October 2014 for a total of 380 study centers screened patients for the study: Italy, Spain, United States, Ukraine, Argentina, Russia, Philippines, Romania, Serbia, Canada, Malaysia, Thailand, Mexico, Peru and Taiwan.
Pre-assignment details
The study consisted of 2 weeks of single-blind placebo lead-in with fixed-dose combination (FDC) long-acting β2-agonist(s) (LABA)/inhaled corticosteroid(s) (ICS) treatment followed by 52 weeks of double-blind treatment in addition to maintenance FDC LABA/ICS.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Dose-matched placebo, oral administration, once per day. | 1,174 |
| Roflumilast Roflumilast 500 µg, oral administration, once per day | 1,178 |
| Total | 2,352 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 64 | 138 |
| Overall Study | Deterioration in pulmonary function | 1 | 4 |
| Overall Study | Lack of Efficacy | 10 | 5 |
| Overall Study | Lost to Follow-up | 9 | 13 |
| Overall Study | Military Conflict - Site Terminated | 20 | 21 |
| Overall Study | Other reasons, such as COPD exacerbation | 44 | 44 |
| Overall Study | Protocol Violation | 43 | 45 |
| Overall Study | Withdrawal by Subject | 63 | 67 |
Baseline characteristics
| Characteristic | Roflumilast | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64.4 years STANDARD_DEVIATION 8.8 | 64.5 years STANDARD_DEVIATION 8.4 | 64.5 years STANDARD_DEVIATION 8.6 |
| Age, Customized Adults 40-65 years | 640 Participants | 634 Participants | 1274 Participants |
| Age, Customized Adults over 65 years | 538 Participants | 540 Participants | 1078 Participants |
| BMI Category Normal weight: >= 18.5 to < 25 | 468 Participants | 480 Participants | 948 Participants |
| BMI Category Obese: >= 30 | 268 Participants | 252 Participants | 520 Participants |
| BMI Category Over weight: >= 25 to < 30 | 342 Participants | 347 Participants | 689 Participants |
| BMI Category Under weight: < 18.5 | 100 Participants | 95 Participants | 195 Participants |
| Body-Mass Index (BMI) | 25.99 kg/m2 STANDARD_DEVIATION 5.91 | 25.72 kg/m2 STANDARD_DEVIATION 5.72 | 25.86 kg/m2 STANDARD_DEVIATION 5.82 |
| Ethnicity Hispanic or Latino | 268 Participants | 272 Participants | 540 Participants |
| Ethnicity Not Hispanic or Latino | 910 Participants | 902 Participants | 1812 Participants |
| Height | 167.80 cm STANDARD_DEVIATION 9.35 | 167.53 cm STANDARD_DEVIATION 9.39 | 167.67 cm STANDARD_DEVIATION 9.37 |
| ICS/LABA Therapy Advair | 768 Participants | 766 Participants | 1534 Participants |
| ICS/LABA Therapy Symbicort | 410 Participants | 408 Participants | 818 Participants |
| Long-acting muscarinic antagonist(s) (LAMA) use LAMA | 548 Participants | 546 Participants | 1094 Participants |
| Long-acting muscarinic antagonist(s) (LAMA) use No-LAMA | 630 Participants | 628 Participants | 1258 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 16 Participants | 6 Participants | 22 Participants |
| Race/Ethnicity, Customized Asian | 167 Participants | 170 Participants | 337 Participants |
| Race/Ethnicity, Customized Black or African American | 35 Participants | 27 Participants | 62 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 23 Participants | 27 Participants | 50 Participants |
| Race/Ethnicity, Customized White | 935 Participants | 944 Participants | 1879 Participants |
| Region of Enrollment Argentina | 198 participants | 197 participants | 395 participants |
| Region of Enrollment Canada | 15 participants | 14 participants | 29 participants |
| Region of Enrollment Colombia | 10 participants | 7 participants | 17 participants |
| Region of Enrollment Italy | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Malaysia | 7 participants | 6 participants | 13 participants |
| Region of Enrollment Mexico | 22 participants | 22 participants | 44 participants |
| Region of Enrollment Peru | 36 participants | 35 participants | 71 participants |
| Region of Enrollment Philippines | 131 participants | 130 participants | 261 participants |
| Region of Enrollment Romania | 54 participants | 55 participants | 109 participants |
| Region of Enrollment Russian Federation | 77 participants | 77 participants | 154 participants |
| Region of Enrollment Serbia | 47 participants | 47 participants | 94 participants |
| Region of Enrollment Spain | 6 participants | 6 participants | 12 participants |
| Region of Enrollment Taiwan | 6 participants | 7 participants | 13 participants |
| Region of Enrollment Thailand | 16 participants | 18 participants | 34 participants |
| Region of Enrollment Ukraine | 95 participants | 95 participants | 190 participants |
| Region of Enrollment United States | 457 participants | 458 participants | 915 participants |
| Sex/Gender, Customized Female | 357 Participants | 380 Participants | 737 Participants |
| Sex/Gender, Customized Male | 821 Participants | 794 Participants | 1615 Participants |
| Weight | 73.63 kg STANDARD_DEVIATION 19.57 | 72.57 kg STANDARD_DEVIATION 18.67 | 73.10 kg STANDARD_DEVIATION 19.13 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 188 / 1,174 | 317 / 1,178 |
| serious Total, serious adverse events | 162 / 1,174 | 180 / 1,178 |
Outcome results
Primary
Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year.
