Pressurised metered-dose inhaler

Pressurised metered-dose inhaler

Pressurised metered-dose inhaler

Pressurised metered-dose inhaler and dry powder for inhalation.

The peak is the highest forced expiratory volume in one second (FEV1) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1.

Observed maximum concentration (Cmax) of Abediterol, taken directly from the individual concentration-time curve.

Time to maximum concentration (Tmax) of Abediterol (h), taken directly from the individual concentration-time curve.

Terminal rate constant (λz) of Abediterol, estimated by log-linear least square regression of the terminal part of the concentration-time curve.

Terminal half-life (h), estimated as (ln2)/λz (t1/2λz).

Area under the plasma concentration-curve of Abediterol from time zero to the time of last quantifiable analyte concentration.

Area under the Abediterol concentration-time curve from time zero extrapolated to infinity (AUC). AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration (AUC).

PK blood samples were collected 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1 (Note that 24 h and 36 h time-points post-dose correspond to Day 2).

Apparent plasma clearance for parent drug estimated as dose divided by AUC (CL/F).

Apparent volume of distribution for parent drug at terminal phase, estimated by dividing the apparent clearance (CL/F) by λz (Vz/F).

Mean residence time (h), calculated by AUMC/AUC, where AUMC is the area under the first moment-time curve (MRT).

All treatment emergent adverse events (TEAEs), including serious AEs. An AE is the development of an undesirable medical condition or the deterioration of a preexisting medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An AE was considered a TEAE if it was not present prior to the date of the first dose of IP or was present prior to the date of the first dose of IP, but increased in severity after IP administration.

Standard 12-lead ECG evaluations were performed prior to IP administration and 1, 4 and 24 h post IP administration at randomisation and after each IP administration. ECGs were recorded after approximately 5 minutes resting in supine position before any blood sampling and spirometry test, preferably always by the same technician for each patient.

Clinically significant abnormalities were defined as listed in the table below for QT interval, QTcB, QTcF, QRS interval, PR interval and heart rate (HR).

BL incr. = increase from baseline.

The peak is the highest forced vital capacity (FVC) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1.

The percentage of patients achieving at least 200 mL and 12% increase from baseline in trough forced expiratory volume in one second (FEV1). Trough was defined as the mean of the FEV1 values obtained at 23 hours and 24 hours after the morning IP administration.

The peak is the highest forced expiratory volume in one second (FEV1) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1.

Change from baseline in normalised FEV1 area under the concentration-curve of Abediterol from time zero to 24 hours post-dose.

Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead.

Change from baseline in normalised FEV1 area under the concentration time curve for Abediterol from time zero to 12 hours post-dose.

Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead.

Change from baseline in normalised FEV1 area under the concentration-curve for Abediterol from time zero to 6 hours post-dose.

Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead.

Change from baseline in normalised FEV1 area under the concentration-curve for Abediterol from time 12 hours post-dose to 24 hours post-dose.

Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead.

Baseline for FVC was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead.

The peak is the highest forced vital capacity (FVC) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1.

Baseline for FVC was defined as the mean of the two measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min), prior to the morning investigational product (IP)administration on Day 1 of each treatment period. If both were missing the screening value was used instead.

Trough was defined as the mean of the FEV1 values obtained at 23 h and 24 h after the morning IP administration. If one of the values was missing, the other one was used as trough.

Change from baseline in normalised FVC area under the concentration curve for Abediterol from time zero to 24 hours post-dose.

Baseline for FVC was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FVC from Visit 2) was used instead.

Dry powder for inhalation, administered via dry powder, inhaler 2.5 μg/inhalation; (1 inhalation).

Pressurised metered-dose, inhaler 0.025 μg/puff; (2 puffs).

Pressurised metered-dose, inhaler 0.078 μg/puff; (2 puffs).

Pressurised metered-dose inhaler 1.25 μg/puff; (2 puffs).

Pressurised metered-dose inhaler (2 puffs) and Dry powder for inhalation administered via dry powder inhaler (1 inhalation).

The percentage of patients achieving at least 200 mL and 12% increase from baseline in peak FEV1 on Day 1 of each treatment. The peak was the highest value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

The peak is the highest forced expiratory volume in one second (FEV1) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

Observed maximum concentration (Cmax) of Abediterol, taken directly from the individual concentration-time curve.

The PK analysis set, defined as all randomised subjects who took at least one dose of IP and had at least one evaluable relevant PK parameter.

Time to maximum concentration (Tmax) of Abediterol (h), taken directly from the individual concentration-time curve.

