Trial Outcomes & Findings for Pharmacokinetics, Safety and Tolerability of Twice-Daily Aclidinium Bromide/Formoterol Fumarate Fixed Dose Combination in Chinese Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (NCT NCT03276078)

NCT ID: NCT03276078

Last Updated: 2019-07-22

Results Overview

Observed maximum concentration, taken directly from the individual concentration-time curve (first dose).

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 20 participants
• Primary outcome timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1
• Results posted on: 2019-07-22

Participant Flow

This study was conducted at a single centre in China. The first participant was enrolled in December 2017 and the last participant visit was in June 2018.

A total of 97 participants were screened. Of these, 20 were enrolled and received treatment.

Participant milestones

Measure	AB/FF 400/12 BID Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Overall Study STARTED	20
Overall Study COMPLETED	19
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Measure	AB/FF 400/12 BID Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Overall Study Adverse Event	1

Baseline Characteristics

Pharmacokinetics, Safety and Tolerability of Twice-Daily Aclidinium Bromide/Formoterol Fumarate Fixed Dose Combination in Chinese Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease

Baseline characteristics by cohort

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Age, Continuous	59.2 Years STANDARD_DEVIATION 6.8 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants
Sex: Female, Male Male	15 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	20 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Observed maximum concentration, taken directly from the individual concentration-time curve (first dose).

Outcome measures

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Cmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). Aclidinium Bromide	45.82 pg/mL Geometric Coefficient of Variation 84.54
Cmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). LAS34850	3149 pg/mL Geometric Coefficient of Variation 55.56
Cmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). LAS34823	38.82 pg/mL Geometric Coefficient of Variation 86.60
Cmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). Formoterol Fumarate	4.786 pg/mL Geometric Coefficient of Variation 62.78

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Time to maximum concentration (h), taken directly from the individual concentration-time curve (first dose).

Outcome measures

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Tmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). Aclidinium Bromide	0.08 hours Interval 0.08 to 0.5
Tmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). LAS34850	3.00 hours Interval 1.5 to 6.0
Tmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). LAS34823	1.75 hours Interval 0.08 to 4.0
Tmax of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). Formoterol Fumarate	1.00 hours Interval 0.08 to 3.0

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Minimum plasma drug concentration at the end of the dosing interval (first dose), where possible.

Outcome measures

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Cmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). Aclidinium Bromide Not calculable	0 pg/mL Geometric Coefficient of Variation 0
Cmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). LAS34850	627.7 pg/mL Geometric Coefficient of Variation 52.02
Cmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). LAS34823 Not calculable	0 pg/mL Geometric Coefficient of Variation 0
Cmin of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). Formoterol Fumarate Not calculable	0 pg/mL Geometric Coefficient of Variation 0

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

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

Outcome measures

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
AUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). Aclidinium Bromide	78.61 pg*hour/mL Geometric Coefficient of Variation 90.69
AUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). LAS34850	20280 pg*hour/mL Geometric Coefficient of Variation 54.28
AUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). LAS34823	201.1 pg*hour/mL Geometric Coefficient of Variation 106.3
AUC(Last) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). Formoterol Fumarate	20.04 pg*hour/mL Geometric Coefficient of Variation 64.22

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post the morning dose on Day 1

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Area under the plasma concentration curve during the first dosing interval, tau (first dose).

Outcome measures

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
AUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). Aclidinium Bromide	85.45 pg*hour/mL Geometric Coefficient of Variation 79.02
AUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). LAS34850	20330 pg*hour/mL Geometric Coefficient of Variation 54.24
AUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). LAS34823	252.9 pg*hour/mL Geometric Coefficient of Variation 60.63
AUC(Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Single Dose). Formoterol Fumarate	22.78 pg*hour/mL Geometric Coefficient of Variation 43.64

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Observed maximum concentration, taken directly from the individual concentration-time curve at steady state.

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Css,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	60.86 pg/mL Geometric Coefficient of Variation 150.0
Css,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34850	3691 pg/mL Geometric Coefficient of Variation 56.03
Css,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34823	81.02 pg/mL Geometric Coefficient of Variation 69.52
Css,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	6.465 pg/mL Geometric Coefficient of Variation 84.34

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Observed minimum concentration, taken directly from the individual concentration-time curve within a dosing interval on Day 5.

