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Trial record 59 of 1645 for:    Slovakia

Evaluation of Tolerability and Pharmacokinetics of Roflumilast, 250μg and 500μg, as add-on to Standard COPD Treatment to Treat Severe COPD (OPTIMIZE)

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ClinicalTrials.gov Identifier: NCT02165826
Recruitment Status : Completed
First Posted : June 18, 2014
Results First Posted : March 14, 2017
Last Update Posted : April 20, 2017
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Chronic Obstructive Pulmonary Disease (COPD)
Interventions Drug: Roflumilast
Drug: Roflumilast Placebo
Drug: Standard of Care COPD Treatment
Enrollment 1323
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.
Arm/Group Title Roflumilast 250 μg OD Then 500 μg OD Roflumilast 500 μg EOD Then 500 μg OD Roflumilast 500 μg OD
Hide Arm/Group Description 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. 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. Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Period Title: Main Treatment Period
Started 441 439 443
Safety Analysis Set: Received Study Drug 441 437 443
Completed 360 349 334
Not Completed 81 90 109
Reason Not Completed
Pre-treatment Event/Adverse Event             44             57             68
Major/Significant Protocol Deviation             0             1             3
Lost to Follow-up             4             2             1
Voluntary Withdrawal             23             23             21
Lack of Efficacy             2             0             0
Reason Not Specified             8             5             16
Did Not Receive Study Drug             0             2             0
Period Title: Down-Titration Period
Started 27 39 38
Safety Analysis Set: Received Study Drug 27 39 38
Completed 20 28 31
Not Completed 7 11 7
Reason Not Completed
Pre-treatment Event/Adverse Event             4             10             3
Voluntary Withdrawal             2             1             2
Reason Not Specified             1             0             2
Arm/Group Title Roflumilast 250 μg OD Then 500 μg OD Roflumilast 500 μg EOD Then 500 μg OD Roflumilast 500 μg OD Total
Hide Arm/Group Description 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. 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. Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period. Total of all reporting groups
Overall Number of Baseline Participants 441 437 443 1321
Hide Baseline Analysis Population Description
Safety Analysis Set (SAS) included all randomized participants who took at least one dose of study medication. Main Treatment Period.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
64.2  (7.81) 65.0  (8.21) 64.6  (8.36) 64.6  (8.13)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
40-64 years 242 202 224 668
65-84 years 199 235 217 651
85 years and over 0 0 2 2
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
Female
121
  27.4%
112
  25.6%
105
  23.7%
338
  25.6%
Male
320
  72.6%
325
  74.4%
338
  76.3%
983
  74.4%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
Hispanic or Latino 1 2 5 8
Not Hispanic or Latino 428 423 426 1277
Missing 12 12 12 36
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
American Indian or Alaskan Native 0 1 0 1
Asian 32 30 32 94
Black or African American 3 3 3 9
Native Hawaiian/Other Pacific Islander 1 4 3 8
White 405 399 405 1209
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
Bulgaria 36 18 30 84
Germany 12 24 16 52
Greece 8 6 6 20
Hungary 82 74 79 235
Korea, Republic Of 22 11 13 46
Philippines 7 13 10 30
Poland 60 68 71 199
Romania 54 46 44 144
Russia 37 48 55 140
Slovakia 40 38 27 105
South Africa 17 18 26 61
Spain 2 2 1 5
Thailand 2 6 9 17
Ukraine 56 58 54 168
United Kingdom 6 7 2 15
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
169.1  (8.73) 168.8  (8.66) 169.1  (8.55) 169.0  (8.64)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
75.59  (18.627) 74.31  (17.808) 75.68  (16.949) 75.20  (17.804)
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
26.36  (5.957) 25.98  (5.614) 26.44  (5.888) 26.26  (5.822)
Smoking Classification  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
Current Smoker 213 198 196 607
Ex-smoker 228 239 247 714
Number of Cigarette Pack-Years   [1] 
Mean (Standard Deviation)
Unit of measure:  Pack-years
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
38.1  (17.49) 40.2  (19.22) 37.6  (17.70) 38.6  (18.17)
[1]
Measure Description: Number of pack-years = (number of cigarettes smoked per day/20) × number of years smoked
Pre-bronchodilator Forced Expiratory Volume in the First Second (FEV1)  
Mean (Standard Deviation)
Unit of measure:  Liters
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
1.022  (0.3177) 1.028  (0.3173) 1.018  (0.3289) 1.023  (0.3211)
Pre-Bronchodilator Forced Vital Capacity (FVC)  
Mean (Standard Deviation)
Unit of measure:  Liters
Number Analyzed 441 participants 437 participants 443 participants 1321 participants
2.304  (0.7418) 2.303  (0.7091) 2.314  (0.6822) 2.307  (0.7109)
1.Primary Outcome
Title Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set (SAS) included all randomized participants who took at least one dose of study medication.