Rate of moderate or severe COPD exacerbations, defined as requiring oral or parenteral glucocorticosteroids (moderate) or requiring hospitalization and/or leading to death (severe), during the double-blind treatment period.
Time frame: Baseline to Week 52
Population: Intent-to-Treat Study Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year. | 1.27 COPD exacerbations per patient per year |
| Roflumilast | Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year. | 1.17 COPD exacerbations per patient per year |
Comparison: Subgroup Analysis - By Sex - Malep-value: 0.019595% CI: [0.71, 0.97]negative binomial regression
Comparison: Rate ratio (Roflumilast/Placebo). A rate ratio \< 1 represents a favorable outcome for the test treatment.p-value: 0.163495% CI: [0.81, 1.04]negative binomial regression
Comparison: Subgroup Analysis - By Sex - Femalep-value: 0.316495% CI: [0.91, 1.35]negative binomial regression
Comparison: Subgroup analysis between patients taking Advair verses patients taking Symbicort as LABA/ICS therapy.p-value: 0.038595% CI: [0.74, 0.99]negative binomial regression
Comparison: Subgroup analysis between patients taking Advair verses patients taking Symbicort as LABA/ICS therapy.p-value: 0.647595% CI: [0.84, 1.32]negative binomial regression
Secondary
Mean Change in Predose Forced Expiratory Volume in 1 Second (FEV1)
Mean change from randomization (Visit 2) over 52 weeks of treatment in predose forced expiratory volume in 1 second (FEV1)
Time frame: Week 0 (Visit 2) to Week 52
Population: Intent-to-Treat Population who the completed 52-week treatment period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change in Predose Forced Expiratory Volume in 1 Second (FEV1) | -0.0091 Liters | Standard Error 0.0047 |
| Roflumilast | Mean Change in Predose Forced Expiratory Volume in 1 Second (FEV1) | 0.0441 Liters | Standard Error 0.0048 |
p-value: <0.000195% CI: [0.04, 0.0664]Mixed Model for Repeated Measures (MMRM)
Secondary
Rate of COPD Exacerbations That Led to Hospitalization or Death (ie, Severe COPD Exacerbations)
Rate of moderate or severe COPD exacerbations, defined as requiring hospitalization and/or leading to death (severe), during the double-blind treatment period.
Time frame: Week 0 (Visit 2) to Week 52
Population: Intent-to-Treat Study Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Rate of COPD Exacerbations That Led to Hospitalization or Death (ie, Severe COPD Exacerbations) | 0.29 COPD exacerbations per patient per year |
| Roflumilast | Rate of COPD Exacerbations That Led to Hospitalization or Death (ie, Severe COPD Exacerbations) | 0.28 COPD exacerbations per patient per year |
p-value: 0.635495% CI: [0.75, 1.19]negative binomial regression
Secondary
Rate of Moderate or Severe COPD Exacerbations or COPD Exacerbations Treated With Antibiotics
Rate of moderate or severe COPD exacerbations treated with antibiotics during the double-blind treatment period.
Time frame: Week 0 (Visit 2) to Week 52
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Rate of Moderate or Severe COPD Exacerbations or COPD Exacerbations Treated With Antibiotics | 1.45 COPD Exacerbations per Patient per Year |
| Roflumilast | Rate of Moderate or Severe COPD Exacerbations or COPD Exacerbations Treated With Antibiotics | 1.31 COPD Exacerbations per Patient per Year |
p-value: 0.088495% CI: [0.8, 1.02]negative binomial regression