The PK analysis set, defined as all randomised subjects who took at least one dose of IP and had at least one evaluable relevant PK parameter.

Terminal rate constant (λz) of Abediterol, estimated by log-linear least square regression of the terminal part of the concentration-time curve.

The PK analysis set, defined as all randomised subjects who took at least one dose of IP and had at least one evaluable relevant PK parameter.

Terminal half-life (h), estimated as (ln2)/λz (t1/2λz).

The PK analysis set, defined as all randomised subjects who took at least one dose of IP and had at least one evaluable relevant PK parameter.

Area under the plasma concentration-curve of Abediterol from time zero to the time of last quantifiable analyte concentration.

The PK analysis set, defined as all randomised subjects who took at least one dose of IP and had at least one evaluable relevant PK parameter.

Area under the Abediterol concentration-time curve from time zero extrapolated to infinity (AUC). AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration (AUC).

PK blood samples were collected 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1 (Note that 24 h and 36 h time-points post-dose correspond to Day 2).

The PK analysis set, defined as all randomised subjects who took at least one dose of IP and had at least one evaluable relevant PK parameter.

Apparent plasma clearance for parent drug estimated as dose divided by AUC (CL/F).

The PK analysis set, defined as all randomised subjects who took at least one dose of IP and had at least one evaluable relevant PK parameter

Apparent volume of distribution for parent drug at terminal phase, estimated by dividing the apparent clearance (CL/F) by λz (Vz/F).

The PK analysis set, defined as all randomised subjects who took at least one dose of IP and had at least one evaluable relevant PK parameter

Mean residence time (h), calculated by AUMC/AUC, where AUMC is the area under the first moment-time curve (MRT).

The PK analysis set, defined as all randomised subjects who took at least one dose of IP and had at least one evaluable relevant PK parameter

All treatment emergent adverse events (TEAEs), including serious AEs. An AE is the development of an undesirable medical condition or the deterioration of a preexisting medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An AE was considered a TEAE if it was not present prior to the date of the first dose of IP or was present prior to the date of the first dose of IP, but increased in severity after IP administration.

All randomised participants who received at least one dose of investigational product

Standard 12-lead ECG evaluations were performed prior to IP administration and 1, 4 and 24 h post IP administration at randomisation and after each IP administration. ECGs were recorded after approximately 5 minutes resting in supine position before any blood sampling and spirometry test, preferably always by the same technician for each patient.

Clinically significant abnormalities were defined as listed in the table below for QT interval, QTcB, QTcF, QRS interval, PR interval and heart rate (HR).

BL incr. = increase from baseline.

All randomised participants who received at least one dose of investigational product

The peak is the highest forced vital capacity (FVC) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

The percentage of patients achieving at least 200 mL and 12% increase from baseline in trough forced expiratory volume in one second (FEV1). Trough was defined as the mean of the FEV1 values obtained at 23 hours and 24 hours after the morning IP administration.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

The peak is the highest forced expiratory volume in one second (FEV1) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

Change from baseline in normalised FEV1 area under the concentration-curve of Abediterol from time zero to 24 hours post-dose.

Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

Change from baseline in normalised FEV1 area under the concentration time curve for Abediterol from time zero to 12 hours post-dose.

Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

Change from baseline in normalised FEV1 area under the concentration-curve for Abediterol from time zero to 6 hours post-dose.

Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

Change from baseline in normalised FEV1 area under the concentration-curve for Abediterol from time 12 hours post-dose to 24 hours post-dose.

Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

Baseline for FVC was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead.

The peak is the highest forced vital capacity (FVC) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

Baseline for FVC was defined as the mean of the two measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min), prior to the morning investigational product (IP)administration on Day 1 of each treatment period. If both were missing the screening value was used instead.

Trough was defined as the mean of the FEV1 values obtained at 23 h and 24 h after the morning IP administration. If one of the values was missing, the other one was used as trough.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

Change from baseline in normalised FVC area under the concentration curve for Abediterol from time zero to 24 hours post-dose.

Baseline for FVC was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FVC from Visit 2) was used instead.

All randomised participants who received investigational product, irrespective of protocol adherence and continued participation in the study

Dry powder for inhalation, administered via dry powder, inhaler 2.5 μg/inhalation; (1 inhalation).

Pressurised metered-dose, inhaler 0.025 μg/puff; (2 puffs).

Pressurised metered-dose, inhaler 0.078 μg/puff; (2 puffs).

Pressurised metered-dose inhaler 1.25 μg/puff; (2 puffs).

Pressurised metered-dose inhaler (2 puffs) and Dry powder for inhalation administered via dry powder inhaler (1 inhalation).