Arm/Group Title Roflumilast 250 μg OD Then 500 μg OD Roflumilast 500 μg EOD Then 500 μg OD Roflumilast 500 μg OD
Hide Arm/Group Description:
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.
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.
Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Overall Number of Participants Analyzed 441 437 443
Measure Type: Number
Unit of Measure: percentage of participants
18.4 20.1 24.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roflumilast 250 μg OD Then 500 μg OD, Roflumilast 500 μg OD
Comments Analyses were performed using a hierarchical testing procedure.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.017
Comments Study treatment, country and baseline forced expiratory volume in the first second (FEV1) as explanatory variables.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.66
Confidence Interval (2-Sided) 95%
0.47 to 0.93
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Roflumilast 250 μg OD Then 500 μg OD, Roflumilast 500 μg OD
Comments Analyses were performed using a hierarchical testing procedure.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.68
Confidence Interval (2-Sided) 95%
0.51 to 0.92
Estimation Comments Cox proportional hazards model with study treatment and country as class effects, and baseline FEV1 as a continuous variable.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Roflumilast 500 μg EOD Then 500 μg OD, Roflumilast 500 μg OD
Comments Analyses were performed using a hierarchical testing procedure.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.114
Comments Study treatment, country and baseline forced expiratory volume in the first second (FEV1) as explanatory variables.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.55 to 1.07
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Roflumilast 500 μg EOD Then 500 μg OD, Roflumilast 500 μg OD
Comments Analyses were performed using a hierarchical testing procedure.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.77
Confidence Interval (2-Sided) 95%
0.58 to 1.02
Estimation Comments Cox proportional hazards model with study treatment and country as class effects, and baseline FEV1 as a continuous variable.
2.Secondary Outcome
Title Percentage of Participants With Adverse Events of Interest
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
SAS included all randomized participants who took at least one dose of study medication.
Arm/Group Title Roflumilast 250 μg OD Then 500 μg OD Roflumilast 500 μg EOD Then 500 μg OD Roflumilast 500 μg OD
Hide Arm/Group Description:
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.
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.
Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Overall Number of Participants Analyzed 441 437 443
Measure Type: Number
Unit of Measure: percentage of participants
45.4 48.3 54.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roflumilast 250 μg OD Then 500 μg OD, Roflumilast 500 μg OD
Comments Analyses were performed using a hierarchical testing procedure.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments Study treatment, country and baseline forced expiratory volume in the first second (FEV1) as explanatory variables.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.47 to 0.83
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Roflumilast 500 μg EOD Then 500 μg OD, Roflumilast 500 μg OD
Comments Analyses were performed using a hierarchical testing procedure.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.091
Comments Study treatment, country and baseline forced expiratory volume in the first second (FEV1) as explanatory variables.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.78
Confidence Interval (2-Sided) 95%
0.59 to 1.04
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline (V0DT) in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) to Final Visit of the Down-Titration Period
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
Hide Arm/Group Description:
Participants in the roflumilast 250 μg once daily (OD) then 500 μg OD who were 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.
Participants in the roflumilast 500 μg, every other day (EOD) treatment arm who were 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.
Participants in the roflumilast 500 μg once daily (OD) treatment arm who were 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.
Overall Number of Participants Analyzed 26 39 38
Mean (Standard Deviation)
Unit of Measure: Liters
0.030  (0.2294) 0.055  (0.4170) 0.007  (0.3555)
4.Secondary Outcome
Title Percentage of Participants Prematurely Discontinuing Study Treatment Due to Any Reason During Down-Titration Period
Hide Description [Not Specified]
Time Frame Baseline DT (Day 1 of Down-Titration Period) to Week 8 (Down-Titration Period)
Hide Outcome Measure Data
Hide Analysis Population Description
Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication.
Arm/Group Title Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
Hide Arm/Group Description:
Participants in the roflumilast 250 μg once daily (OD) then 500 μg OD who were 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.
Participants in the roflumilast 500 μg, every other day (EOD) treatment arm who were 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.
Participants in the roflumilast 500 μg once daily (OD) treatment arm who were 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.
Overall Number of Participants Analyzed 27 39 38
Measure Type: Number
Unit of Measure: percentage of participants
25.9 28.2 18.4
5.Secondary Outcome
Title Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Down-Titration Period
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
Hide Arm/Group Description:
Participants in the roflumilast 250 μg once daily (OD) then 500 μg OD who were 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.
Participants in the roflumilast 500 μg, every other day (EOD) treatment arm who were 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.
Participants in the roflumilast 500 μg once daily (OD) treatment arm who were 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.
Overall Number of Participants Analyzed 27 39 38
Mean (Standard Deviation)
Unit of Measure: Liters
Day 14 (n=20, 32, 34) 0.128  (0.3708) 0.223  (0.4101) 0.097  (0.2532)
Day 28 (n=20, 29, 31) 0.162  (0.4274) 0.218  (0.4443) 0.070  (0.2067)
Day 56 (n=26, 39, 38) 0.162  (0.3311) 0.261  (0.4616) 0.127  (0.3334)
6.Secondary Outcome
Title Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) During the Main Period
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Roflumilast 250 μg OD Then 500 μg OD Roflumilast 500 μg EOD Then 500 μg OD Roflumilast 500 μg OD
Hide Arm/Group Description:
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.
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.
Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Overall Number of Participants Analyzed 441 439 443
Mean (Standard Deviation)
Unit of Measure: Liters
Day 15 (n=409, 406, 386) 0.067  (0.2299) 0.094  (0.2573) 0.094  (0.2566)
Day 29 (n=402, 389, 365) 0.099  (0.2605) 0.115  (0.2629) 0.116  (0.2440)
Day 57 (n=376, 367, 352) 0.104  (0.2659) 0.161  (0.2765) 0.133  (0.2705)
Day 84 (n=402, 411, 409) 0.117  (0.2690) 0.141  (0.2882) 0.122  (0.2705)
7.Secondary Outcome
Title Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Main Period
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Roflumilast 250 μg OD Then 500 μg OD Roflumilast 500 μg EOD Then 500 μg OD Roflumilast 500 μg OD
Hide Arm/Group Description:
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.
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.
Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Overall Number of Participants Analyzed 441 439 443
Mean (Standard Deviation)
Unit of Measure: Liters
Day 15 (n=409, 406, 386) 0.096  (0.4053) 0.112  (0.4168) 0.104  (0.4166)
Day 29 (n=402, 389, 365) 0.139  (0.3826) 0.143  (0.4172) 0.149  (0.4173)
Day 57 (n=376, 367, 352) 0.156  (0.4346) 0.194  (0.4974) 0.162  (0.4341)
Day 84 (n=402, 411, 409) 0.157  (0.4746) 0.207  (0.4925) 0.147  (0.4555)
8.Secondary Outcome
Title Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) During the Down-Titration Period
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication.
Arm/Group Title Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
Hide Arm/Group Description:
Participants in the roflumilast 250 μg once daily (OD) then 500 μg OD who were 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.
Participants in the roflumilast 500 μg, every other day (EOD) treatment arm who were 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.
Participants in the roflumilast 500 μg once daily (OD) treatment arm who were 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.
Overall Number of Participants Analyzed 27 39 38
Mean (Standard Deviation)
Unit of Measure: Liters
Day 14 (n=20, 32, 34) 0.087  (0.5392) 0.303  (0.5103) 0.104  (0.4568)
Day 28 (n=20, 29, 31) 0.125  (0.6151) 0.191  (0.4780) 0.067  (0.3522)
Day 56 (n=26, 39, 38) 0.167  (0.5492) 0.113  (0.5100) 0.029  (0.4628)
9.Secondary Outcome
Title Change From Baseline in Treatment Satisfaction Scores During the Main Period
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Roflumilast 250 μg OD Then 500 μg OD Roflumilast 500 μg EOD Then 500 μg OD Roflumilast 500 μg OD
Hide Arm/Group Description:
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.
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.
Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Overall Number of Participants Analyzed 441 439 443
Mean (Standard Deviation)
Unit of Measure: score on a scale
Day 15 (n=410, 408, 386) -0.4  (1.12) -0.3  (1.15) -0.3  (1.07)
Day 29 (n=403, 390, 366) -0.5  (1.23) -0.5  (1.16) -0.5  (1.22)
Day 57 (n=375, 369, 351) -0.6  (1.24) -0.6  (1.26) -0.5  (1.29)
Day 84 (n=407, 416, 412) -0.5  (1.43) -0.5  (1.51) -0.3  (1.52)
10.Secondary Outcome
Title Change From Baseline in Treatment Satisfaction Scores During the Down-Titration Period
Hide Description 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)
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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/Group Title Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
Hide Arm/Group Description:
Participants in the roflumilast 250 μg once daily (OD) then 500 μg OD who were 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.
Participants in the roflumilast 500 μg, every other day (EOD) treatment arm who were 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.
Participants in the roflumilast 500 μg once daily (OD) treatment arm who were 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.
Overall Number of Participants Analyzed 27 39 38
Mean (Standard Deviation)
Unit of Measure: score on a scale
Day 14 (n=20, 32, 34) -1.1  (1.85) -0.8  (1.57) -0.8  (1.84)
Day 28 (n=20, 29, 31) -1.2  (2.01) -0.8  (1.75) -0.9  (1.81)
Day 56 (n=26, 39, 38) -0.8  (2.23) -0.3  (2.15) -0.4  (2.26)
11.Secondary Outcome
Title Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide
Hide Description 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
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Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
Arm/Group Title All PK Participants_Roflumilast All PK Participants_Roflumilast N-oxide
Hide Arm/Group Description:
All PK participants who received any dose of roflumilast. Results for roflumilast.
All PK participants who received any dose of rofumilast. Results for roflumilast N-oxide.
Overall Number of Participants Analyzed 1238 1238
Measure Type: Number
Unit of Measure: units per hour (1/h)
Weight=33.5 kg 0.90 0.57
Weight=70 kg 0.90 0.57
Weight=160 kg 0.90 0.57
Age=40 0.90 0.57
Age=60 0.90 0.57
Age=92 0.90 0.57
Smoking=former 0.90 0.57
Smoking=current 0.90 0.57
Sex=female 0.90 0.57
Sex=male 0.90 0.57
12.Secondary Outcome
Title Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide
Hide Description 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
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Hide Analysis Population Description
Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
Arm/Group Title All PK Participants_Roflumilast All PK Participants_Roflumilast N-oxide
Hide Arm/Group Description:
All PK participants who received any dose of roflumilast. Results for roflumilast.
All PK participants who received any dose of rofumilast. Results for roflumilast N-oxide.
Overall Number of Participants Analyzed 1238 1238
Measure Type: Number
Unit of Measure: liters per hour (L/h)
Weight=33.5 kg 5.64 0.73
Weight=70 kg 5.64 0.89
Weight=160 kg 5.64 1.12
Age=40 7.23 1.11
Age=60 5.64 0.89
Age=92 4.35 0.71
Smoking=former 5.64 0.89
Smoking=current 6.50 1.03
Sex=female 5.64 0.89
Sex=male 5.64 0.79
13.Secondary Outcome
Title Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
Arm/Group Title All PK Participants_Roflumilast All PK Participants_Roflumilast N-oxide
Hide Arm/Group Description:
All PK participants who received any dose of roflumilast. Results for roflumilast.
All PK participants who received any dose of rofumilast. Results for roflumilast N-oxide.
Overall Number of Participants Analyzed 1238 1238
Measure Type: Number
Unit of Measure: liters (L)
Weight=33.5 kg 26.0 4.5
Weight=70 kg 63.9 11.0
Weight=160 kg 175.2 30.2
Age=40 63.9 11.0
Age=60 63.9 11.0
Age=92 63.9 11.0
Smoking=former 63.9 11.0
Smoking=current 63.9 11.0
Sex=female 63.9 11.0
Sex=male 63.9 11.0
14.Secondary Outcome
Title Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
Arm/Group Title All PK Participants_Roflumilast All PK Participants_Roflumilast N-oxide
Hide Arm/Group Description:
All PK participants who received any dose of roflumilast. Results for roflumilast.
All PK participants who received any dose of rofumilast. Results for roflumilast N-oxide.
Overall Number of Participants Analyzed 1238 1238
Measure Type: Number
Unit of Measure: L
Weight=33.5 kg 69.6 5.0
Weight=70 kg 171.0 12.4
Weight=160 kg 468.8 34.0
Age=40 171.0 12.4
Age=60 171.0 12.4
Age=92 171.0 12.4
Smoking=former 171.0 12.4
Smoking=current 171.0 12.4
Sex=female 171.0 12.4
Sex=male 171.0 12.4
15.Secondary Outcome
Title Total PDE4 Inhibitory Activity (tPDE4i)
Hide Description 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.
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Hide Analysis Population Description
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/Group Title Roflumilast 500 μg OD Roflumilast 500 μg EOD Roflumilast 250 μg OD Roflumilast 250 µg Down-Titration
Hide Arm/Group Description:
Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Roflumilast 500 μg, tablets, orally, every other day (EOD) in the Main Period.
Roflumilast 250 μg tablets, orally, once daily in the Main Period.
250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
Overall Number of Participants Analyzed 392 399 404 101
Median (90% Confidence Interval)
Unit of Measure: unitless
Overall
1.17
(0.366 to 2.05)
0.608
(0.227 to 1.03)
0.563
(0.157 to 1.01)
0.583
(0.210 to 1.24)
Age < 65 (n=198,187,229,45)
1.06
(0.323 to 1.85)
0.559
(0.237 to 0.998)
0.518
(0.160 to 0.958)
0.511
(0.205 to 0.984)
Age ≥ 65 to < 75 (n=146,159,136,39)
1.24
(0.550 to 2.08)
0.660
(0.177 to 1.04)
0.614
(0.138 to 1.10)
0.683
(0.207 to 1.23)
Age ≥ 75 (n=48,53,39,17)
1.24
(0.318 to 2.31)
0.676
(0.188 to 1.12)
0.616
(0.195 to 1.01)
0.712
(0.300 to 1.32)
Weight < 60 kg (n=56,78,73,17)
1.34
(0.591 to 2.64)
0.755
(0.258 to 1.22)
0.653
(0.156 to 1.12)
0.934
(0.325 to 1.39)
Weight ≥ 60 kg (n=336,321,331,84)
1.12
(0.339 to 1.99)
0.592
(0.223 to 1.01)
0.552
(0.158 to 0.971)
0.538
(0.202 to 1.02)
Males (n=300,297,290,66)
1.12
(0.363 to 1.96)
0.585
(0.226 to 0.994)
0.558
(0.145 to 0.998)
0.575
(0.213 to 1.14)
Females (n=92,102,114,35)
1.29
(0.468 to 2.38)
0.696
(0.260 to 1.15)
0.618
(0.189 to 1.01)
0.626
(0.217 to 1.25)
Current Smoker (n=179,183,200,45)
1.04
(0.327 to 1.88)
0.568
(0.247 to 0.976)
0.514
(0.101 to 0.949)
0.554
(0.228 to 1.21)
Former Smoker (n=213,216,204,56)
1.25
(0.416 to 2.15)
0.632
(0.186 to 1.09)
0.626
(0.196 to 1.10)
0.624
(0.207 to 1.30)
16.Secondary Outcome
Title Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i)
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Roflumilast 500 μg OD Roflumilast 250 μg OD
Hide Arm/Group Description:
Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Roflumilast 500 μg at least one dose in the Main Period followed by Roflumilast 250 μg tablets, orally, once daily in the Down -Titration Period.
Overall Number of Participants Analyzed 1114 76
Median (90% Confidence Interval)
Unit of Measure: unitless
All Participants (n=1114,76)
1.17
(0.352 to 2.03)
0.611
(0.197 to 1.243)
Discontinuation due to Any AEI=Yes (n=67,62)
1.28
(0.427 to 2.22)
0.647
(0.201 to 1.239)
Discontinuation due to Any AEI=No (n=1047,14)
1.16
(0.339 to 2.02)
0.436
(0.212 to 1.069)
Discontinuation due to Any AE=Yes (n=77,64)
1.29
(0.464 to 2.10)
0.647
(0.204 to 1.237)
Discontinuation due to Any AE=No (n=1037,12)
1.16
(0.337 to 2.02)
0.408
(0.209 to 1.006)
Discontinuation Due to Any Reason=Yes (n=106,75)
1.23
(0.416 to 2.06)
0.600
(0.197 to 1.243)
Discontinuation Due to Any Reason=No (n=1008,1)
1.16
(0.332 to 2.02)
0.626
(0.626 to 0.626)
At Least 1 AEI=Yes (n=536,75)
1.23
(0.453 to 2.09)
0.600
(0.197 to 1.243)
At Least 1 AEI=No (578,1)
1.12
(0.297 to 1.98)
0.929
(0.929 to 0.929)
At Least 1 AE=Yes (n=693,76)
1.22
(0.416 to 2.07)
0.611
(0.197 to 1.243)
At Least 1 AE=No (n=421,0)
1.08
(0.294 to 1.97)
NA [1] 
(NA to NA)
[1]
No participants in this category for this arm.
17.Secondary Outcome
Title Median Simulated Percentage of Participants With Adverse Events of Interest
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Roflumilast 250 μg OD Roflumilast 500 μg EOD Roflumilast 500 μg OD
Hide Arm/Group Description:
Roflumilast 250 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Roflumilast 500 μg, orally, every other day (EOD) at least 1 dose in the Main Period
Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
Overall Number of Participants Analyzed 1000 1000 1000
Measure Type: Number
Unit of Measure: percentage of participants
Weight=48 kg (tPDE4i=0.72,0.72,1.45) 53.2 53.2 61.8
Weight=74 kg (tPDE4i=0.65,0.65,1.30) 52.3 52.3 60.1
Weight=105 kg (tPDE4i=0.60.0.60,1.19) 51.7 51.7 58.8
Former Smoker (tPDE4i=0.65,0.65,1.30) 52.3 52.3 60.1
Current Smoker (tPDE4i=0.56,0.56,1.13) 42.5 42.5 49.2
Male (tPDE4i=0.65,0.65,1.30) 52.3 52.3 60.1
Female (tPDE4i=0.72,0.72,1.45) 53.2 53.2 61.8
Age=51 (tPDE4i=0.58,0.58,1.15) 51.4 51.4 58.4
Age=64 (tPDE4i=0.65,0.65,1.30) 52.3 52.3 60.1
Age=77 (tPDE4i=0.72,0.72,1.44) 53.2 53.2 61.7
With LAMA (tPDE4i=0.65,0.65,1.30) 52.3 52.3 60.1
Without LAMA (tPDE4i=0.65,0.65,1.30) 43.5 43.5 51.4
18.Secondary Outcome
Title Median Simulated Absolute Change From Baseline in FEV1 at Weeks 4 and 12
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Roflumilast 500 μg OD_CFB in FEV1 @ Week 4 Roflumilast 500 μg OD_CFB in FEV1 @ Week 12
Hide Arm/Group Description:
Roflumilast 500 μg, tablets, orally, once daily (OD) for 12 weeks. Results for Change from Baseline in FEV1 at Week 4.
Roflumilast 500 μg, tablets, orally, once daily (OD) for 12 weeks. Results for Change from Baseline in FEV1 at Week 12.
Overall Number of Participants Analyzed 1000 1000
Measure Type: Number
Unit of Measure: milliliters (mL)
Weight=33.5 kg (tPDE4i=1.012,1.012) 50 32
Weight=70 kg (tPDE4i=0.839,0.839) 60.5 56
Weight=160 kg (tPDE4i=0.681,0.681) 108 157
Current Smoker (tPDE4i=0.729,0.729) 99.5 96.5
Former/Never Smoker (tPDE4i=0.839,0.839) 60.5 56
Male (tPDE4i=0.839,0.839) 60.5 56
Female (tPDE4i=0.937,0.937) 53.2 49.8
Age=40 years (tPDE4i=0.675,0.675) 57.6 52.2
Age=60 years (tPDE4i=0.839,0.839) 60.5 56
Age=92 years (tPDE4i=1.06,1.06) 56.4 53.3
Asian (tPDE4i=0.839,0.839) 56.1 52
non-Asian (tPDE4i=0.839,0.839) 60.5 56
COPD_Not Very Severe (tPDE4i=0.839,0.839) 60.5 56
COPD_Very Severe (tPDE4i=0.839,0.839) 42.2 39.1
LAMA=Yes (tPDE4i=0.839,0.839) 60.5 56
LAMA=No (tPDE4i=0.839,0.839) 63.5 58.8
%FEV1 Reversibility=-28% (tPDE4i=0.839,0.839) 68.1 63.1
%FEV1 Reversibility=10% (tPDE4i=0.839,0.839) 60.5 56
%FEV1 Reversibility=147% (tPDE4i=0.839,0.839) 32.9 30.5
Time Frame Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days).
Adverse Event Reporting Description Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
 
Arm/Group Title Roflumilast 250 μg OD Then 500 μg OD_Main Treatment Period Roflumilast 500 μg EOD Then 500 μg OD_Main Treatment Period Roflumilast 500 μg OD_Main Treatment Period Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
Hide Arm/Group Description 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. 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. Roflumilast 500 μg tablets, orally, once daily for 12 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. Participants in the roflumilast 250 μg once daily (OD) then 500 μg OD who were 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. Participants in the roflumilast 500 μg, every other day (EOD) treatment arm who were 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. Participants in the roflumilast 500 μg once daily (OD) treatment arm who were 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.
All-Cause Mortality
Roflumilast 250 μg OD Then 500 μg OD_Main Treatment Period Roflumilast 500 μg EOD Then 500 μg OD_Main Treatment Period Roflumilast 500 μg OD_Main Treatment Period Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Roflumilast 250 μg OD Then 500 μg OD_Main Treatment Period Roflumilast 500 μg EOD Then 500 μg OD_Main Treatment Period Roflumilast 500 μg OD_Main Treatment Period Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   19/441 (4.31%)   22/437 (5.03%)   20/443 (4.51%)   1/27 (3.70%)   0/39 (0.00%)   0/38 (0.00%) 
Cardiac disorders             
Myocardial infarction  1 [1]  1/441 (0.23%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Myocardial ischaemia  1  0/441 (0.00%)  1/437 (0.23%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Atrial fibrillation  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Cardiac failure  1 [2]  1/441 (0.23%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Cardiopulmonary failure  1 [2]  1/441 (0.23%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Ear and labyrinth disorders             
Vertigo  1  1/441 (0.23%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Gastrointestinal disorders             
Abdominal mass  1  1/441 (0.23%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Colitis ulcerative  1  1/441 (0.23%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Femoral hernia incarcerated  1  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Small intestinal obstruction  1  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Infections and infestations             
Pneumonia  1  2/441 (0.45%)  1/437 (0.23%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Infective exacerbation of chronic obstructive airways disease  1  1/441 (0.23%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Acute sinusitis  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Appendicitis  1  1/441 (0.23%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Bronchopneumonia  1  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Respiratory tract infection  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Upper respiratory tract infection  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Injury, poisoning and procedural complications             
Lower limb fracture  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Metabolism and nutrition disorders             
Decreased appetite  1  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Gout  1  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Musculoskeletal and connective tissue disorders             
Spinal osteoarthritis  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Lung adenocarcinoma  1 [3]  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Malignant melanoma  1  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Prostate cancer  1  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Transitional cell carcinoma  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Nervous system disorders             
Sciatica  1  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Syncope  1  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Transient ischaemic attack  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Psychiatric disorders             
Anxiety  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Chronic obstructive pulmonary disease  1 [4]  8/441 (1.81%)  13/437 (2.97%)  7/443 (1.58%)  1/27 (3.70%)  0/39 (0.00%)  0/38 (0.00%) 
Dyspnoea  1  3/441 (0.68%)  0/437 (0.00%)  3/443 (0.68%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Acute respiratory failure  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Haemoptysis  1  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Pleural effusion  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Pneumothorax spontaneous  1 [5]  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Pulmonary hypertension  1  1/441 (0.23%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Vascular disorders             
Hypertension  1  0/441 (0.00%)  0/437 (0.00%)  1/443 (0.23%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Hypertensive crisis  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Vasculitis  1  0/441 (0.00%)  1/437 (0.23%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
[1]
One treatment-emergent death occurred during treatment with roflumilast 500 μg OD and is not related (previous AE included severe syncope).
[2]
One treatment-emergent death occurred during treatment with roflumilast 250 μg OD then 500 μg OD and is not related (previous AE included moderate COPD).
[3]
One treatment-emergent death occurred during treatment with roflumilast 500 μg OD and is not related (previous AE included concurrent moderate haemoptysis).
[4]
One treatment-emergent death occurred during treatment with roflumilast 250 μg OD then 500 μg OD and is not related (previous AE included concurrent moderate pneumonia).
[5]
One treatment-emergent death occurred during treatment with roflumilast 500 µg EOD then 500 µg OD and is not related.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Roflumilast 250 μg OD Then 500 μg OD_Main Treatment Period Roflumilast 500 μg EOD Then 500 μg OD_Main Treatment Period Roflumilast 500 μg OD_Main Treatment Period Roflumilast 250 μg OD Then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   239/441 (54.20%)   248/437 (56.75%)   272/443 (61.40%)   13/27 (48.15%)   21/39 (53.85%)   25/38 (65.79%) 
Blood and lymphatic system disorders             
Anaemia  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  1/39 (2.56%)  0/38 (0.00%) 
Eye disorders             
Chalazion  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  1/38 (2.63%) 
Gastrointestinal disorders             
Diarrhoea  1  107/441 (24.26%)  113/437 (25.86%)  134/443 (30.25%)  3/27 (11.11%)  6/39 (15.38%)  11/38 (28.95%) 
Nausea  1  87/441 (19.73%)  92/437 (21.05%)  110/443 (24.83%)  1/27 (3.70%)  5/39 (12.82%)  8/38 (21.05%) 
Abdominal pain  1  69/441 (15.65%)  58/437 (13.27%)  64/443 (14.45%)  0/27 (0.00%)  6/39 (15.38%)  5/38 (13.16%) 
Abdominal pain upper  1  19/441 (4.31%)  15/437 (3.43%)  27/443 (6.09%)  0/27 (0.00%)  3/39 (7.69%)  3/38 (7.89%) 
Bowel movement irregularity  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  1/38 (2.63%) 
Duodenitis  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  1/38 (2.63%) 
Dyspepsia  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  1/27 (3.70%)  0/39 (0.00%)  0/38 (0.00%) 
General disorders             
Fatigue  1  4/441 (0.91%)  10/437 (2.29%)  5/443 (1.13%)  0/27 (0.00%)  0/39 (0.00%)  1/38 (2.63%) 
Feeling hot  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  1/27 (3.70%)  0/39 (0.00%)  0/38 (0.00%) 
Malaise  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  1/27 (3.70%)  0/39 (0.00%)  0/38 (0.00%) 
Infections and infestations             
Nasopharyngitis  1  7/441 (1.59%)  11/437 (2.52%)  12/443 (2.71%)  0/27 (0.00%)  0/39 (0.00%)  3/38 (7.89%) 
Pharyngitis  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  1/27 (3.70%)  0/39 (0.00%)  2/38 (5.26%) 
Candida infection  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  1/27 (3.70%)  0/39 (0.00%)  0/38 (0.00%) 
Rhinitis  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  1/27 (3.70%)  0/39 (0.00%)  0/38 (0.00%) 
Viral pharyngitis  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  1/38 (2.63%) 
Bronchitis  1  6/441 (1.36%)  4/437 (0.92%)  9/443 (2.03%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Injury, poisoning and procedural complications             
Procedural dizziness  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  1/27 (3.70%)  0/39 (0.00%)  0/38 (0.00%) 
Skin abrasion  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  1/27 (3.70%)  0/39 (0.00%)  0/38 (0.00%) 
Investigations             
Weight decreased  1  10/441 (2.27%)  9/437 (2.06%)  17/443 (3.84%)  0/27 (0.00%)  0/39 (0.00%)  2/38 (5.26%) 
Blood glucose increased  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  1/39 (2.56%)  0/38 (0.00%) 
Metabolism and nutrition disorders             
Decreased appetite  1  100/441 (22.68%)  105/437 (24.03%)  129/443 (29.12%)  3/27 (11.11%)  8/39 (20.51%)  9/38 (23.68%) 
Hypokalaemia  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  1/39 (2.56%)  0/38 (0.00%) 
Musculoskeletal and connective tissue disorders             
Pain in extremity  1  20/441 (4.54%)  21/437 (4.81%)  20/443 (4.51%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Arthralgia  1  8/441 (1.81%)  7/437 (1.60%)  9/443 (2.03%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Nervous system disorders             
Headache  1  107/441 (24.26%)  115/437 (26.32%)  115/443 (25.96%)  2/27 (7.41%)  7/39 (17.95%)  10/38 (26.32%) 
Dizziness  1  16/441 (3.63%)  20/437 (4.58%)  14/443 (3.16%)  0/27 (0.00%)  0/39 (0.00%)  0/38 (0.00%) 
Tremor  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  2/27 (7.41%)  1/39 (2.56%)  0/38 (0.00%) 
Amnesia  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  1/27 (3.70%)  0/39 (0.00%)  0/38 (0.00%) 
Psychiatric disorders             
Insomnia  1  97/441 (22.00%)  100/437 (22.88%)  106/443 (23.93%)  2/27 (7.41%)  10/39 (25.64%)  6/38 (15.79%) 
Reproductive system and breast disorders             
Postmenopausal haemorrhage  1  0/441 (0.00%)  0/437 (0.00%)  0/443 (0.00%)  0/27 (0.00%)  0/39 (0.00%)  1/38 (2.63%) 
Respiratory, thoracic and mediastinal disorders             
Chronic obstructive pulmonary disease  1  34/441 (7.71%)  39/437 (8.92%)  38/443 (8.58%)  3/27 (11.11%)  3/39 (7.69%)  1/38 (2.63%) 
Dyspnoea  1  15/441 (3.40%)  13/437 (2.97%)  11/443 (2.48%)  1/27 (3.70%)  0/39 (0.00%)  0/38 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: AstraZeneca Clinical Study Information Center
Organization: AstraZeneca
Phone: 1-877-240-9479
EMail: information.center@astrazeneca.com
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02165826     History of Changes
Other Study ID Numbers: RO-2455-302-RD
U1111-1150-2477 ( Other Identifier: World Health Organization )
2013-001788-21 ( EudraCT Number )
First Submitted: May 2, 2014
First Posted: June 18, 2014
Results First Submitted: September 16, 2016
Results First Posted: March 14, 2017
Last Update Posted: April 20, 2017