Trial Outcomes & Findings for Efficacy and Safety of NVA237 in Patients With Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT01119950)

Results Overview

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. The maximal response of incremental once daily and twice daily doses of NVA237 that each dose achieves in relation to the maximal effect of NVA237 on Trough FEV1 was measured at Day 28. FEV1 was measured in response to all doses administered (see Outcome Measure #19). All trough FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All trough FEV1 data are reported as a percentage of the theoretical maximal response. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

388 participants

Primary outcome timeframe

Day 28

Results posted on

2015-03-23

Participant Flow

Participants were randomized to 1 of 8 treatment groups during period 1; participants were then switched to a different treatment group during period 2 after a 7 days wash out. Each period lasted up to 29 days.

For this crossover study, a participant is counted in 2 treatment groups

Participant milestones

Participant milestones
Measure	Overall Study For the overall study, 388 participants were randomized and 1 non-randomized participant received drug in error and was discontinued. This participant was excluded from randomized number of patients but included in number of treated participants and in the safety set. Out of the 388 participants randomized, 341 completed study treatment and 47 discontinued, including 3 misrandomized participants who did not receive any study medication.
Overall Study STARTED	388
Overall Study NVA237 12.5 ug q.d.	96
Overall Study NVA237 25 ug q.d.	99
Overall Study NVA237 12.5 ug b.i.d.	99
Overall Study NVA237 50 ug q.d.	96
Overall Study NVA237 25 ug b.i.d.	100
Overall Study NVA237 100 ug q.d.	98
Overall Study NVA237 50 ug b.i.d.	94
Overall Study Placebo	94
Overall Study COMPLETED	341
Overall Study NOT COMPLETED	47

Reasons for withdrawal

Reasons for withdrawal
Measure	Overall Study For the overall study, 388 participants were randomized and 1 non-randomized participant received drug in error and was discontinued. This participant was excluded from randomized number of patients but included in number of treated participants and in the safety set. Out of the 388 participants randomized, 341 completed study treatment and 47 discontinued, including 3 misrandomized participants who did not receive any study medication.
Overall Study Adverse Event	25
Overall Study Withdrawal by Subject	9
Overall Study Protocol Violation	5
Overall Study Lost to Follow-up	4
Overall Study Administrative	2
Overall Study Abnormal lab value	1
Overall Study Death	1

Baseline Characteristics

Efficacy and Safety of NVA237 in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=386 Participants All participants in the safety set
Age, Continuous	61.2 Years STANDARD_DEVIATION 7.91 • n=5 Participants
Sex: Female, Male Female	251 Participants n=5 Participants
Sex: Female, Male Male	135 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. The maximal response of incremental once daily and twice daily doses of NVA237 that each dose achieves in relation to the maximal effect of NVA237 on Trough FEV1 was measured at Day 28. FEV1 was measured in response to all doses administered (see Outcome Measure #19). All trough FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All trough FEV1 data are reported as a percentage of the theoretical maximal response. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values.

Outcome measures

Outcome measures
Measure	Overall Study n=81 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=88 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=90 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=88 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=87 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=90 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=81 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Maximal Response of Incremental Once Daily and Twice Daily Doses of NVA237 That Each Dose Achieves in Relation to the Maximal Effect of NVA237 on Trough Forced Expiratory Volume in One Second at Day 28	27.1 Percentage of maximal response 90% Confidence Interval 0.454 • Interval 16.4 to 44.3	42.0 Percentage of maximal response 90% Confidence Interval 0.471 • Interval 26.5 to 61.4	61.6 Percentage of maximal response 90% Confidence Interval 0.456 • Interval 36.6 to 82.1	58.5 Percentage of maximal response 90% Confidence Interval 0.389 • Interval 37.5 to 76.2	75.5 Percentage of maximal response 90% Confidence Interval 0.508 • Interval 48.7 to 90.2	73.0 Percentage of maximal response 90% Confidence Interval 0.512 • Interval 49.0 to 86.5	85.4 Percentage of maximal response 90% Confidence Interval 0.463 • Interval 60.4 to 94.8	—

SECONDARY outcome

Timeframe: day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. FEV1 was measured between dosing regimens (over the range 20 micrograms to 55 micrograms total daily dose) after 28 days of treatment. Mean trough FEV1 was measured in response to all doses administered (12.5 µg q.d., 25.0 µg q.d., 12.5 µg b.i.d., 50 µg q.d., 25 µg b.i.d., 100 µg q.d., 50.0 µg b.i.d., and Placebo; see Outcome Measure # 19), and was used to compute modeled dose-response curves for once-daily and twice-daily regimens separately. The difference between those curves was computed at pre-specified theoretical doses (20 µg, 25 µg, 30 µg, 35 µg, 40 µg, 45 µg, 50 µg, and 55 µg) chosen at points likely to show the largest differences between the once-daily and twice-daily regimens. The theoretical responses to each dosing schedule separately and the difference between the once-daily and twice-daily regimens are represented below.

Outcome measures

Outcome measures
Measure	Overall Study n=385 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Trough Forced Expiratory Volume in One Second for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237 Total daily dose 20 ug	0.037 Liters Interval 0.013 to 0.053	—	—	—	—	—	—	—
Trough Forced Expiratory Volume in One Second for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237 Total daily dose 25 ug	0.037 Liters Interval 0.013 to 0.052	—	—	—	—	—	—	—
Trough Forced Expiratory Volume in One Second for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237 Total daily dose 30 ug	0.036 Liters Interval 0.013 to 0.051	—	—	—	—	—	—	—
Trough Forced Expiratory Volume in One Second for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237 Total daily dose 35 ug	0.035 Liters Interval 0.013 to 0.05	—	—	—	—	—	—	—
Trough Forced Expiratory Volume in One Second for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237 Total daily dose 40 ug	0.034 Liters Interval 0.013 to 0.049	—	—	—	—	—	—	—
Trough Forced Expiratory Volume in One Second for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237 Total daily dose 45 ug	0.033 Liters Interval 0.013 to 0.047	—	—	—	—	—	—	—
Trough Forced Expiratory Volume in One Second for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237 Total daily dose 50 ug	0.032 Liters Interval 0.012 to 0.046	—	—	—	—	—	—	—
Trough Forced Expiratory Volume in One Second for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237 Total daily dose 55 ug	0.031 Liters Interval 0.012 to 0.045	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 5 min, 15 min, 1,2,3,4,6,8,10 hours, 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 doses on FEV1 Area Under the Curve (AUC) 0-24 hours at day 28 of treatment was calculated from measurements taken at 5 min, 15 min, 1,2,3,4,6,8,10 hours, 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on day 28. AUC FEV1 was measured in response to all doses administered (see Outcome Measure #20). All FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=82 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=90 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=90 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=92 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=91 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=82 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours at Day 28 of Treatment	28.9 Percentage of maximal response * hours Interval 18.7 to 41.6	44.8 Percentage of maximal response * hours Interval 31.6 to 58.8	49.0 Percentage of maximal response * hours Interval 34.1 to 64.1	61.9 Percentage of maximal response * hours Interval 48.0 to 74.0	65.7 Percentage of maximal response * hours Interval 50.9 to 78.1	76.4 Percentage of maximal response * hours Interval 64.8 to 85.1	79.3 Percentage of maximal response * hours Interval 67.5 to 87.7	—

SECONDARY outcome

Timeframe: -25 min,-15 min (predose); 5 min,15 min, 1,2,3,4,6,8,10 hours, 11 hours 55min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. The Area Under the Curve (AUC) 0-24 hours FEV1 between dosing regimens over the range 20 micrograms to 55 micrograms total daily dose at -25 min,-15 min (predose); 5 min, 15 min, 1,2,3,4,6,8,10 hours, 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on day 28. AUC 0-24 hours FEV1 was measured in response to all doses administered (12.5 µg q.d., 25.0 µg q.d., 12.5 µg b.i.d., 50 µg q.d., 25 µg b.i.d., 100 µg q.d., 50.0 µg b.i.d., and Placebo; see Outcome Measure # 20), and was used to compute modeled dose-response curves for once-daily and twice-daily regimens separately. The difference between those curves was computed at pre-specified theoretical doses (20 µg, 25 µg, 30 µg, 35 µg, 40 µg, 45 µg, 50 µg, and 55 µg) chosen at points likely to show the largest differences between the once-daily and twice-daily regimens.