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Css,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	4.528 pg/mL Geometric Coefficient of Variation 47.34
Css,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34850	1032 pg/mL Geometric Coefficient of Variation 43.05
Css,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34823	22.88 pg/mL Geometric Coefficient of Variation 47.22
Css,Min of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	1.281 pg/mL Geometric Coefficient of Variation 36.63

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Time to maximum concentration (h), taken directly from the individual concentration-time curve at steady state.

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Tss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	0.08 hours Interval 0.08 to 0.5
Tss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34850	3.00 hours Interval 0.08 to 4.0
Tss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34823	0.50 hours Interval 0.08 to 3.0
Tss,Max of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	0.08 hours Interval 0.08 to 1.5

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

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

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	0.053 1/hours Standard Deviation 0.040
λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34850	0.045 1/hours Standard Deviation 0.018
λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34823	0.048 1/hours Standard Deviation 0.021
λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	0.057 1/hours Standard Deviation 0.029

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

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

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
t½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	19.42 hours Standard Deviation 11.10
t½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34850	20.95 hours Standard Deviation 18.78
t½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34823	17.34 hours Standard Deviation 8.096
t½λz of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	14.06 hours Standard Deviation 4.796

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Area under the plasma concentration curve during the dosing interval, tau at steady state.

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
AUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	168.8 pg*hour/mL Geometric Coefficient of Variation 82.15
AUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34850	27300 pg*hour/mL Geometric Coefficient of Variation 52.29
AUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34823	540.9 pg*hour/mL Geometric Coefficient of Variation 54.97
AUC(ss,Tau) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	31.98 pg*hour/mL Geometric Coefficient of Variation 51.60

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Apparent plasma clearance for parent drug estimated as dose divided by AUCss

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
CL/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	3140 L/hour Standard Deviation 2868
CL/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	422.2 L/hour Standard Deviation 222.7

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

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

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Vz/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	81990 L Standard Deviation 87200
Vz/F of Aclidinium Bromide and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	8284 L Standard Deviation 5161

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Average plasma concentration during a dosing interval, estimated as AUC(ss,tau)/12

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Cav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	14.07 pg/mL Geometric Coefficient of Variation 82.15
Cav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34850	2275 pg/mL Geometric Coefficient of Variation 52.29
Cav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34823	45.07 pg/mL Geometric Coefficient of Variation 54.97
Cav of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	2.665 pg/mL Geometric Coefficient of Variation 51.60

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Fluctuation index during a dosing interval estimated as 100*(Cmax-Cmin)/Cav (%).

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	452.5 Percentage Standard Deviation 269.4
%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34850	117.0 Percentage Standard Deviation 24.69
%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34823	132.0 Percentage Standard Deviation 57.81
%Fluctuation of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	205.9 Percentage Standard Deviation 90.94

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Accumulation ratio for Cmax estimated as Css,max on Day 5/Cmax on Day 1

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Rac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	1.297 ratio Geometric Coefficient of Variation 216.6
Rac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34850	1.185 ratio Geometric Coefficient of Variation 80.29
Rac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34823	2.070 ratio Geometric Coefficient of Variation 113.5
Rac(Cmax) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	1.384 ratio Geometric Coefficient of Variation 90.21

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Accumulation ratio for AUC(tau) estimated as AUC(ss,tau) on Day 5/AUC(tau) on Day 1

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Rac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	1.436 ratio Geometric Coefficient of Variation 56.27
Rac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	1.966 ratio Geometric Coefficient of Variation 108.9
Rac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34850	1.355 ratio Geometric Coefficient of Variation 76.54
Rac[AUC(Tau)] of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34823	2.157 ratio Geometric Coefficient of Variation 82.00

PRIMARY outcome

Timeframe: Pre-dose and 5, 15, and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the morning dose on Day 5

Population: Pharmacokinetic analysis set: All participants who took at least one dose of the IP and had at least one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,tau) evaluable and were assumed not to be affected by factors such as important protocol deviations.

