Trial Outcomes & Findings for A Chronic Obstructive Pulmonary Disease (COPD) Trial Investigating Roflumilast on Safety and Effectiveness in China, Hong Kong and Singapore: (NCT NCT01313494)

Last Updated: 2017-02-01

Results Overview

FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV1, time and a treatment-by-time interaction as independent variables.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

626 participants

Primary outcome timeframe

Baseline to Week 24

Results posted on

2017-02-01

Participant Flow

Participants took part in the study at 43 investigative sites in mainland China, Hong Kong and Singapore from 04 Mar 2011 to 16 May 2012.

Participants with a diagnosis of chronic obstructive pulmonary disease (COPD) were randomized in 1 of 2 treatment groups (placebo and roflumilast 500 μg once daily).

Participant milestones

Participant milestones
Measure	Roflumilast Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Overall Study STARTED	313	313
Overall Study Safety Set	315	311
Overall Study COMPLETED	246	263
Overall Study NOT COMPLETED	67	50

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Chronic Obstructive Pulmonary Disease (COPD) Trial Investigating Roflumilast on Safety and Effectiveness in China, Hong Kong and Singapore:

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Roflumilast n=313 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=313 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.	Total n=626 Participants Total of all reporting groups
Age, Continuous	64.2 Years STANDARD_DEVIATION 8.76 • n=5 Participants	64.0 Years STANDARD_DEVIATION 8.27 • n=7 Participants	64.1 Years STANDARD_DEVIATION 8.51 • n=5 Participants
Gender Female	30 Participants n=5 Participants	27 Participants n=7 Participants	57 Participants n=5 Participants
Gender Male	283 Participants n=5 Participants	286 Participants n=7 Participants	569 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	313 Participants n=5 Participants	313 Participants n=7 Participants	626 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Height	166.2 cm STANDARD_DEVIATION 7.27 • n=5 Participants	165.9 cm STANDARD_DEVIATION 7.12 • n=7 Participants	166.1 cm STANDARD_DEVIATION 7.20 • n=5 Participants
Weight	60.4 kg STANDARD_DEVIATION 11.00 • n=5 Participants	61.8 kg STANDARD_DEVIATION 10.54 • n=7 Participants	61.1 kg STANDARD_DEVIATION 10.78 • n=5 Participants
Body Mass Index (BMI)	21.8 kg/m^2 STANDARD_DEVIATION 3.42 • n=5 Participants	22.4 kg/m^2 STANDARD_DEVIATION 3.43 • n=7 Participants	22.1 kg/m^2 STANDARD_DEVIATION 3.44 • n=5 Participants
Chronic obstructive pulmonary disease (COPD) severity Mild	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Chronic obstructive pulmonary disease (COPD) severity Moderate	28 Participants n=5 Participants	16 Participants n=7 Participants	44 Participants n=5 Participants
Chronic obstructive pulmonary disease (COPD) severity Severe	196 Participants n=5 Participants	204 Participants n=7 Participants	400 Participants n=5 Participants
Chronic obstructive pulmonary disease (COPD) severity Very severe	88 Participants n=5 Participants	92 Participants n=7 Participants	180 Participants n=5 Participants
COPD disease characteristics Predominantly chronic bronchitis	56 Participants n=5 Participants	61 Participants n=7 Participants	117 Participants n=5 Participants
COPD disease characteristics Combined emphysema and chronic bronchitis	217 Participants n=5 Participants	216 Participants n=7 Participants	433 Participants n=5 Participants
COPD disease characteristics Predominantly emphysema	40 Participants n=5 Participants	36 Participants n=7 Participants	76 Participants n=5 Participants
Smoking status Former smoker	238 Participants n=5 Participants	221 Participants n=7 Participants	459 Participants n=5 Participants
Smoking status Current smoker	75 Participants n=5 Participants	92 Participants n=7 Participants	167 Participants n=5 Participants
Cigarette pack years	37.2 pack years STANDARD_DEVIATION 21.18 • n=5 Participants	37.5 pack years STANDARD_DEVIATION 23.00 • n=7 Participants	37.4 pack years STANDARD_DEVIATION 22.09 • n=5 Participants
Pre-bronchodilator forced expiratory volume in the first second (FEV1)	0.8 Liters STANDARD_DEVIATION 0.31 • n=5 Participants	0.8 Liters STANDARD_DEVIATION 0.24 • n=7 Participants	0.8 Liters STANDARD_DEVIATION 0.28 • n=5 Participants
Post-bronchodilator FEV1	1.0 Liters STANDARD_DEVIATION 0.35 • n=5 Participants	0.9 Liters STANDARD_DEVIATION 0.27 • n=7 Participants	0.9 Liters STANDARD_DEVIATION 0.31 • n=5 Participants
Pre-bronchodilator FEV1 predicted	32.7 Percent of predicted STANDARD_DEVIATION 10.23 • n=5 Participants	32.7 Percent of predicted STANDARD_DEVIATION 9.00 • n=7 Participants	32.7 Percent of predicted STANDARD_DEVIATION 9.63 • n=5 Participants
Post-bronchodilator FEV1 predicted	36.8 Percent of predicted STANDARD_DEVIATION 11.42 • n=5 Participants	36.4 Percent of predicted STANDARD_DEVIATION 10.13 • n=7 Participants	36.6 Percent of predicted STANDARD_DEVIATION 10.79 • n=5 Participants
FEV1 reversibility increase	108.4 mL STANDARD_DEVIATION 110.83 • n=5 Participants	94.8 mL STANDARD_DEVIATION 104.71 • n=7 Participants	101.6 mL STANDARD_DEVIATION 107.94 • n=5 Participants
FEV1 reversibility % increase	13.6 Percent reversibility STANDARD_DEVIATION 15.29 • n=5 Participants	11.8 Percent reversibility STANDARD_DEVIATION 13.15 • n=7 Participants	12.7 Percent reversibility STANDARD_DEVIATION 14.27 • n=5 Participants
Post-bronchodilator FEV1/forced vital capacity (FVC)	35.8 FEV1/FVC percent STANDARD_DEVIATION 9.69 • n=5 Participants	35.3 FEV1/FVC percent STANDARD_DEVIATION 8.92 • n=7 Participants	35.5 FEV1/FVC percent STANDARD_DEVIATION 9.31 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population included all randomly assigned patients who took at least 1 dose of trial treatment after randomization. Patients were assigned to the treatment group based on the treatment to which they were randomly assigned. Only patients with available data at Baseline and with at least 1 post-baseline measurement are included.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)	0.049 liters Standard Error 0.009	-0.022 liters Standard Error 0.009