Outcome measures

Outcome measures
Measure	Overall Study n=385 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Forced Expiratory Volume in One Second AUC 0-24 Hours for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237, After 28 Days of Treatment Total daily dose 20 ug	0.008 Liters Interval -0.008 to 0.023	—	—	—	—	—	—	—
Forced Expiratory Volume in One Second AUC 0-24 Hours for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237, After 28 Days of Treatment Total daily dose 25 ug	0.008 Liters Interval -0.008 to 0.024	—	—	—	—	—	—	—
Forced Expiratory Volume in One Second AUC 0-24 Hours for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237, After 28 Days of Treatment Total daily dose 30 ug	0.008 Liters Interval -0.008 to 0.024	—	—	—	—	—	—	—
Forced Expiratory Volume in One Second AUC 0-24 Hours for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237, After 28 Days of Treatment Total daily dose 35 ug	0.008 Liters Interval -0.008 to 0.023	—	—	—	—	—	—	—
Forced Expiratory Volume in One Second AUC 0-24 Hours for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237, After 28 Days of Treatment Total daily dose 40 ug	0.008 Liters Interval -0.008 to 0.023	—	—	—	—	—	—	—
Forced Expiratory Volume in One Second AUC 0-24 Hours for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237, After 28 Days of Treatment Total daily dose 45 ug	0.008 Liters Interval -0.008 to 0.022	—	—	—	—	—	—	—
Forced Expiratory Volume in One Second AUC 0-24 Hours for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237, After 28 Days of Treatment Total daily dose 50 ug	0.008 Liters Interval -0.008 to 0.022	—	—	—	—	—	—	—
Forced Expiratory Volume in One Second AUC 0-24 Hours for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237, After 28 Days of Treatment Total daily dose 55 ug	0.007 Liters Interval -0.007 to 0.021	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 5 min,15 min, 1,2,3,4,6,8,10 hours, 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 doses on FEV1 Area Under the Curve (AUC) 0-4 Hours, 0-8 Hours, 0-12 Hours, 12-24 Hours were calculated from measurements taken at: 5 min, 15 min, 1,2,3,4,6,8,10 hours, 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on day 28. AUC FEV1 was measured in response to all doses administered (see Outcome Measure #21). All FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=82 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=90 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=90 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=92 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=91 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=82 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve at Different Time Points (0-4 Hours, 0-8 Hours, 0-12 Hours, 12-24 Hours) on Day 28 AUC 0-4h (n=82,90,91,89,92,91,82)	50.8 Percentage of maximal response* hours Interval 38.7 to 63.6	66.9 Percentage of maximal response* hours Interval 53.7 to 77.7	58.9 Percentage of maximal response* hours Interval 45.9 to 71.5	79.7 Percentage of maximal response* hours Interval 67.4 to 87.4	73.7 Percentage of maximal response* hours Interval 60.6 to 83.4	88.3 Percentage of maximal response* hours Interval 77.8 to 93.3	84.4 Percentage of maximal response* hours Interval 73.0 to 91.0	—
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve at Different Time Points (0-4 Hours, 0-8 Hours, 0-12 Hours, 12-24 Hours) on Day 28 AUC 0-8h (n=82,90,91,90,92,91,82)	45.8 Percentage of maximal response* hours Interval 33.2 to 58.8	62.8 Percentage of maximal response* hours Interval 49.9 to 74.1	55.5 Percentage of maximal response* hours Interval 42.0 to 68.4	77.1 Percentage of maximal response* hours Interval 66.6 to 85.1	71.4 Percentage of maximal response* hours Interval 59.1 to 81.2	87.1 Percentage of maximal response* hours Interval 79.9 to 91.9	83.3 Percentage of maximal response* hours Interval 74.3 to 89.7	—
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve at Different Time Points (0-4 Hours, 0-8 Hours, 0-12 Hours, 12-24 Hours) on Day 28 AUC 0-12h (n=82,90,91,90,92,91,82)	41.1 Percentage of maximal response* hours Interval 28.8 to 54.5	58.3 Percentage of maximal response* hours Interval 44.7 to 70.6	50.5 Percentage of maximal response* hours Interval 37.0 to 64.1	73.6 Percentage of maximal response* hours Interval 61.8 to 82.8	67.1 Percentage of maximal response* hours Interval 54.0 to 78.1	84.8 Percentage of maximal response* hours Interval 76.4 to 90.6	80.3 Percentage of maximal response* hours Interval 70.1 to 87.7	—
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve at Different Time Points (0-4 Hours, 0-8 Hours, 0-12 Hours, 12-24 Hours) on Day 28 AUC 12-24h (n=82,90,91,89,92,91,81)	25.6 Percentage of maximal response* hours Interval 15.5 to 42.5	40.1 Percentage of maximal response* hours Interval 24.2 to 59.6	56.6 Percentage of maximal response* hours Interval 31.4 to 78.2	56.4 Percentage of maximal response* hours Interval 33.0 to 74.7	71.4 Percentage of maximal response* hours Interval 41.5 to 87.8	71.2 Percentage of maximal response* hours Interval 42.6 to 85.5	82.4 Percentage of maximal response* hours Interval 51.2 to 93.5	—

SECONDARY outcome

Timeframe: 12 hours on day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response within different doses/regimens of NVA237 was measured using FEV1 at 12 hours on day 28 of treatment. FEV1 was measured in response to all doses administered (see Outcome Measure #22). All FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=79 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=88 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=85 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=87 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=88 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=78 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second at 12 Hours at Day 28 of Treatment	27.1 Percentage of maximal response Interval 14.7 to 44.6	42.7 Percentage of maximal response Interval 25.7 to 61.7	35.5 Percentage of maximal response Interval 20.4 to 54.0	59.8 Percentage of maximal response Interval 40.9 to 76.3	52.4 Percentage of maximal response Interval 33.9 to 70.2	74.9 Percentage of maximal response Interval 58.0 to 86.6	68.7 Percentage of maximal response Interval 50.7 to 82.5	—

SECONDARY outcome

Timeframe: day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Peak FEV1 is the maximum FEV1 recorded in a pre-determined period of time. Percentage of the maximal response of NVA237 within different doses/regimens of NVA237 on Peak FEV1 was measured at day 28 of treatment. Peak FEV1 was measured in response to all doses administered (see Outcome Measure #23). All FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=82 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=90 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=89 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=92 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=91 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=82 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Peak Forced Expiratory Volume in One Second at Day 28 of Treatment	53.3 Percentage of maximal response Interval 41.2 to 65.5	69.2 Percentage of maximal response Interval 56.7 to 79.2	61.1 Percentage of maximal response Interval 48.2 to 73.4	81.5 Percentage of maximal response Interval 71.1 to 88.4	75.6 Percentage of maximal response Interval 63.4 to 84.7	89.6 Percentage of maximal response Interval 82.4 to 93.9	85.8 Percentage of maximal response Interval 76.5 to 91.7	—

SECONDARY outcome

Timeframe: day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Percentage of the maximal response of NVA237 within different doses/regimens of NVA237 on Forced Vital Capacity (FVC) was measured at day 28 of treatment. FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC at day 28 of treatment was measured via spirometry (see Outcome Measure #24). All FVC responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FVC data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=81 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=88 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=90 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=88 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=87 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=90 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=81 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Forced Vital Capacity at Day 28 of Treatment	23.3 Percentage of maximal response Interval 11.3 to 45.3	37.4 Percentage of maximal response Interval 19.8 to 62.7	53.6 Percentage of maximal response Interval 26.5 to 81.2	54.0 Percentage of maximal response Interval 30.9 to 77.2	69.3 Percentage of maximal response Interval 38.6 to 89.7	69.7 Percentage of maximal response Interval 43.6 to 87.2	81.4 Percentage of maximal response Interval 52.5 to 94.6	—

SECONDARY outcome

Timeframe: Days 1, 7 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 doses on Trough FEV1 was measured on Days 1, 7 and 14. Through FEV1 was measured in response to all doses administered (see Outcome Measure #25). All FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values.