Accumulation ratio for Cmin estimated as Css,min on Day 5/Cmin on Day 1.

Additional parameters may be determined where appropriate.

Outcome measures

Measure	AB/FF 400/12 BID n=19 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Rac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Aclidinium Bromide	1.877 ratio Geometric Coefficient of Variation 45.19
Rac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34850	1.641 ratio Geometric Coefficient of Variation 69.91
Rac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). LAS34823	2.601 ratio Geometric Coefficient of Variation 54.86
Rac(Cmin) of Aclidinium Bromide, Its Metabolites and Formoterol Fumarate (Multiple Doses). Formoterol Fumarate	1.822 ratio Geometric Coefficient of Variation 31.43

SECONDARY outcome

Timeframe: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of the investigational product.

Assessment of the safety in terms of the incidences of AEs/SAEs after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Outcome measures

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Adverse Events (AEs)/Serious AEs (SAEs) Any AE	5 Participants
Adverse Events (AEs)/Serious AEs (SAEs) Any SAE	1 Participants

SECONDARY outcome

Timeframe: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of investigational product.

Assessment of the safety in terms of notable changes from baseline in blood pressure after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Outcome measures

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Treatment-emergent AEs Related to Blood Pressure Blood pressure increased	1 Participants

SECONDARY outcome

Timeframe: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of investigational product.

Assessment of the safety in terms of haematology parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Outcome measures

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Treatment-emergent AEs Related to Clinical Laboratory Parameters (Haematology)	0 Participants

SECONDARY outcome

Timeframe: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of investigational product.

Assessment of the safety in terms of urinalysis parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Outcome measures

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Treatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis) Urine protein present	3 Participants
Treatment-emergent AEs Related to Clinical Laboratory Parameters (Urinalysis) Haematuria	1 Participants

SECONDARY outcome

Timeframe: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of investigational product.

Assessment of the safety in terms of serum biochemistry parameters (Alanine aminotransferase [ALT], Aspartate aminotransferase [AST], alkaline phosphatase [ALP], Gamma-glutamyl transferase [GGT], bilirubin, creatine kinase, lactate dehydrogenase, urea nitrogen, creatinine, urate, cholesterol, glucose, sodium, potassium, calcium, chloride, phosphate, protein, and albumin) after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Outcome measures

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Treatment-emergent AEs Related to Clinical Laboratory Parameters (Serum Biochemistry)	0 Participants

SECONDARY outcome

Timeframe: Screening (Day -21) to Follow-up visit (Days 8-12)

Population: Safety analysis set: All participants who received at least one dose of investigational product.

Assessment of the safety in terms of the 12-lead ECG parameters after administration of Aclidinium Bromide/Formoterol Fumarate 400/12 μg BID for 5 days.

Outcome measures

Measure	AB/FF 400/12 BID n=20 Participants Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Treatment-emergent AEs Related to 12-lead ECG Parameters	0 Participants

Adverse Events

AB/FF 400/12 BID

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Measure	AB/FF 400/12 BID n=20 participants at risk Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Infections and infestations Bronchitis	5.0% 1/20 • Number of events 1 • Screening (Day -21) to Follow-up visit (Days 8-12) The Safety population included all participants who received at least one dose of investigational product. AE summary includes treatment-emergent AEs, that is AEs starting after the first administration of investigational product, until 15 days from last dose.

Other adverse events

Measure	AB/FF 400/12 BID n=20 participants at risk Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Investigations Protein urine present	15.0% 3/20 • Number of events 3 • Screening (Day -21) to Follow-up visit (Days 8-12) The Safety population included all participants who received at least one dose of investigational product. AE summary includes treatment-emergent AEs, that is AEs starting after the first administration of investigational product, until 15 days from last dose.

Additional Information

Dr Sami Daoud

AstraZeneca PLC

Phone: 1-877-240-9479

Email: Information.centre@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee Publication and / or presentation whether complete or partial, of any part of the data or results of this study will not be allowed until global publication and study results disclosure by the sponsor as per EMA / FDA regulatory compliance obligations, and only after mutual agreement between the Investigator and AstraZeneca
• Publication restrictions are in place

Restriction type: OTHER