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV1, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Post-bronchodilator FEV1	0.045 liters Standard Error 0.009	-0.023 liters Standard Error 0.009

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

Vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Pre-bronchodilator Forced Vital Capacity (FVC)	0.100 liters Standard Error 0.017	-0.009 liters Standard Error 0.017

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

Vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Post-bronchodilator Forced Vital Capacity (FVC)	0.094 liters Standard Error 0.017	-0.007 liters Standard Error 0.016

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

Forced expiratory flow 25-75% (FEF25-75%) is the flow (or speed) of air coming out of the lung during the middle half of a forced expiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Pre-bronchodilator Forced Expiratory Flow 25-75%	0.023 liters/second Standard Error 0.005	-0.010 liters/second Standard Error 0.005

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

Forced expiratory flow 25-75% (FEF25-75%) is the flow (or speed) of air coming out of the lung during the middle half of a forced expiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Post-bronchodilator Forced Expiratory Flow 25-75%	0.022 liters/second Standard Error 0.005	-0.008 liters/second Standard Error 0.005

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

FEV3 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV3, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3)	0.072 liters Standard Error 0.012	-0.030 liters Standard Error 0.012

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

FEV3 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV3, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Post-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3)	0.064 liters Standard Error 0.012	-0.030 liters Standard Error 0.011

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first six seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV6, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6)	0.084 liters Standard Error 0.014	-0.031 liters Standard Error 0.014

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV6, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=304 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Post-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6)	0.078 liters Standard Error 0.013	-0.032 liters Standard Error 0.013

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

PEF is the maximal flow (or speed) achieved during the maximally forced expiration initiated at full inspiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Pre-bronchodilator Peak Expiratory Flow Rate (PEF)	0.096 liters/minute Standard Error 0.027	-0.036 liters/minute Standard Error 0.026

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

PEF is the maximal flow (or speed) achieved during the maximally forced expiration initiated at full inspiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Post-bronchodilator Peak Expiratory Flow Rate (PEF)	0.099 liters/minute Standard Error 0.027	-0.030 liters/minute Standard Error 0.027

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Intent-to-treat population with available data; last observation carried forward (LOCF) was used.

