A 6-week Dose Ranging Study of CHF 5259 pMDI in Subjects With Chronic Obstructive Pulmonary Disease

Change from baseline in FEV1 AUC(0-12h), normalized by time, on Day 1.

Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours).

Definitions:

AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;

Change from baseline in FEV1 AUC(0-4h), normalized by time on Day 1 of treatment (Week 0).

Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 and at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (4 hours).

Definitions:

AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-4h)=Mean FEV1 after inhalation, measured at prespecified times for up to 4-h observation period (0-4h), normalized by time;

Change from baseline in FEV1 peak(0-4h) (L) on Day 1 and at Week 6.

Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication.

Definitions:

Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; Peak(0-4h)=Maximum FEV1 between 0 and 4 h.

Change from baseline in FVC AUC(0-12h), normalized by time, on Day 1 and at the end of treatment (Week 6).

Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours).

Definitions:

AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-12h)=Mean FVC after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;

Change from baseline in FVC AUC(0-4h), normalized by time, on Day 1 and at the end of treatment (Week 6).

Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours).

Definitions:

AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-4)=Mean FVC after inhalation, measured at prespecified times for up to 4-h observation period (0-4 h), normalized by time;

Change from baseline in FVC peak(0-4h) (L) on Day 1 and at the end of treatment at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication.

Definitions:

Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; Peak(0-4h)=Maximum FEV1 between 0 and 4 h.

Time to onset of action is defined as the time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥100 mL.

Number of patients achieving onset of action was defined as a change from baseline in post-dose FEV1 ≥100 mL on Day 1. These are the patients who contributed to the results, reported as median and 95% CI for 'time to onset of action' presented in Outcome Measure 8, above.

Change from baseline in FEV1 at treatment visit 3 (Week 3) and treatment visit 4 (Week 6) of treatment. Spirometry, used to measure FEV1, was performed according to internationally accepted standards.

Definitions:

Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second;

Change from baseline in IC at treatment Visit 3 (Week 3) and treatment Visit 4 (Week 6). Spirometry was used to measure IC and was performed according to internationally accepted standards.

Definitions:

Baseline: value of the measurement recorded at 45 mins pre-dose at Visit 2 (Week 0); IC=Inspiratory capacity;

Number of subjects achieving TDI focal score ≥1, at treatment visit 3 (Week 3) and at treatment visit 4 (Week 6).

TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement); total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important.

Definitions:

Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;

Transitional Dyspnea Index (TDI) focal score at treatment visit 3 (Week 3) and treatment visit 4 (Week 6).

TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement), with a total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important.

Definitions:

Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;

Evaluate the number of rescue medication-free days compared with baseline. Results are shown as percentage (%) of rescue medication-free days; an increased value indicates improvement from baseline.

Definitions:

Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3, Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0).

Evaluate the change from baseline in average use of rescue medication (number of puffs/day) during the inter-visit periods and the entire treatment period.

Results are shown as number of puffs/day; a decrease (implies improvement) from baseline in average use of rescue medication.

Definitions:

Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3 (Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0);

Change from baseline in average EXACT-Respiratory Symptom (E-RS) total score during inter-visit periods and the entire treatment period

E-RS in COPD uses 11 respiratory symptom items from the 14-item EXAcerbations of COPD tool (EXACT). E-RS total score quantifies respiratory symptom severity on a scale ranging from 0 to 40. Higher E-RS total scores indicate more severe symptoms and a declining total score indicates health improvement. E-RS questionnaire was completed by the patient each evening (e-diary).

Definitions:

For details on baseline, inter-visit periods, and the entire treatment period, please refer to outcome measure #15.

Vital signs -- Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were measured at prespecified times, using a 12-Lead single ECGs were recorded at all study visits (pre-dose at V1 (Week -2) and V3 (Week 3), as well as at pre-dose and 1.5 hours post-dose at Visit 2 (Week 0) and Visit 4 (Week 6).

Results are shown by treatment group, as change from baseline (in mmHg) for representative timepoints.

Definitions:

Baseline=Values recorded pre-dose (Visit 2, Week 0); Day 1=Day of the first dose of randomized study drug (Visit 2, Week 0);

Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Heart rate (HR)

Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5m, +55m, and at +2.5 h.

Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - PR Interval

Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.

Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - QRS Interval

Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.

Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Fridericia-corrected QT interval (QTcF).

Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.

24-hour Holter ECG - Prolonged QTcF - Male subjects.

Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.

24-hour Holter ECG - Prolonged QTcF - Female subjects.

Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.

24-hour Holter ECG - Prolonged QTcF - Change from baseline.

Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.

Results are presented as the number of subjects who had a change from baseline in QTcF of: > 30 msec, > 60 msec, and no prolongation (by > 30 msec or > 60 msec).