Outcome measures

Outcome measures
Measure	Overall Study n=88 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=92 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=91 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=95 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=94 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Trough Forced Expiratory Volume in One Second at Days 1, 7 and 14 Day 1 (n= 88,92,91, 90, 94, 94, 87)	28.5 Percentage of maximal response Interval 17.5 to 45.3	43.8 Percentage of maximal response Interval 27.8 to 62.3	63.3 Percentage of maximal response Interval 37.9 to 82.5	60.1 Percentage of maximal response Interval 38.2 to 76.8	76.7 Percentage of maximal response Interval 49.3 to 90.5	74.3 Percentage of maximal response Interval 48.6 to 86.9	86.2 Percentage of maximal response Interval 59.8 to 95.0	—
Percentage of the Maximal Response of NVA237 Doses on Trough Forced Expiratory Volume in One Second at Days 1, 7 and 14 Day 7 (n= 87,92,90, 91, 95, 93, 85)	27.1 Percentage of maximal response Interval 16.3 to 44.3	42.0 Percentage of maximal response Interval 26.3 to 61.4	61.6 Percentage of maximal response Interval 36.4 to 82.1	58.5 Percentage of maximal response Interval 37.3 to 76.1	75.5 Percentage of maximal response Interval 48.3 to 90.1	73.0 Percentage of maximal response Interval 48.7 to 86.4	85.4 Percentage of maximal response Interval 59.8 to 94.8	—
Percentage of the Maximal Response of NVA237 Doses on Trough Forced Expiratory Volume in One Second at Days 1, 7 and 14 Day 14 (n= 85,90,91, 88, 94, 93, 81)	27.1 Percentage of maximal response Interval 16.4 to 44.3	42.0 Percentage of maximal response Interval 26.4 to 61.4	61.6 Percentage of maximal response Interval 36.6 to 82.1	58.5 Percentage of maximal response Interval 37.4 to 76.1	75.5 Percentage of maximal response Interval 48.5 to 90.2	73.0 Percentage of maximal response Interval 48.8 to 86.5	85.4 Percentage of maximal response Interval 60.1 to 94.8	—

SECONDARY outcome

Timeframe: 5 min,15 min, 1,2,3,4,6,8,10 hours, 11 hours 55min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on days 1 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 doses on FEV1 Area Under the Curve (AUC) 0-24 hours, was calculated from measurements taken at 5 min,15 min, 1,2,3,4,6,8,10 hours, 11 hours 55min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on days 1 and 14. FEV1 AUC 0-24 hours was measured on days 1 and 14 of treatment in response to all doses administered (see Outcome Measure #26). All FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=92 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Effect of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours on Days 1 and 14 of Treatment Day 1 (n= 89,94,93,92,96,96,87)	38.3 Percentage of maximal response* hours Interval 25.3 to 53.4	55.4 Percentage of maximal response* hours Interval 40.4 to 69.6	59.5 Percentage of maximal response* hours Interval 42.8 to 74.2	71.3 Percentage of maximal response* hours Interval 57.5 to 82.1	74.6 Percentage of maximal response* hours Interval 60.0 to 85.2	83.2 Percentage of maximal response* hours Interval 73.0 to 90.2	85.4 Percentage of maximal response* hours Interval 75.0 to 92.0	—
Percentage of the Maximal Effect of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours on Days 1 and 14 of Treatment Day 14 (n= 86,92,91,91,95,93,84)	28.9 Percentage of maximal response* hours Interval 18.7 to 41.6	44.8 Percentage of maximal response* hours Interval 31.6 to 58.8	49.0 Percentage of maximal response* hours Interval 34.1 to 64.1	61.9 Percentage of maximal response* hours Interval 48.0 to 74.0	65.7 Percentage of maximal response* hours Interval 50.9 to 78.1	76.4 Percentage of maximal response* hours Interval 64.8 to 85.1	79.3 Percentage of maximal response* hours Interval 67.5 to 87.7	—

SECONDARY outcome

Timeframe: 5 min,15 min, 1,2,3,4 hours (postdose) on Days 1, 7 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 doses on FEV1 Area Under the Curve (AUC) 0-4 hours was calculated from measurements taken at 5 min,15 min, 1,2,3,4 hours (postdose) on Days 1, 7 and 14, in response to all doses administered (see Outcome Measure #27). All AUC FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=92 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=86 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve 0-4 Hours on Days 1, 7 and 14 of Treatment Day 7 (n=87,93,90,92,95,94,85)	50.8 Percentage of maximal response* hours Interval 38.7 to 63.6	66.9 Percentage of maximal response* hours Interval 53.7 to 77.7	58.9 Percentage of maximal response* hours Interval 45.9 to 71.5	79.7 Percentage of maximal response* hours Interval 67.4 to 87.4	73.7 Percentage of maximal response* hours Interval 60.6 to 83.4	88.3 Percentage of maximal response* hours Interval 77.8 to 93.3	84.4 Percentage of maximal response* hours Interval 73.0 to 91.0	—
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve 0-4 Hours on Days 1, 7 and 14 of Treatment Day 14 (n=86,92,91,91,95,93,84)	50.8 Percentage of maximal response* hours Interval 38.7 to 63.6	66.9 Percentage of maximal response* hours Interval 53.7 to 77.7	58.9 Percentage of maximal response* hours Interval 45.9 to 71.5	79.7 Percentage of maximal response* hours Interval 67.4 to 87.4	73.7 Percentage of maximal response* hours Interval 60.6 to 83.4	88.3 Percentage of maximal response* hours Interval 77.8 to 93.3	84.4 Percentage of maximal response* hours Interval 73.0 to 91.0	—
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve 0-4 Hours on Days 1, 7 and 14 of Treatment Day 1 (n=89,94,93,91,96,96,86)	58.4 Percentage of maximal response* hours Interval 44.4 to 71.8	73.2 Percentage of maximal response* hours Interval 59.1 to 83.6	66.1 Percentage of maximal response* hours Interval 51.6 to 78.6	84.1 Percentage of maximal response* hours Interval 72.0 to 91.1	79.1 Percentage of maximal response* hours Interval 65.6 to 88.0	91.1 Percentage of maximal response* hours Interval 81.5 to 95.3	88.0 Percentage of maximal response* hours Interval 77.1 to 93.6	—

SECONDARY outcome

Timeframe: at 5 min,15 min, 1,2,3,4,6,8 hours (postdose) on days 1, 7 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 doses on FEV1 Area Under the Curve (AUC) 0-8 was calculated from measurements taken at 5 min,15 min, 1,2,3,4,6,8 hours (postdose) on days 1, 7, and 14. AUC FEV1 was measured in response to all doses administered (see Outcome Measure #28). All FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=92 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second of Area Under the Curve 0-8 Hours Days 1, 7, and 14 Day 1 (n=89, 94, 93, 91, 96, 96, 87)	54.2 Percentage of maximal response* hours Interval 40.1 to 67.8	70.3 Percentage of maximal response* hours Interval 57.2 to 80.8	63.6 Percentage of maximal response* hours Interval 49.0 to 76.3	82.6 Percentage of maximal response* hours Interval 72.8 to 89.4	77.8 Percentage of maximal response* hours Interval 65.8 to 86.5	90.5 Percentage of maximal response* hours Interval 84.3 to 94.4	87.5 Percentage of maximal response* hours Interval 79.4 to 92.8	—
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second of Area Under the Curve 0-8 Hours Days 1, 7, and 14 Day 7 (n= 87, 93, 91, 92, 95, 94, 85)	45.8 Percentage of maximal response* hours Interval 33.2 to 58.8	62.8 Percentage of maximal response* hours Interval 49.9 to 74.1	55.5 Percentage of maximal response* hours Interval 42.0 to 68.4	77.1 Percentage of maximal response* hours Interval 66.6 to 85.1	71.4 Percentage of maximal response* hours Interval 59.1 to 81.2	87.1 Percentage of maximal response* hours Interval 79.9 to 91.9	83.3 Percentage of maximal response* hours Interval 74.3 to 89.7	—
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second of Area Under the Curve 0-8 Hours Days 1, 7, and 14 Day 14 (n=86, 92, 91, 91, 95, 93, 84)	45.8 Percentage of maximal response* hours Interval 33.2 to 58.8	62.8 Percentage of maximal response* hours Interval 49.9 to 74.1	55.5 Percentage of maximal response* hours Interval 42.0 to 68.4	77.1 Percentage of maximal response* hours Interval 66.6 to 85.1	71.4 Percentage of maximal response* hours Interval 59.1 to 81.2	87.1 Percentage of maximal response* hours Interval 79.9 to 91.9	83.3 Percentage of maximal response* hours Interval 74.3 to 89.7	—

SECONDARY outcome

Timeframe: 5 min,15 min, 1,2,3,4,6,8,10 hours, 11h 55 min (postdose) on days 1 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 doses was calculated on FEV1 Area Under the Curve (AUC) 0-12 hours from measurements taken at at 5 min,15 min, 1,2,3,4,6,8,10 hours, 11h 55 min (postdose) on days 1 and 14 in response to all doses administered (see Outcome Measure #29). All AUC FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=91 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve 0-12 Hours at Day 1 and 14 of Treatment Day 1 (n=89, 94, 93, 91, 96, 96, 87)	49.5 Percentage of maximal response* hours Interval 35.5 to 63.6	66.2 Percentage of maximal response* hours Interval 52.4 to 77.8	58.8 Percentage of maximal response* hours Interval 44.0 to 72.3	79.6 Percentage of maximal response* hours Interval 68.7 to 87.5	74.1 Percentage of maximal response* hours Interval 61.1 to 83.9	88.7 Percentage of maximal response* hours Interval 81.5 to 93.3	85.1 Percentage of maximal response* hours Interval 75.9 to 91.3	—
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve 0-12 Hours at Day 1 and 14 of Treatment Day 14 (n=86, 92, 91, 91, 95, 93, 84)	41.1 Percentage of maximal response* hours Interval 28.8 to 54.5	58.3 Percentage of maximal response* hours Interval 44.7 to 70.6	50.5 Percentage of maximal response* hours Interval 37.0 to 64.1	73.6 Percentage of maximal response* hours Interval 61.8 to 82.8	67.1 Percentage of maximal response* hours Interval 54.0 to 78.1	84.8 Percentage of maximal response* hours Interval 76.4 to 90.6	80.3 Percentage of maximal response* hours Interval 70.1 to 87.7	—