The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Pre-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Vital Capacity	-0.570 percent FEV1/FVC Full Range 4.5667 • Interval -14.32 to 28.35	-1.370 percent FEV1/FVC Full Range 4.9968 • Interval -19.81 to 27.36

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Intent-to-treat population with available data; last observation carried forward (LOCF) was used.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Post-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Vital Capacity	-0.320 percent FEV1/FVC Full Range 4.5400 • Interval -16.38 to 18.3	-0.940 percent FEV1/FVC Full Range 5.1677 • Interval -23.53 to 33.77

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Intent-to-treat population with available data; last observation carried forward (LOCF) was used.

The FEV1/FEV6 ratio represents the percentage of the volume of air expired in the first six seconds that is expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Pre-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Expiratory Volume After 6 Seconds	-0.210 percentage of FEV1/FEV6 Full Range 3.9213 • Interval -14.05 to 27.48	-0.950 percentage of FEV1/FEV6 Full Range 3.9173 • Interval -17.09 to 21.03

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Intent-to-treat population with available data; last observation carried forward (LOCF) was used.

Outcome measures

Outcome measures
Measure	Roflumilast n=295 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=304 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Post-bronchodilator Ratio of Forced Expiratory Volume After 1 Second to Forced Expiratory Volume After 6 Seconds	-0.340 percentage of FEV1/FEV6 Full Range 3.7240 • Interval -25.56 to 17.08	-0.420 percentage of FEV1/FEV6 Full Range 4.1957 • Interval -20.53 to 25.55

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

Symptoms of chronic bronchitis with respect to cough and sputum production were assessed daily by the patient and recorded in a diary. Symptoms were assessed on a 4-point scale as follows: Cough: 0: no cough; 1: mild cough (at some time during the day); 2: moderate cough (regularly during the day); 3: severe cough (never free of cough or feeling free of need to cough). Sputum production: 0: no sputum production (unnoticeable); 1: mild sputum production (noticeable as a problem); 2: moderate sputum production (frequent inconvenience); 3: severe sputum production (constant problem). Change from Baseline is reported for cough and sputum separately, and for the sum of the 2 scores (range 0 - 6). Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=284 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=299 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in COPD Symptom Scores Cough (n=284, 299)	-0.019 units on a scale Standard Error 0.029	0.036 units on a scale Standard Error 0.028
Change From Baseline in COPD Symptom Scores Sputum (n=284, 296)	0.035 units on a scale Standard Error 0.030	0.037 units on a scale Standard Error 0.029
Change From Baseline in COPD Symptom Scores Score Sum (n=282, 296)	0.013 units on a scale Standard Error 0.054	0.064 units on a scale Standard Error 0.053

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

Salbutamol (given by metered dose inhaler and spacer) was used as rescue medication according to the individual needs of a patient. Each use was documented in the patient's paper diary. Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=286 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=293 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Change From Baseline in Use of Rescue Medication	-0.485 puffs/day Standard Error 0.134	-0.518 puffs/day Standard Error 0.131

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Intent-to-treat population with available data.

The TDI is a recognized questionnaire to measure dyspnoea (shortness of breath) in patients with COPD. Questions from the TDI were used to assess the 3 components: "change in functional impairment", "change in magnitude of task" and "change in magnitude of effort". Transitions or changes from baseline are rated from -3 (major deterioration) to +3 (major improvement), and summed to give a total score ranging from -9 to +9. Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Outcome measures

Outcome measures
Measure	Roflumilast n=299 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=305 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Transition Dyspnoea Index (TDI) Total Score at Week 24	1.335 units on a scale Standard Error 0.124	1.396 units on a scale Standard Error 0.122

SECONDARY outcome

Timeframe: 24 weeks

Population: Intent-to-treat

A COPD exacerbation is an event characterised by a worsening in the patient's baseline dyspnoea, or cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management, and may be accompanied by increased wheeze, chest tightness, purulent sputum and symptoms of cold and/or fatigue. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.

Outcome measures

Outcome measures
Measure	Roflumilast n=313 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=313 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Percentage of Participants With Moderate or Severe COPD Exacerbations No exacerbations	81.8 percentage of participants	84.7 percentage of participants
Percentage of Participants With Moderate or Severe COPD Exacerbations One exacerbation	15.0 percentage of participants	12.8 percentage of participants
Percentage of Participants With Moderate or Severe COPD Exacerbations Two exacerbations	2.6 percentage of participants	1.9 percentage of participants
Percentage of Participants With Moderate or Severe COPD Exacerbations Three exacerbations	0.6 percentage of participants	0.6 percentage of participants

SECONDARY outcome

Timeframe: 24 weeks

Population: Intent-to-treat

The mean rate of COPD exacerbations per patient per year rate = (number of exacerbations per treatment group/time to study withdrawal per treatment group) \* 365. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.

Outcome measures

Outcome measures
Measure	Roflumilast n=313 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=313 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Mean Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year	0.55 exacerbations per patient per year	0.44 exacerbations per patient per year

SECONDARY outcome

Timeframe: 24 weeks

Population: Intent-to-treat population with at least one moderate or severe exacerbation

Time to onset of a COPD exacerbation is defined as onset date of COPD exacerbation - date of first intake of study drug + 1 day. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.

Outcome measures

Outcome measures
Measure	Roflumilast n=57 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=48 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Time to Onset of First Moderate or Severe COPD Exacerbation	67.0 days Interval 3.0 to 165.0	86.0 days Interval 2.0 to 168.0

SECONDARY outcome

Timeframe: 24 weeks

Population: Intent-to-treat population who experienced a second moderate to severe COPD exacerbation.

Time to onset of a COPD exacerbation is defined as onset date of COPD exacerbation - date of first intake of study drug + 1 day. At least 10 days between the stop date of an exacerbation and the start date of the following exacerbation was required for these to be be considered as two separate COPD exacerbations. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.

Outcome measures

Outcome measures
Measure	Roflumilast n=10 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=8 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Time to Onset of Second Moderate or Severe COPD Exacerbation	119.5 days Interval 50.0 to 166.0	117.0 days Interval 71.0 to 163.0

SECONDARY outcome

Timeframe: 24 weeks

Population: Safety population, all randomized patients who took at least 1 dose of the trial treatment after randomization.

An adverse event (AE) is any untoward medical occurrence in a clinical trial participant regardless of causal relationship to study drug and regardless whether study drug has been administered. A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. A non-serious AE is any AE that does not meet the criteria above. Each AE was assessed by the Investigator as either 'related' or 'not related' to study drug.

Outcome measures

Outcome measures
Measure	Roflumilast n=315 Participants Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=311 Participants Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Number of Participants With Adverse Events Non-serious AEs	189 participants	172 participants
Number of Participants With Adverse Events Serious AEs (including death)	62 participants	48 participants
Number of Participants With Adverse Events Serious AEs not including death	60 participants	46 participants
Number of Participants With Adverse Events AEs with suggested relationship to trial treatment	65 participants	18 participants
Number of Participants With Adverse Events AEs leading to withdrawal from the trial	15 participants	2 participants
Number of Participants With Adverse Events AEs with changes in concomitant medication	164 participants	155 participants
Number of Participants With Adverse Events All AEs	213 participants	196 participants
Number of Participants With Adverse Events Death	2 participants	2 participants
Number of Participants With Adverse Events AEs not recovered at trial termination	54 participants	45 participants

Adverse Events

Roflumilast

Serious events: 62 serious events

Other events: 143 other events

Deaths: 0 deaths

Placebo

Serious events: 48 serious events

Other events: 133 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Roflumilast n=315 participants at risk Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Placebo n=311 participants at risk Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	28.6% 90/315 • 24 weeks. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	28.6% 89/311 • 24 weeks. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Nasopharyngitis	8.9% 28/315 • 24 weeks. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	14.5% 45/311 • 24 weeks. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Upper respiratory tract infection	5.4% 17/315 • 24 weeks. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.8% 18/311 • 24 weeks. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Diarrhoea	6.7% 21/315 • 24 weeks. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.96% 3/311 • 24 weeks. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Decreased appetite	6.0% 19/315 • 24 weeks. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.64% 2/311 • 24 weeks. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Additional Information

AstraZeneca Clinical Study Information Center

AstraZeneca

Phone: 1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER