Aclidinium bromide and formoterol

Change from baseline in 1-hour morning post-dose FEV1 of Aclidinium bromide 400 μg/Formoterol fumarate 12 μg compared to Aclidinium bromide at Week 24. Baseline was defined as the average of the two FEV1 values measure prior to the administration of the first dose of the IP at randomisation visit. If one of the two values was missing, the available one was used as baseline. If both values were missing, the screening pre-bronchodilator value was used. Estimand is based on the while on-treatment approach, where treatment estimates are analysed while subjects are taking IP.

Change from baseline in morning pre-dose (trough) FEV1 of Aclidinium bromide 400 μg/Formoterol fumarate 12 μg compared to Formoterol fumarate 12 μg at Week 24. Morning pre-dose (trough) FEV1 was defined as the average of the two FEV1 values at morning pre-dose of IP at Week 24. If one value was missing, the remaining was used as the trough value. Estimand is based on the while on-treatment approach, where treatment estimates are analysed while subjects are taking IP.

Change from baseline in morning pre-dose (trough) FEV1 of Aclidinium bromide 400 μg compared to placebo at Week 24. Morning pre-dose (trough) FEV1 was defined as the average of the two FEV1 values at morning pre-dose of IP at Week 24. If one value was missing, the remaining was used as the trough value. Estimand is based on the while on-treatment approach, where treatment estimates are analysed while subjects are taking IP.

Peak FEV1 define at the highest value observed in the 3h after the morning IMP administration

For each safety parameter, the last assessment made before the first dose of investigational product in the lead-in study (LAC MD-31) was used as the baseline for all analyses of that safety parameter in this extension study

Change from baseline in endurance time during constant work rate cycle ergometry to symptom limitation at 75% of Maximum Work load (Wmax) after 3 weeks of treatment.

Change from baseline in normalised FEV1 area under the curve over the 24-h period immediately after morning Investigational Medicinal Product administration (AUC0-24h ) after 6 weeks on treatment. The normalised AUC were calculated by means of a trapezoidal method, dividing by the corresponding time interval.

TEAEs were coded Version 16.0 of the Medical Dictionary for Regulatory Activities (MedDRA)

Change from baseline in trough forced expiratory volume in 1 second before the morning dose of aclidinium bromide, Last Observation Carried Forward (LOCF)

Change from baseline in Trough forced expiratory volume in 1 second before the morning dose of aclidinium bromide, Last Observation Carried Forward (LOCF)

Change from Baseline in Morning Pre-dose (trough) Forced Expiratory Volume in 1 Second (FEV1) at Week 52, Lost Observation Carried Forward (LOCF)

Exercise endurance time is defined as the time from the increase in work rate at 75% Wmax (watts) to the point of symptom limitation. The Wmax is defined as the highest work rate the patients were able to maintain for at least 30 seconds.

Percentage of patients achieving a FEV1 increase from baseline equal to or greater than 10% at 30 minutes

Trough FEV1 (mean FEV1 value of the two highest FEV1 readings measured at 23 and 24 hours after inhalation) at 28 weeks

Trough FEV1 (mean FEV1 value of the two highest FEV1 readings measured at 23 and 24 hours after inhalation) at 12 weeks

Trough FEV1 (mean of two highest FEV1 values assessed at 23 and 24 hours after inhalation) at 12 weeks

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Accumulation ratio for Cmin estimated as Css,min on Day 5/Cmin on Day 1. Additional parameters may be determined where appropriate.