SECONDARY outcome

Timeframe: 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on Days 1 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 on FEV1 Area under the curve (AUC) 12-24 hours was calculated from measurements taken at 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on Days 1 and 14. AUC FEV1 was measured in response to all doses administered (see Outcome Measure #30). All FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=92 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second of Area Under the Curve 12-24 Hours Over Days 1, and 14 of Treatment Day 1 (n=89, 94, 93, 92, 96, 96, 87)	23.9 Percentage of maximal response* hours Interval 1.2 to 90.7	37.9 Percentage of maximal response* hours Interval 2.4 to 95.2	54.4 Percentage of maximal response* hours Interval 4.5 to 97.8	54.1 Percentage of maximal response* hours Interval 4.7 to 97.6	69.5 Percentage of maximal response* hours Interval 8.6 to 98.9	69.3 Percentage of maximal response* hours Interval 9.0 to 98.8	81.1 Percentage of maximal response* hours Interval 15.5 to 99.5	—
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second of Area Under the Curve 12-24 Hours Over Days 1, and 14 of Treatment Day 14 (n= 86, 92, 91, 91, 95, 93, 84)	25.6 Percentage of maximal response* hours Interval 15.5 to 42.5	40.1 Percentage of maximal response* hours Interval 24.2 to 59.6	56.6 Percentage of maximal response* hours Interval 31.3 to 78.2	56.4 Percentage of maximal response* hours Interval 32.9 to 74.7	71.4 Percentage of maximal response* hours Interval 41.4 to 87.8	71.2 Percentage of maximal response* hours Interval 42.5 to 85.5	82.4 Percentage of maximal response* hours Interval 51.2 to 93.5	—

SECONDARY outcome

Timeframe: Days 1 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 doses on FEV1 at 12 hours was measured on days 1 and 14. FEV1 was measured in response to all doses administered (see Outcome Measure #31). All FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=84 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=91 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=90 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=90 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=92 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=83 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second at 12 Hours on Days 1 and 14 of Treatment Day 1 (n=83, 90, 91, 85, 89, 90, 83)	35.1 Percentage of maximal response Interval 19.1 to 55.7	52.0 Percentage of maximal response Interval 32.0 to 71.6	44.4 Percentage of maximal response Interval 25.7 to 64.7	68.4 Percentage of maximal response Interval 48.5 to 83.4	61.5 Percentage of maximal response Interval 41.0 to 78.5	81.2 Percentage of maximal response Interval 65.3 to 91.0	76.1 Percentage of maximal response Interval 58.1 to 88.0	—
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second at 12 Hours on Days 1 and 14 of Treatment Day 14 (n=84, 91, 88, 90, 90, 92, 78)	27.1 Percentage of maximal response Interval 14.7 to 44.6	42.7 Percentage of maximal response Interval 25.7 to 61.7	35.5 Percentage of maximal response Interval 20.4 to 54.0	59.8 Percentage of maximal response Interval 40.9 to 76.3	52.4 Percentage of maximal response Interval 33.9 to 70.2	74.9 Percentage of maximal response Interval 58.0 to 86.6	66.7 Percentage of maximal response Interval 50.7 to 82.5	—

SECONDARY outcome

Timeframe: Days 1, 7, and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Peak FEV1 is the maximum FEV1 recorded in a pre-determined period of time. Percentage of the maximal response of NVA237 doses on Peak FEV1 was measured on days 1, 7 and 14 of treatment. Peak FEV1 was measured in response to all doses administered (see Outcome Measure #32). All FEV1 responses to active doses were corrected using the placebo response. A modeled dose response curve was fit to the placebo-corrected data, and extrapolated to estimate the maximal response. All FEV1 data are reported as a percentage of the theoretical maximal response.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=92 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=86 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment Day 1 (n=89, 94, 93, 91, 96, 96, 86)	61.7 Percentage of maximal response Interval 47.4 to 74.7	76.0 Percentage of maximal response Interval 62.5 to 85.5	68.9 Percentage of maximal response Interval 54.1 to 81.1	86.1 Percentage of maximal response Interval 75.8 to 92.2	81.3 Percentage of maximal response Interval 68.7 to 89.6	92.3 Percentage of maximal response Interval 85.6 to 96.0	89.5 Percentage of maximal response Interval 80.6 to 94.5	—
Percentage of the Maximal Response of NVA237 Doses on Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment Day 7 (n=87, 93, 90, 92, 95, 94, 85)	53.3 Percentage of maximal response Interval 41.2 to 65.5	69.2 Percentage of maximal response Interval 56.7 to 79.2	61.1 Percentage of maximal response Interval 48.2 to 73.4	81.5 Percentage of maximal response Interval 71.1 to 88.4	75.6 Percentage of maximal response Interval 63.4 to 84.7	89.6 Percentage of maximal response Interval 82.4 to 93.9	85.8 Percentage of maximal response Interval 76.5 to 91.7	—
Percentage of the Maximal Response of NVA237 Doses on Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment Day 14 (n=86, 92, 91, 91, 95, 93, 84)	53.3 Percentage of maximal response Interval 41.2 to 65.5	69.2 Percentage of maximal response Interval 56.7 to 79.2	61.1 Percentage of maximal response Interval 48.2 to 73.4	81.5 Percentage of maximal response Interval 71.1 to 88.4	75.6 Percentage of maximal response Interval 63.4 to 84.7	89.6 Percentage of maximal response Interval 82.4 to 93.9	85.8 Percentage of maximal response Interval 76.5 to 91.7	—

SECONDARY outcome

Timeframe: Days 1, 7 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Percentage of the maximal response of NVA237 Doses on Trough Forced Vital Capacity (FVC) on Days 1, 7 and 14. FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Trough FVC was assessed via spirometry. (see Outcome Measure #33). Trough FVC is defined as the mean of the FVC values measured at 23 hours 15 mins and 23 hours 45 mins post-dose.

Outcome measures

Outcome measures
Measure	Overall Study n=88 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=92 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=91 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=95 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=94 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo Placebo to NVA237 once daily
Percentage of the Maximal Response of NVA237 Doses on Trough Forced Vital Capacity on Days 1, 7 and 14 Day 1 (n=88, 92, 91, 90, 94, 94, 87)	22.8 Percentage of maximal response Interval 11.3 to 43.5	36.8 Percentage of maximal response Interval 19.6 to 60.9	52.9 Percentage of maximal response Interval 26.2 to 79.9	53.4 Percentage of maximal response Interval 30.7 to 75.8	68.7 Percentage of maximal response Interval 38.3 to 88.9	69.1 Percentage of maximal response Interval 43.4 to 86.3	81.0 Percentage of maximal response Interval 52.3 to 94.1	—
Percentage of the Maximal Response of NVA237 Doses on Trough Forced Vital Capacity on Days 1, 7 and 14 Day 7 (n=87, 92, 90, 91, 95, 93, 85, 87)	23.3 Percentage of maximal response Interval 11.2 to 45.2	37.4 Percentage of maximal response Interval 19.6 to 62.5	53.6 Percentage of maximal response Interval 26.3 to 81.2	54.0 Percentage of maximal response Interval 30.7 to 77.1	69.3 Percentage of maximal response Interval 38.3 to 89.7	69.7 Percentage of maximal response Interval 43.3 to 87.1	81.4 Percentage of maximal response Interval 52.0 to 94.6	—
Percentage of the Maximal Response of NVA237 Doses on Trough Forced Vital Capacity on Days 1, 7 and 14 Day 14 (n= 85, 90, 91, 88, 94, 93, 81, 84)	23.3 Percentage of maximal response Interval 11.3 to 45.3	37.4 Percentage of maximal response Interval 19.7 to 65.5	53.6 Percentage of maximal response Interval 26.4 to 81.2	54.0 Percentage of maximal response Interval 30.8 to 77.1	69.3 Percentage of maximal response Interval 38.5 to 89.7	69.7 Percentage of maximal response Interval 43.5 to 87.2	81.4 Percentage of maximal response Interval 52.2 to 94.6	—

SECONDARY outcome

Timeframe: Baseline, Weeks 1, 2, 3 and 4

Population: Only patients with a non-missing value at both period baseline and the respective post-baseline visit were included. The modeling approach is not suitable for these data as the modeling assumptions do not hold.

Mean daily use of rescue medication by treatment and time points. Baseline was defined as the average of the total number of puffs of rescue medication during the week prior to treatment start, divided by the total number of days with non-missing rescue data during that week, then puffs were counted during weeks 1, 2, 3 and 4 postdose.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=95 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=95 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=92 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=86 Participants NVA237 50.0 µg twice daily	Placebo n=91 Participants Placebo to NVA237 once daily
Mean Daily Use of Rescue Medication by Treatment at Different Time Points Baseline (n=89, 95, 95, 92, 96, 96, 86, 91)	4.16 Number of Puffs Standard Deviation 3.131	4.16 Number of Puffs Standard Deviation 2.925	3.83 Number of Puffs Standard Deviation 3.218	4.45 Number of Puffs Standard Deviation 3.068	3.47 Number of Puffs Standard Deviation 2.996	4.81 Number of Puffs Standard Deviation 3.276	4.25 Number of Puffs Standard Deviation 3.613	4.62 Number of Puffs Standard Deviation 3.710
Mean Daily Use of Rescue Medication by Treatment at Different Time Points Week 1 (n=89, 95, 95, 91, 96, 96, 86, 90)	2.41 Number of Puffs Standard Deviation 2.338	2.23 Number of Puffs Standard Deviation 2.158	2.10 Number of Puffs Standard Deviation 2.337	2.36 Number of Puffs Standard Deviation 2.291	2.13 Number of Puffs Standard Deviation 2.349	2.53 Number of Puffs Standard Deviation 2.609	2.54 Number of Puffs Standard Deviation 2.678	2.94 Number of Puffs Standard Deviation 3.075
Mean Daily Use of Rescue Medication by Treatment at Different Time Points Week 2 (n=86, 94, 94, 91, 95, 93, 84, 89)	2.74 Number of Puffs Standard Deviation 2.784	2.20 Number of Puffs Standard Deviation 2.054	2.22 Number of Puffs Standard Deviation 2.541	2.38 Number of Puffs Standard Deviation 2.541	2.08 Number of Puffs Standard Deviation 2.568	2.59 Number of Puffs Standard Deviation 2.658	2.82 Number of Puffs Standard Deviation 3.003	3.32 Number of Puffs Standard Deviation 3.455
Mean Daily Use of Rescue Medication by Treatment at Different Time Points Week 3 (n= 86, 93, 94, 89, 93, 93, 83, 87)	2.75 Number of Puffs Standard Deviation 2.736	2.40 Number of Puffs Standard Deviation 2.316	2.29 Number of Puffs Standard Deviation 2.354	2.37 Number of Puffs Standard Deviation 2.580	2.23 Number of Puffs Standard Deviation 2.743	2.75 Number of Puffs Standard Deviation 2.868	2.69 Number of Puffs Standard Deviation 2.977	3.34 Number of Puffs Standard Deviation 3.660
Mean Daily Use of Rescue Medication by Treatment at Different Time Points Week 4 (n=86, 92, 94, 88, 93, 93, 82, 85)	2.91 Number of Puffs Standard Deviation 2.968	2.52 Number of Puffs Standard Deviation 2.476	2.42 Number of Puffs Standard Deviation 2.773	2.46 Number of Puffs Standard Deviation 2.504	2.32 Number of Puffs Standard Deviation 2.990	2.65 Number of Puffs Standard Deviation 2.828	2.78 Number of Puffs Standard Deviation 2.899	3.41 Number of Puffs Standard Deviation 3.761

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values.

Outcome measures

Outcome measures
Measure	Overall Study n=81 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=88 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=90 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=88 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=87 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=90 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=81 Participants NVA237 50.0 µg twice daily	Placebo n=82 Participants Placebo to NVA237 once daily
Trough Forced Expiratory Volume in One Second by Treatment at Day 28	1.319 Liters Standard Deviation 0.505	1.368 Liters Standard Deviation 0.436	1.354 Liters Standard Deviation 0.484	1.340 Liters Standard Deviation 0.400	1.384 Liters Standard Deviation 0.472	1.410 Liters Standard Deviation 0.522	1.493 Liters Standard Deviation 0.449	1.268 Liters Standard Deviation 0.483

OTHER_PRE_SPECIFIED outcome

Timeframe: 5 min, 15 min, 1,2,3,4,6,8,10 hours, 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Spirometry was performed according to internationally accepted standards. FEV1 Area Under the Curve (AUC) measurements were taken at 5 min, 15 min, 1,2,3,4,6,8,10 hours, 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on day 28. FEV1 AUC was calculated as the sum of trapezoids divided by the length of time.

Outcome measures

Outcome measures
Measure	Overall Study n=82 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=90 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=90 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=92 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=91 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=82 Participants NVA237 50.0 µg twice daily	Placebo n=82 Participants Placebo to NVA237 once daily
Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours at Day 28 of Treatment	1.307 Liters Standard Deviation 0.469	1.351 Liters Standard Deviation 0.392	1.321 Liters Standard Deviation 0.469	1.317 Liters Standard Deviation 0.390	1.339 Liters Standard Deviation 0.462	1.395 Liters Standard Deviation 0.496	1.457 Liters Standard Deviation 0.453	1.247 Liters Standard Deviation 0.467

OTHER_PRE_SPECIFIED outcome

Timeframe: 5 min,15 min, 1,2,3,4,6,8,10 hours, 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Spirometry was performed according to internationally accepted standards. FEV1 Area Under the Curve (AUC) measurements were taken at: 5 min,15 min, 1,2,3,4,6,8,10 hours, 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose). FEV1 AUC was calculated as the sum of trapezoids divided by the length of time.

Outcome measures

Outcome measures
Measure	Overall Study n=82 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=90 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=90 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=92 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=91 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=82 Participants NVA237 50.0 µg twice daily	Placebo n=82 Participants Placebo to NVA237 once daily
Forced Expiratory Volume in One Second Area Under the Curve at Different Time Points (0-4 Hours, 0-8 Hours, 0-12 Hours, 12-24 Hours) AUC 0-4h (n=82,90,91,89,92,91,82,82)	1.415 Liters Standard Deviation 0.494	1.478 Liters Standard Deviation 0.439	1.414 Liters Standard Deviation 0.489	1.431 Liters Standard Deviation 0.411	1.417 Liters Standard Deviation 0.487	1.490 Liters Standard Deviation 0.532	1.553 Liters Standard Deviation 0.504	1.315 Liters Standard Deviation 0.490
Forced Expiratory Volume in One Second Area Under the Curve at Different Time Points (0-4 Hours, 0-8 Hours, 0-12 Hours, 12-24 Hours) AUC 0-8h (n=82,90,91,90,92,91,82,82)	1.386 Liters Standard Deviation 0.477	1.447 Liters Standard Deviation 0.423	1.392 Liters Standard Deviation 0.491	1.397 Liters Standard Deviation 0.411	1.397 Liters Standard Deviation 0.476	1.461 Liters Standard Deviation 0.520	1.527 Liters Standard Deviation 0.495	1.305 Liters Standard Deviation 0.485
Forced Expiratory Volume in One Second Area Under the Curve at Different Time Points (0-4 Hours, 0-8 Hours, 0-12 Hours, 12-24 Hours) AUC 0-12h (n=82,90,91,90,92,91,82,82)	1.364 Liters Standard Deviation 0.480	1.416 Liters Standard Deviation 0.416	1.362 Liters Standard Deviation 0.487	1.377 Liters Standard Deviation 0.408	1.375 Liters Standard Deviation 0.469	1.442 Liters Standard Deviation 0.515	1.505 Liters Standard Deviation 0.480	1.285 Liters Standard Deviation 0.476
Forced Expiratory Volume in One Second Area Under the Curve at Different Time Points (0-4 Hours, 0-8 Hours, 0-12 Hours, 12-24 Hours) AUC 12-24h (n=82,90,91,89,92,91,81,82)	1.251 Liters Standard Deviation 0.464	1.287 Liters Standard Deviation 0.382	1.280 Liters Standard Deviation 0.458	1.264 Liters Standard Deviation 0.378	1.299 Liters Standard Deviation 0.459	1.350 Liters Standard Deviation 0.480	1.421 Liters Standard Deviation 0.426	1.208 Liters Standard Deviation 0.461

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 hours on day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Spirometry was performed according to internationally accepted standards.

Outcome measures

Outcome measures
Measure	Overall Study n=79 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=88 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=85 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=87 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=88 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=78 Participants NVA237 50.0 µg twice daily	Placebo n=80 Participants Placebo to NVA237 once daily
Forced Expiratory Volume in One Second at 12 Hours on Day 28 of Treatment	1.272 Liters Standard Deviation 0.471	1.330 Liters Standard Deviation 0.415	1.279 Liters Standard Deviation 0.476	1.330 Liters Standard Deviation 0.384	1.320 Liters Standard Deviation 0.466	1.391 Liters Standard Deviation 0.498	1.429 Liters Standard Deviation 0.449	1.256 Liters Standard Deviation 0.472

OTHER_PRE_SPECIFIED outcome

Timeframe: 25 min , 15 min pre-dose, 5 min, 15 min, 1 , 2 ,3 , 4 , 6 , 8 , 10 hours , 11 hour 55 min and 14 hour post-dose on day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Spirometry was performed according to internationally accepted standards. Peak FEV1 is the maximum FEV1 recorded in a pre-determined period of time. Measurements were taken at 25 min , 15 min pre-dose, 5 min, 15 min, 1 , 2 ,3 , 4 , 6 , 8 , 10 hours , 11 hour 55 min and 14 hour post-dose on day 28.

Outcome measures

Outcome measures
Measure	Overall Study n=82 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=90 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=89 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=92 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=91 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=82 Participants NVA237 50.0 µg twice daily	Placebo n=82 Participants Placebo to NVA237 once daily
Peak Forced Expiratory Volume in One Second at Day 28 of Treatment	1.500 Liters Standard Deviation 0.516	1.563 Liters Standard Deviation 0.453	1.494 Liters Standard Deviation 0.507	1.514 Liters Standard Deviation 0.432	1.504 Liters Standard Deviation 0.516	1.570 Liters Standard Deviation 0.546	1.630 Liters Standard Deviation 0.513	1.397 Liters Standard Deviation 0.515

OTHER_PRE_SPECIFIED outcome

Timeframe: 23 hours 15 mins and 23 hours 45 mins post-dose on Day 28

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Vital Capacity (FVC) after 28 days of treatment. FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed via spirometry. Trough FVC was defined as the mean of the FVC values measured at 23 hours 15 mins and 23 hours 45 mins post-dose.

Outcome measures

Outcome measures
Measure	Overall Study n=81 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=88 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=90 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=88 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=87 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=90 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=81 Participants NVA237 50.0 µg twice daily	Placebo n=82 Participants Placebo to NVA237 once daily
Trough Forced Vital Capacity After 28 Days of Treatment	2.939 Liters Standard Deviation 0.878	3.007 Liters Standard Deviation 0.910	2.954 Liters Standard Deviation 0.849	2.973 Liters Standard Deviation 0.825	3.041 Liters Standard Deviation 0.770	2.974 Liters Standard Deviation 0.999	3.080 Liters Standard Deviation 0.913	2.703 Liters Standard Deviation 0.857

OTHER_PRE_SPECIFIED outcome

Timeframe: 23 hours 15 mins and 23 hours 45 mins post-dose on Days 1, 7 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Spirometry was performed according to internationally accepted standards. Trough FEV1 was measured on Days 1, 7 and 14 of treatment. Trough FEV1 was defined as the mean of the FEV1 values measured at 23 hours 15 mins and 23 hours 45 mins post-dose.

Outcome measures

Outcome measures
Measure	Overall Study n=88 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=92 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=91 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=95 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=94 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo n=87 Participants Placebo to NVA237 once daily
Trough Forced Expiratory Volume in One Second at Days 1, 7 and 14 Day 14 (n= 85,90,91, 88, 94, 93, 81, 84)	1.336 Liters Standard Deviation 0.442	1.349 Liters Standard Deviation 0.446	1.335 Liters Standard Deviation 0.444	1.356 Liters Standard Deviation 0.391	1.359 Liters Standard Deviation 0.479	1.375 Liters Standard Deviation 0.519	1.500 Liters Standard Deviation 0.455	1.284 Liters Standard Deviation 0.471
Trough Forced Expiratory Volume in One Second at Days 1, 7 and 14 Day 1 (n= 88,92,91, 90, 94, 94, 87, 86)	1.299 Liters Standard Deviation 0.490	1.387 Liters Standard Deviation 0.477	1.375 Liters Standard Deviation 0.477	1.371 Liters Standard Deviation 0.406	1.355 Liters Standard Deviation 0.503	1.367 Liters Standard Deviation 0.514	1.492 Liters Standard Deviation 0.483	1.290 Liters Standard Deviation 0.471
Trough Forced Expiratory Volume in One Second at Days 1, 7 and 14 Day 7 (n= 87,92,90, 91, 95, 93, 85, 87)	1.332 Liters Standard Deviation 0.499	1.422 Liters Standard Deviation 0.432	1.349 Liters Standard Deviation 0.467	1.391 Liters Standard Deviation 0.392	1.375 Liters Standard Deviation 0.486	1.372 Liters Standard Deviation 0.501	1.480 Liters Standard Deviation 0.474	1.294 Liters Standard Deviation 0.491

OTHER_PRE_SPECIFIED outcome

Timeframe: 5 min, 15 min, 1,2,3,4,6,8,10 hours, 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on days 1 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Spirometry was performed according to internationally accepted standards. FEV1 Area Under the Curve (AUC) measurements were taken at 5 min, 15 min, 1,2,3,4,6,8,10 hours, 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on days 1 and 14 of treatment. FEV1 AUC was calculated as the sum of trapezoids divided by the length of time.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=92 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo n=90 Participants Placebo to NVA237 once daily
Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours on Days 1 and 14 of Treatment Day 14 (n= 86,92,91,91,95,93,84,86)	1.306 Liters Standard Deviation 0.427	1.353 Liters Standard Deviation 0.420	1.324 Liters Standard Deviation 0.430	1.348 Liters Standard Deviation 0.372	1.335 Liters Standard Deviation 0.460	1.386 Liters Standard Deviation 0.493	1.449 Liters Standard Deviation 0.453	1.253 Liters Standard Deviation 0.473
Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours on Days 1 and 14 of Treatment Day 1 (n= 89,94,93,92,96,96,87,90)	1.318 Liters Standard Deviation 0.470	1.370 Liters Standard Deviation 0.444	1.354 Liters Standard Deviation 0.462	1.361 Liters Standard Deviation 0.393	1.336 Liters Standard Deviation 0.460	1.376 Liters Standard Deviation 0.526	1.466 Liters Standard Deviation 0.471	1.256 Liters Standard Deviation 0.469

OTHER_PRE_SPECIFIED outcome

Timeframe: 5 min,15 min, 1,2,3,4 hours (postdose) on Days 1, 7 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Spirometry was performed according to internationally accepted standards. FEV1 Area Under the Curve (AUC) measurements were taken at 5 min, 15 min, 1,2,3,4 hours (postdose) on days 1, 7 and 14 of treatment. FEV1 AUC was calculated as the sum of trapezoids divided by the length of time.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=92 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=86 Participants NVA237 50.0 µg twice daily	Placebo n=89 Participants Placebo to NVA237 once daily
Forced Expiratory Volume in One Second Area Under the Curve 0-4 Hours on Days 1, 7 and 14 of Treatment Day 1 (n=89,94,93,91,96,96,86,89)	1.428 Liters Standard Deviation 0.492	1.483 Liters Standard Deviation 0.485	1.421 Liters Standard Deviation 0.489	1.469 Liters Standard Deviation 0.428	1.411 Liters Standard Deviation 0.483	1.453 Liters Standard Deviation 0.551	1.533 Liters Standard Deviation 0.501	1.312 Liters Standard Deviation 0.494
Forced Expiratory Volume in One Second Area Under the Curve 0-4 Hours on Days 1, 7 and 14 of Treatment Day 7 (n=87,93,90,92,95,94,85,89)	1.403 Liters Standard Deviation 0.468	1.483 Liters Standard Deviation 0.463	1.397 Liters Standard Deviation 0.478	1.432 Liters Standard Deviation 0.407	1.390 Liters Standard Deviation 0.472	1.453 Liters Standard Deviation 0.505	1.537 Liters Standard Deviation 0.494	1.310 Liters Standard Deviation 0.491
Forced Expiratory Volume in One Second Area Under the Curve 0-4 Hours on Days 1, 7 and 14 of Treatment Day 14 (n=86,92,91,91,95,93,84,86)	1.451 Liters Standard Deviation 0.456	1.473 Liters Standard Deviation 0.456	1.390 Liters Standard Deviation 0.471	1.468 Liters Standard Deviation 0.409	1.429 Liters Standard Deviation 0.503	1.460 Liters Standard Deviation 0.514	1.545 Liters Standard Deviation 0.485	1.314 Liters Standard Deviation 0.500

OTHER_PRE_SPECIFIED outcome

Timeframe: at 5 min,15 min, 1,2,3,4,6,8 hours (postdose) on days 1, 7 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 doses on FEV1 Area Under the Curve (AUC) 0-8 was calculated from measurements taken at 5 min,15 min, 1,2,3,4,6,8 hours (postdose) on days 1, 7, and 14. FEV1 AUC was calculated as the sum of trapezoids divided by the length of time.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=92 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo n=90 Participants Placebo to NVA237 once daily
Forced Expiratory Volume in One Second of Area Under the Curve 0-8 Hours Days 1, 7, and 14 Day 14 (n=86, 92, 91, 91, 95, 93, 84, 86)	1.381 Liters Standard Deviation 0.453	1.441 Liters Standard Deviation 0.452	1.375 Liters Standard Deviation 0.463	1.435 Liters Standard Deviation 0.398	1.400 Liters Standard Deviation 0.486	1.442 Liters Standard Deviation 0.508	1.514 Liters Standard Deviation 0.479	1.293 Liters Standard Deviation 0.498
Forced Expiratory Volume in One Second of Area Under the Curve 0-8 Hours Days 1, 7, and 14 Day 1 (n=89, 94, 93, 91, 96, 96, 87, 90)	1.400 Liters Standard Deviation 0.486	1.450 Liters Standard Deviation 0.476	1.401 Liters Standard Deviation 0.483	1.451 Liters Standard Deviation 0.426	1.390 Liters Standard Deviation 0.476	1.446 Liters Standard Deviation 0.548	1.519 Liters Standard Deviation 0.493	1.301 Liters Standard Deviation 0.488
Forced Expiratory Volume in One Second of Area Under the Curve 0-8 Hours Days 1, 7, and 14 Day 7 (n= 87, 93, 91, 92, 95, 94, 85, 89)	1.386 Liters Standard Deviation 0.471	1.462 Liters Standard Deviation 0.455	1.375 Liters Standard Deviation 0.464	1.409 Liters Standard Deviation 0.397	1.373 Liters Standard Deviation 0.470	1.433 Liters Standard Deviation 0.503	1.516 Liters Standard Deviation 0.481	1.293 Liters Standard Deviation 0.489

OTHER_PRE_SPECIFIED outcome

Timeframe: 5 min,15 min, 1,2,3,4,6,8,10 hours, 11h 55 min (postdose) on days 1 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 doses was calculated on FEV1 Area Under the Curve (AUC) 0-12 hours from measurements taken at at 5 min,15 min, 1,2,3,4,6,8,10 hours, 11h 55 min (postdose) on days 1 and 14. FEV1 AUC was calculated as the sum of trapezoids divided by the length of time.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=91 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo n=90 Participants Placebo to NVA237 once daily
Forced Expiratory Volume in One Second Area Under the Curve 0-12 Hours at Day 1 and 14 of Treatment Day 14 (n=86, 92, 91, 91, 95, 93, 84, 86)	1.360 Liters Standard Deviation 0.447	1.416 Liters Standard Deviation 0.445	1.357 Liters Standard Deviation 0.452	1.406 Liters Standard Deviation 0.388	1.378 Liters Standard Deviation 0.480	1.427 Liters Standard Deviation 0.503	1.494 Liters Standard Deviation 0.472	1.281 Liters Standard Deviation 0.493
Forced Expiratory Volume in One Second Area Under the Curve 0-12 Hours at Day 1 and 14 of Treatment Day 1 (n=89, 94, 93, 91, 96, 96, 87, 90)	1.382 Liters Standard Deviation 0.488	1.425 Liters Standard Deviation 0.465	1.379 Liters Standard Deviation 0.474	1.430 Liters Standard Deviation 0.421	1.364 Liters Standard Deviation 0.470	1.431 Liters Standard Deviation 0.544	1.498 Liters Standard Deviation 0.484	1.289 Liters Standard Deviation 0.482

OTHER_PRE_SPECIFIED outcome

Timeframe: 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on Days 1 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 on FEV1 Area under the curve (AUC) 12-24 hours was calculated from measurements taken at 11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on Days 1 and 14. FEV1 AUC was calculated as the sum of trapezoids divided by the length of time.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=92 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo n=90 Participants Placebo to NVA237 once daily
Forced Expiratory Volume in One Second of Area Under the Curve 12-24 Hours Over Days 1, and 14 of Treatment Day 1 (n=89, 94, 93, 92, 96, 96, 87, 90)	1.257 Liters Standard Deviation 0.459	1.315 Liters Standard Deviation 0.432	1.329 Liters Standard Deviation 0.455	1.295 Liters Standard Deviation 0.375	1.306 Liters Standard Deviation 0.454	1.322 Liters Standard Deviation 0.512	1.437 Liters Standard Deviation 0.461	1.224 Liters Standard Deviation 0.459
Forced Expiratory Volume in One Second of Area Under the Curve 12-24 Hours Over Days 1, and 14 of Treatment Day 14 (n= 86, 92, 91, 91, 95, 93, 84, 86)	1.251 Liters Standard Deviation 0.417	1.289 Liters Standard Deviation 0.405	1.290 Liters Standard Deviation 0.415	1.291 Liters Standard Deviation 0.366	1.291 Liters Standard Deviation 0.450	1.344 Liters Standard Deviation 0.488	1.406 Liters Standard Deviation 0.437	1.225 Liters Standard Deviation 0.459

OTHER_PRE_SPECIFIED outcome

Timeframe: Days 1 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Percentage of the maximal response of NVA237 doses on FEV1 at 12 hours was measured on days 1 and 14.

Outcome measures

Outcome measures
Measure	Overall Study n=84 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=91 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=90 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=90 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=92 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=83 Participants NVA237 50.0 µg twice daily	Placebo n=83 Participants Placebo to NVA237 once daily
Forced Expiratory Volume in One Second at 12 Hours on Days 1 and 14 of Treatment Day 1 (n=83, 90, 91, 85, 89, 90, 83, 81)	1.319 Liters Standard Deviation 0.502	1.364 Liters Standard Deviation 0.452	1.327 Liters Standard Deviation 0.465	1.345 Liters Standard Deviation 0.405	1.299 Liters Standard Deviation 0.457	1.374 Liters Standard Deviation 0.549	1.439 Liters Standard Deviation 0.459	1.244 Liters Standard Deviation 0.449
Forced Expiratory Volume in One Second at 12 Hours on Days 1 and 14 of Treatment Day 14 (n=84, 91, 88, 90, 90, 92, 78, 83)	1.290 Liters Standard Deviation 0.431	1.356 Liters Standard Deviation 0.431	1.303 Liters Standard Deviation 0.428	1.329 Liters Standard Deviation 0.368	1.329 Liters Standard Deviation 0.455	1.389 Liters Standard Deviation 0.506	1.469 Liters Standard Deviation 0.436	1.268 Liters Standard Deviation 0.477

OTHER_PRE_SPECIFIED outcome

Timeframe: Days 1, 7, and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Peak FEV1 is the maximum FEV1 recorded in a pre-determined period of time. Percentage of the maximal response of NVA237 doses on Peak FEV1 was measured on days 1, 7 and 14 of treatment.

Outcome measures

Outcome measures
Measure	Overall Study n=89 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=94 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=93 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=92 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=96 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=96 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=86 Participants NVA237 50.0 µg twice daily	Placebo n=89 Participants Placebo to NVA237 once daily
Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment Day 1 (n=89, 94, 93, 91, 96, 96, 86, 89)	1.503 Liters Standard Deviation 0.515	1.558 Liters Standard Deviation 0.497	1.494 Liters Standard Deviation 0.507	1.541 Liters Standard Deviation 0.442	1.483 Liters Standard Deviation 0.495	1.521 Liters Standard Deviation 0.567	1.597 Liters Standard Deviation 0.510	1.378 Liters Standard Deviation 0.504
Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment Day 7 (n=87, 93, 90, 92, 95, 94, 85, 89)	1.459 Liters Standard Deviation 0.477	1.540 Liters Standard Deviation 0.474	1.455 Liters Standard Deviation 0.496	1.501 Liters Standard Deviation 0.426	1.448 Liters Standard Deviation 0.491	1.513 Liters Standard Deviation 0.524	1.598 Liters Standard Deviation 0.510	1.364 Liters Standard Deviation 0.504
Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment Day 14 (n=86, 92, 91, 91, 95, 93, 84, 86)	1.487 Liters Standard Deviation 0.471	1.547 Liters Standard Deviation 0.465	1.465 Liters Standard Deviation 0.484	1.537 Liters Standard Deviation 0.429	1.506 Liters Standard Deviation 0.513	1.528 Liters Standard Deviation 0.529	1.615 Liters Standard Deviation 0.497	1.380 Liters Standard Deviation 0.509

OTHER_PRE_SPECIFIED outcome

Timeframe: Days 1, 7 and 14

Population: Full analysis set includes all randomized patients who received at least one dose of study drug and data available for analysis. Only patients with non-missing values were included.

Trough Forced Vital Capacity (FVC) on Days 1, 7 and 14. FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed via spirometry. (see Outcome Measure #23). Trough FVC was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values.

Outcome measures

Outcome measures
Measure	Overall Study n=88 Participants A statistical modeling process was used to achieve the key objective. A set of 4 candidate models based on the Emax dose-response shape was derived plus their sigmoidal Emax counterparts (a total of 8 models) that describe the evolution of dose response over time. A model-averaging process was then employed to obtain response predictions as the weighted average of individual model predictions and confidence limits derived using a simulation-based procedure.	NVA237 25.0 µg q.d. n=92 Participants NVA237 25.0 µg once daily	NVA237 12.5 µg b.i.d. n=91 Participants NVA237 12.5 µg twice daily	NVA237 50.0 µg q.d. n=91 Participants NVA237 50.0 µg once daily	NVA237 25.0 µg b.i.d. n=95 Participants NVA237 25.0 µg twice daily	NVA237 100.0 µg q.d. n=94 Participants NVA237 100.0 µg once daily	NVA237 50.0 µg b.i.d. n=87 Participants NVA237 50.0 µg twice daily	Placebo n=87 Participants Placebo to NVA237 once daily
Trough Forced Vital Capacity on Days 1, 7 and 14 Day 1 (n=88, 92, 91, 90, 94, 94, 87, 86)	2.895 Liters Standard Deviation 0.830	3.063 Liters Standard Deviation 0.967	2.997 Liters Standard Deviation 0.835	3.017 Liters Standard Deviation 0.820	2.956 Liters Standard Deviation 0.810	2.944 Liters Standard Deviation 1.001	3.088 Liters Standard Deviation 0.961	2.779 Liters Standard Deviation 0.838
Trough Forced Vital Capacity on Days 1, 7 and 14 Day 7 (n=87, 92, 90, 91, 95, 93, 85, 87)	2.982 Liters Standard Deviation 0.833	3.135 Liters Standard Deviation 0.928	2.991 Liters Standard Deviation 0.873	3.072 Liters Standard Deviation 0.833	2.993 Liters Standard Deviation 0.798	2.977 Liters Standard Deviation 0.987	3.114 Liters Standard Deviation 0.975	2.759 Liters Standard Deviation 0.875
Trough Forced Vital Capacity on Days 1, 7 and 14 Day 14 (n= 85, 90, 91, 88, 94, 93, 81, 84)	2.958 Liters Standard Deviation 0.772	3.000 Liters Standard Deviation 0.934	2.965 Liters Standard Deviation 0.862	3.003 Liters Standard Deviation 0.812	2.960 Liters Standard Deviation 0.763	2.941 Liters Standard Deviation 0.987	3.113 Liters Standard Deviation 0.941	2.744 Liters Standard Deviation 0.841

Adverse Events

NVA237 12.5 ug q.d.

Serious events: 2 serious events

Other events: 9 other events

Deaths: 0 deaths

NVA237 25 ug q.d.

Serious events: 2 serious events

Other events: 11 other events

Deaths: 0 deaths

NVA237 12.5 ug b.i.d.

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

NVA237 50 ug q.d.

Serious events: 3 serious events

Other events: 7 other events

Deaths: 0 deaths

NVA237 25 ug b.i.d.

Serious events: 4 serious events

Other events: 8 other events

Deaths: 0 deaths

NVA237 100 ug q.d.

Serious events: 3 serious events

Other events: 9 other events

Deaths: 0 deaths

NVA237 50 ug b.i.d.

Serious events: 1 serious events

Other events: 9 other events

Deaths: 0 deaths

Placebo

Serious events: 3 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	NVA237 12.5 ug q.d. n=89 participants at risk NVA237 12.5 ug q.d.	NVA237 25 ug q.d. n=96 participants at risk NVA237 25 ug q.d.	NVA237 12.5 ug b.i.d. n=96 participants at risk NVA237 12.5 ug b.i.d.	NVA237 50 ug q.d. n=92 participants at risk NVA237 50 ug q.d.	NVA237 25 ug b.i.d. n=96 participants at risk NVA237 25 ug b.i.d.	NVA237 100 ug q.d. n=96 participants at risk NVA237 100 ug q.d.	NVA237 50 ug b.i.d. n=87 participants at risk NVA237 50 ug b.i.d.	Placebo n=91 participants at risk Placebo
Cardiac disorders Angina pectoris	0.00% 0/89	0.00% 0/96	0.00% 0/96	0.00% 0/92	0.00% 0/96	0.00% 0/96	0.00% 0/87	1.1% 1/91
Cardiac disorders Ventricular extrasystoles	0.00% 0/89	0.00% 0/96	0.00% 0/96	0.00% 0/92	0.00% 0/96	0.00% 0/96	1.1% 1/87	0.00% 0/91
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/89	0.00% 0/96	0.00% 0/96	0.00% 0/92	1.0% 1/96	0.00% 0/96	0.00% 0/87	0.00% 0/91
Gastrointestinal disorders Pancreatitis acute	0.00% 0/89	1.0% 1/96	0.00% 0/96	0.00% 0/92	0.00% 0/96	0.00% 0/96	0.00% 0/87	0.00% 0/91
General disorders Non-cardiac chest pain	0.00% 0/89	0.00% 0/96	0.00% 0/96	0.00% 0/92	1.0% 1/96	1.0% 1/96	0.00% 0/87	0.00% 0/91
General disorders Sudden death	0.00% 0/89	0.00% 0/96	0.00% 0/96	1.1% 1/92	0.00% 0/96	0.00% 0/96	0.00% 0/87	0.00% 0/91
Infections and infestations Gastroenteritis	0.00% 0/89	0.00% 0/96	0.00% 0/96	1.1% 1/92	0.00% 0/96	0.00% 0/96	0.00% 0/87	0.00% 0/91
Infections and infestations Herpes zoster	0.00% 0/89	0.00% 0/96	0.00% 0/96	0.00% 0/92	0.00% 0/96	0.00% 0/96	0.00% 0/87	1.1% 1/91
Infections and infestations Pneumonia	0.00% 0/89	0.00% 0/96	0.00% 0/96	0.00% 0/92	1.0% 1/96	0.00% 0/96	0.00% 0/87	0.00% 0/91
Infections and infestations Respiratory tract infection	0.00% 0/89	0.00% 0/96	0.00% 0/96	0.00% 0/92	0.00% 0/96	0.00% 0/96	0.00% 0/87	1.1% 1/91
Injury, poisoning and procedural complications Incisional hernia	0.00% 0/89	1.0% 1/96	0.00% 0/96	0.00% 0/92	0.00% 0/96	0.00% 0/96	0.00% 0/87	0.00% 0/91
Injury, poisoning and procedural complications Injury	0.00% 0/89	0.00% 0/96	0.00% 0/96	0.00% 0/92	1.0% 1/96	0.00% 0/96	0.00% 0/87	0.00% 0/91
Nervous system disorders Cerebrovascular accident	0.00% 0/89	0.00% 0/96	0.00% 0/96	1.1% 1/92	0.00% 0/96	0.00% 0/96	0.00% 0/87	0.00% 0/91
Reproductive system and breast disorders Epididymitis	1.1% 1/89	0.00% 0/96	0.00% 0/96	0.00% 0/92	0.00% 0/96	0.00% 0/96	0.00% 0/87	0.00% 0/91
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.1% 1/89	0.00% 0/96	1.0% 1/96	0.00% 0/92	2.1% 2/96	1.0% 1/96	0.00% 0/87	0.00% 0/91
Vascular disorders Hypertensive crisis	0.00% 0/89	0.00% 0/96	0.00% 0/96	0.00% 0/92	0.00% 0/96	1.0% 1/96	0.00% 0/87	0.00% 0/91

Other adverse events

Other adverse events
Measure	NVA237 12.5 ug q.d. n=89 participants at risk NVA237 12.5 ug q.d.	NVA237 25 ug q.d. n=96 participants at risk NVA237 25 ug q.d.	NVA237 12.5 ug b.i.d. n=96 participants at risk NVA237 12.5 ug b.i.d.	NVA237 50 ug q.d. n=92 participants at risk NVA237 50 ug q.d.	NVA237 25 ug b.i.d. n=96 participants at risk NVA237 25 ug b.i.d.	NVA237 100 ug q.d. n=96 participants at risk NVA237 100 ug q.d.	NVA237 50 ug b.i.d. n=87 participants at risk NVA237 50 ug b.i.d.	Placebo n=91 participants at risk Placebo
Infections and infestations Nasopharyngitis	4.5% 4/89	8.3% 8/96	2.1% 2/96	4.3% 4/92	3.1% 3/96	4.2% 4/96	5.7% 5/87	6.6% 6/91
Nervous system disorders Headache	1.1% 1/89	1.0% 1/96	2.1% 2/96	3.3% 3/92	3.1% 3/96	4.2% 4/96	3.4% 3/87	6.6% 6/91
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	6.7% 6/89	3.1% 3/96	1.0% 1/96	0.00% 0/92	3.1% 3/96	2.1% 2/96	1.1% 1/87	4.4% 4/91

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 41 61 324 1111

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER