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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01119950
• Collaborator: (none)
• Enrollment: 388
• Locations: 29
• Arms: 8
• Duration (Months): 8
• Patients Per Site: 13.4
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

This study was designed to investigate the efficacy and safety of NVA237, a long-acting muscarinic antagonist, in patients with moderate to severe COPD.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: NVA237 12.5 µg once daily; Drug: NVA237 25.0 µg once daily; Drug: NVA237 12.5 µg twice daily; Drug: NVA237 50.0 µg once daily; Drug: NVA237 25.0 µg twice daily; Drug: NVA237 100.0 µg once daily; Drug: NVA237 50.0 µg twice daily; Drug: Placebo to NVA237 once daily	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 388 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, 2-period, Cross-over Study to Assess the Efficacy and Safety of Differing Doses of NVA237 Administered Either Once Daily or Twice Daily, in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NVA237 12.5 µg q.d. NVA237 12.5 µg once daily	Drug: NVA237 12.5 µg once daily; NVA237 12.5 µg via dry powder inhaler once daily for 28 days during either period 1 or during period 2.
Experimental: NVA237 25.0 µg q.d. NVA237 25.0 µg once daily	Drug: NVA237 25.0 µg once daily; NVA237 25.0 µg via dry powder inhaler once daily for 28 days during either period 1 or during period 2.
Experimental: NVA237 12.5 µg b.i.d. NVA237 12.5 µg twice daily	Drug: NVA237 12.5 µg twice daily; NVA237 12.5 µg via dry powder inhaler twice daily for 28 days during either period 1 or during period 2.
Experimental: NVA237 50.0 µg q.d. NVA237 50.0 µg once daily	Drug: NVA237 50.0 µg once daily; NVA237 50.0 µg via dry powder inhaler once daily for 28 days during either period 1 or during period 2.
Experimental: NVA237 25.0 µg b.i.d. NVA237 25.0 µg twice daily	Drug: NVA237 25.0 µg twice daily; NVA237 25.0 µg via dry powder inhaler twice daily for 28 days during either period 1 or during period 2.
Experimental: NVA237 100.0 µg q.d. NVA237 100.0 µg once daily	Drug: NVA237 100.0 µg once daily; NVA237 100.0 µg via dry powder inhaler once daily for 28 days during either period 1 or during period 2.
Experimental: NVA237 50.0 µg b.i.d. NVA237 50.0 µg twice daily	Drug: NVA237 50.0 µg twice daily; NVA237 50.0 µg via dry powder inhaler twice daily for 28 days during either period 1 or during period 2.
Placebo Comparator: Placebo Placebo to NVA237 once daily	Drug: Placebo to NVA237 once daily; Placebo to NVA237 via dry powder inhaler once daily for 28 days during either period 1 or during period 2.

Outcome Measures

Primary Outcome Measures

1. 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 [Day 28]

   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.

Secondary Outcome Measures

1. Trough Forced Expiratory Volume in One Second for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237 [day 28]

   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.

2. 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 [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]

   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.

3. 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 [-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]

   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.

4. 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 [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]

   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.

5. Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second at 12 Hours at Day 28 of Treatment [12 hours on day 28]

   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.

6. Percentage of the Maximal Response of NVA237 Doses on Peak Forced Expiratory Volume in One Second at Day 28 of Treatment [day 28]

   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.

7. Percentage of the Maximal Response of NVA237 Doses on Forced Vital Capacity at Day 28 of Treatment [day 28]

   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.

8. Percentage of the Maximal Response of NVA237 Doses on Trough Forced Expiratory Volume in One Second at Days 1, 7 and 14 [Days 1, 7 and 14]

   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.

9. 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 [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]

   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.

10. 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 [5 min,15 min, 1,2,3,4 hours (postdose) on Days 1, 7 and 14]

    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.

11. 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 [at 5 min,15 min, 1,2,3,4,6,8 hours (postdose) on days 1, 7 and 14]

    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.

12. 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 [5 min,15 min, 1,2,3,4,6,8,10 hours, 11h 55 min (postdose) on days 1 and 14]

    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.

13. 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 [11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on Days 1 and 14]

    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.

14. 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 [Days 1 and 14]

    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.

15. Percentage of the Maximal Response of NVA237 Doses on Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment [Days 1, 7, and 14]

    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.

16. Percentage of the Maximal Response of NVA237 Doses on Trough Forced Vital Capacity on Days 1, 7 and 14 [Days 1, 7 and 14]

    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.

17. Mean Daily Use of Rescue Medication by Treatment at Different Time Points [Baseline, Weeks 1, 2, 3 and 4]

    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.

Other Outcome Measures

1. Trough Forced Expiratory Volume in One Second by Treatment at Day 28 [Day 28]

   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.

2. Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours at Day 28 of Treatment [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]

   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.

3. 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) [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]

   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.

4. Forced Expiratory Volume in One Second at 12 Hours on Day 28 of Treatment [12 hours on day 28]

   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.

5. Peak Forced Expiratory Volume in One Second at Day 28 of Treatment [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]

   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.

6. Trough Forced Vital Capacity After 28 Days of Treatment [23 hours 15 mins and 23 hours 45 mins post-dose on Day 28]

   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.

7. Trough Forced Expiratory Volume in One Second at Days 1, 7 and 14 [23 hours 15 mins and 23 hours 45 mins post-dose on Days 1, 7 and 14]

   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.

8. Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours on Days 1 and 14 of Treatment [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]

   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.

9. Forced Expiratory Volume in One Second Area Under the Curve 0-4 Hours on Days 1, 7 and 14 of Treatment [5 min,15 min, 1,2,3,4 hours (postdose) on Days 1, 7 and 14]

   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.

10. Forced Expiratory Volume in One Second of Area Under the Curve 0-8 Hours Days 1, 7, and 14 [at 5 min,15 min, 1,2,3,4,6,8 hours (postdose) on days 1, 7 and 14]

    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.

11. Forced Expiratory Volume in One Second Area Under the Curve 0-12 Hours at Day 1 and 14 of Treatment [5 min,15 min, 1,2,3,4,6,8,10 hours, 11h 55 min (postdose) on days 1 and 14]

    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.

12. Forced Expiratory Volume in One Second of Area Under the Curve 12-24 Hours Over Days 1, and 14 of Treatment [11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on Days 1 and 14]

    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.

13. Forced Expiratory Volume in One Second at 12 Hours on Days 1 and 14 of Treatment [Days 1 and 14]

    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.

14. Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment [Days 1, 7, and 14]

    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.

15. Trough Forced Vital Capacity on Days 1, 7 and 14 [Days 1, 7 and 14]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female patients age 40 years or more

• Diagnosis of Chronic Obstructive Lung Disease (COPD) (moderate to severe as classified by the Global Initiative for COPD (GOLD) Guidelines, 2008

• Smoking history of at least 10 pack-years

• Post-bronchodilator Forced Expiratory Volume in 1 second (FEV1) <80% and ≥30% of the predicted normal value

• Post-bronchodilator FEV1/Forced Vital Capacity (FVC) <0.7

• Symptomatic patients, according to daily electronic diary data between visit 2 (Day -8) and Visit 3 (Day 1), with a total score of 1 or more on at least 4 of the last 7 days prior to visit 3

Exclusion Criteria:

• Patients who have had a COPD exacerbation requiring systemic corticosteroids and/or antibiotics and/or hospitalization in the 6 weeks prior to the first visit

• Patients who have had a respiratory tract infection within 4 weeks prior to the first visit

• Patients with concomitant pulmonary disease

• Patients with diabetes Type I or uncontrolled diabetes Type II

• Any patient with lung cancer or a history of lung cancer

• Patients with a history of certain cardiovascular co-morbid conditions

• Patients with a history of asthma or a blood eosinophil count >600/mm3 or onset of symptoms prior to 40 years

• Patients with eczema, known high IgE levels or a known positive skin prick test

• Patients participating in the active phase of a pulmonary rehabilitation programme

• Patients contraindicated for the treatment with anticholinergics, long and short-acting beta-2 agonists or sympathomimetic amines

• Patients with a history of alpha-1 anti-trypsin deficiency

• Patients on long term oxygen therapy (>15hr per day)

• Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Anniston	Alabama	United States	36201
2	Novartis Investigative Site	San Diego	California	United States	92101
3	Novartis Investigative Site	Torrance	California	United States	90501
4	Novartis Investigative Site	Denver	Colorado	United States	80012
5	Novartis Investigative Site	Omaha	Nebraska	United States	68104
6	Novartis Investigative Site	Philadelphia	Pennsylvania	United States	19102
7	Novartis Investigative Site	Antwerpen		Belgium
8	Novartis Investigative Site	Genk		Belgium
9	Novartis Investigative site	Jambes		Belgium
10	Novartis Investigative Site	Muenchen		Germany
11	Novartis Investigative Site	Balassagyarmat		Hungary
12	Novartis Investigative Site	Balatonfured		Hungary
13	Novartis Investigative Site	Budapest		Hungary
14	Novartis Investigative Site	Debrecen		Hungary
15	Novartis Investigative Site	Szolnok		Hungary
16	Novartis Investigative Site	Torokbalint		Hungary
17	Novartis Investigative Site	Almelo		Netherlands
18	Novartis Investigative Site	Eindhoven		Netherlands
19	Novartis Investigative Site	Harderwijk		Netherlands
20	Novartis Investigative Site	Heerlen		Netherlands
21	Novartis Investigative Site	Helmond		Netherlands
22	Novartis Investigative Site	Veldhoven		Netherlands
23	Novartis Investigative Site	Zutphen		Netherlands
24	Novartis Investigative Site	Izabelin		Poland
25	Novartis Investigative Site	Lodz		Poland
26	Novartis Investigative Site	Warszawa		Poland
27	Novartis Investigative Site	Alicante		Spain
28	Novartis Investigative Site	La Coruña		Spain
29	Novartis Investigative Site	Ponferrada		Spain

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01119950
• Other Study ID Numbers: CNVA237A2208; 2009-014038-11
• First Posted: May 10, 2010
• Last Update Posted: Mar 23, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by Novartis Pharmaceuticals: COPD
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Glycopyrrolate

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	For this crossover study, a participant is counted in 2 treatment groups

Arm/Group Title	Overall Study
Arm/Group Description	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.
Period Title: Overall Study
STARTED	388
NVA237 12.5 ug q.d.	96
NVA237 25 ug q.d.	99
NVA237 12.5 ug b.i.d.	99
NVA237 50 ug q.d.	96
NVA237 25 ug b.i.d.	100
NVA237 100 ug q.d.	98
NVA237 50 ug b.i.d.	94
Placebo	94
COMPLETED	341
NOT COMPLETED	47

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All participants in the safety set
Overall Participants	386
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.2 (7.91)
Sex: Female, Male (Count of Participants)
Female	251 65%
Male	135 35%

Outcome Measures

1. Secondary Outcome

Title	Trough Forced Expiratory Volume in One Second for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237
Description	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.
Time Frame	day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Overall Study
Arm/Group Description	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.
Measure Participants	385
Total daily dose 20 ug	0.037
Total daily dose 25 ug	0.037
Total daily dose 30 ug	0.036
Total daily dose 35 ug	0.035
Total daily dose 40 ug	0.034
Total daily dose 45 ug	0.033
Total daily dose 50 ug	0.032
Total daily dose 55 ug	0.031

2. Secondary Outcome

Title	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
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	82	90	91	90	92	91	82
Mean (90% Confidence Interval) [Percentage of maximal response * hours]	28.9	44.8	49.0	61.9	65.7	76.4	79.3

3. Secondary Outcome

Title	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
Description	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.
Time Frame	-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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Overall Study
Arm/Group Description	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.
Measure Participants	385
Total daily dose 20 ug	0.008
Total daily dose 25 ug	0.008
Total daily dose 30 ug	0.008
Total daily dose 35 ug	0.008
Total daily dose 40 ug	0.008
Total daily dose 45 ug	0.008
Total daily dose 50 ug	0.008
Total daily dose 55 ug	0.007

4. Secondary Outcome

Title	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
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	82	90	91	90	92	91	82
AUC 0-4h (n=82,90,91,89,92,91,82)	50.8	66.9	58.9	79.7	73.7	88.3	84.4
AUC 0-8h (n=82,90,91,90,92,91,82)	45.8	62.8	55.5	77.1	71.4	87.1	83.3
AUC 0-12h (n=82,90,91,90,92,91,82)	41.1	58.3	50.5	73.6	67.1	84.8	80.3
AUC 12-24h (n=82,90,91,89,92,91,81)	25.6	40.1	56.6	56.4	71.4	71.2	82.4

5. Secondary Outcome

Title	Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second at 12 Hours at Day 28 of Treatment
Description	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.
Time Frame	12 hours on day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	79	88	91	85	87	88	78
Mean (90% Confidence Interval) [Percentage of maximal response]	27.1	42.7	35.5	59.8	52.4	74.9	68.7

6. Secondary Outcome

Title	Percentage of the Maximal Response of NVA237 Doses on Peak Forced Expiratory Volume in One Second at Day 28 of Treatment
Description	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.
Time Frame	day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	82	90	91	89	92	91	82
Mean (90% Confidence Interval) [Percentage of maximal response]	53.3	69.2	61.1	81.5	75.6	89.6	85.8

7. Secondary Outcome

Title	Percentage of the Maximal Response of NVA237 Doses on Forced Vital Capacity at Day 28 of Treatment
Description	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.
Time Frame	day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	81	88	90	88	87	90	81
Mean (90% Confidence Interval) [Percentage of maximal response]	23.3	37.4	53.6	54.0	69.3	69.7	81.4

8. Secondary Outcome

Title	Percentage of the Maximal Response of NVA237 Doses on Trough Forced Expiratory Volume in One Second at Days 1, 7 and 14
Description	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.
Time Frame	Days 1, 7 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	88	92	91	91	95	94	87
Day 1 (n= 88,92,91, 90, 94, 94, 87)	28.5	43.8	63.3	60.1	76.7	74.3	86.2
Day 7 (n= 87,92,90, 91, 95, 93, 85)	27.1	42.0	61.6	58.5	75.5	73.0	85.4
Day 14 (n= 85,90,91, 88, 94, 93, 81)	27.1	42.0	61.6	58.5	75.5	73.0	85.4

9. Secondary Outcome

Title	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
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	89	94	93	92	96	96	87
Day 1 (n= 89,94,93,92,96,96,87)	38.3	55.4	59.5	71.3	74.6	83.2	85.4
Day 14 (n= 86,92,91,91,95,93,84)	28.9	44.8	49.0	61.9	65.7	76.4	79.3

10. Secondary Outcome

Title	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
Description	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.
Time Frame	5 min,15 min, 1,2,3,4 hours (postdose) on Days 1, 7 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	89	94	93	92	96	96	86
Day 1 (n=89,94,93,91,96,96,86)	58.4	73.2	66.1	84.1	79.1	91.1	88.0
Day 7 (n=87,93,90,92,95,94,85)	50.8	66.9	58.9	79.7	73.7	88.3	84.4
Day 14 (n=86,92,91,91,95,93,84)	50.8	66.9	58.9	79.7	73.7	88.3	84.4

11. Secondary Outcome

Title	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
Description	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.
Time Frame	at 5 min,15 min, 1,2,3,4,6,8 hours (postdose) on days 1, 7 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	89	94	93	92	96	96	87
Day 1 (n=89, 94, 93, 91, 96, 96, 87)	54.2	70.3	63.6	82.6	77.8	90.5	87.5
Day 7 (n= 87, 93, 91, 92, 95, 94, 85)	45.8	62.8	55.5	77.1	71.4	87.1	83.3
Day 14 (n=86, 92, 91, 91, 95, 93, 84)	45.8	62.8	55.5	77.1	71.4	87.1	83.3

12. Secondary Outcome

Title	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
Description	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.
Time Frame	5 min,15 min, 1,2,3,4,6,8,10 hours, 11h 55 min (postdose) on days 1 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	89	94	93	91	96	96	87
Day 1 (n=89, 94, 93, 91, 96, 96, 87)	49.5	66.2	58.8	79.6	74.1	88.7	85.1
Day 14 (n=86, 92, 91, 91, 95, 93, 84)	41.1	58.3	50.5	73.6	67.1	84.8	80.3

13. Secondary Outcome

Title	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
Description	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.
Time Frame	11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on Days 1 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	89	94	93	92	96	96	87
Day 1 (n=89, 94, 93, 92, 96, 96, 87)	23.9	37.9	54.4	54.1	69.5	69.3	81.1
Day 14 (n= 86, 92, 91, 91, 95, 93, 84)	25.6	40.1	56.6	56.4	71.4	71.2	82.4

14. Secondary Outcome

Title	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
Description	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.
Time Frame	Days 1 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	84	91	91	90	90	92	83
Day 1 (n=83, 90, 91, 85, 89, 90, 83)	35.1	52.0	44.4	68.4	61.5	81.2	76.1
Day 14 (n=84, 91, 88, 90, 90, 92, 78)	27.1	42.7	35.5	59.8	52.4	74.9	66.7

15. Secondary Outcome

Title	Percentage of the Maximal Response of NVA237 Doses on Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment
Description	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.
Time Frame	Days 1, 7, and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	89	94	93	92	96	96	86
Day 1 (n=89, 94, 93, 91, 96, 96, 86)	61.7	76.0	68.9	86.1	81.3	92.3	89.5
Day 7 (n=87, 93, 90, 92, 95, 94, 85)	53.3	69.2	61.1	81.5	75.6	89.6	85.8
Day 14 (n=86, 92, 91, 91, 95, 93, 84)	53.3	69.2	61.1	81.5	75.6	89.6	85.8

16. Secondary Outcome

Title	Percentage of the Maximal Response of NVA237 Doses on Trough Forced Vital Capacity on Days 1, 7 and 14
Description	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.
Time Frame	Days 1, 7 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	88	92	91	91	95	94	87
Day 1 (n=88, 92, 91, 90, 94, 94, 87)	22.8	36.8	52.9	53.4	68.7	69.1	81.0
Day 7 (n=87, 92, 90, 91, 95, 93, 85, 87)	23.3	37.4	53.6	54.0	69.3	69.7	81.4
Day 14 (n= 85, 90, 91, 88, 94, 93, 81, 84)	23.3	37.4	53.6	54.0	69.3	69.7	81.4

17. Secondary Outcome

Title	Mean Daily Use of Rescue Medication by Treatment at Different Time Points
Description	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.
Time Frame	Baseline, Weeks 1, 2, 3 and 4

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	89	95	95	92	96	96	86	91
Baseline (n=89, 95, 95, 92, 96, 96, 86, 91)	4.16 (3.131)	4.16 (2.925)	3.83 (3.218)	4.45 (3.068)	3.47 (2.996)	4.81 (3.276)	4.25 (3.613)	4.62 (3.710)
Week 1 (n=89, 95, 95, 91, 96, 96, 86, 90)	2.41 (2.338)	2.23 (2.158)	2.10 (2.337)	2.36 (2.291)	2.13 (2.349)	2.53 (2.609)	2.54 (2.678)	2.94 (3.075)
Week 2 (n=86, 94, 94, 91, 95, 93, 84, 89)	2.74 (2.784)	2.20 (2.054)	2.22 (2.541)	2.38 (2.541)	2.08 (2.568)	2.59 (2.658)	2.82 (3.003)	3.32 (3.455)
Week 3 (n= 86, 93, 94, 89, 93, 93, 83, 87)	2.75 (2.736)	2.40 (2.316)	2.29 (2.354)	2.37 (2.580)	2.23 (2.743)	2.75 (2.868)	2.69 (2.977)	3.34 (3.660)
Week 4 (n=86, 92, 94, 88, 93, 93, 82, 85)	2.91 (2.968)	2.52 (2.476)	2.42 (2.773)	2.46 (2.504)	2.32 (2.990)	2.65 (2.828)	2.78 (2.899)	3.41 (3.761)

18. Primary Outcome

Title	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
Description	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.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily
Measure Participants	81	88	90	88	87	90	81
Mean (90% Confidence Interval) [Percentage of maximal response]	27.1 (0.454)	42.0 (0.471)	61.6 (0.456)	58.5 (0.389)	75.5 (0.508)	73.0 (0.512)	85.4 (0.463)

19. Other Pre-specified Outcome

Title	Trough Forced Expiratory Volume in One Second by Treatment at Day 28
Description	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.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 ug q.d.	NVA237 25 ug q.d.	NVA237 12.5 ug b.i.d.	NVA237 50 ug q.d.	NVA237 25 ug b.i.d.	NVA237 100 ug q.d.	NVA237 50 ug b.i.d.	Placebo
Arm/Group Description	NVA237 25 ug once daily	NVA237 12.5 ug once daily	NVA237 12.5 ug twice daily	NVA237 50 ug once daily	NVA237 25 ug twice daily	NVA237 100 ug once daily	NVA237 50 ug twice daily	Placebo to NVA237 once daily
Measure Participants	81	88	90	88	87	90	81	82
Mean (Standard Deviation) [Liters]	1.319 (0.505)	1.368 (0.436)	1.354 (0.484)	1.340 (0.400)	1.384 (0.472)	1.410 (0.522)	1.493 (0.449)	1.268 (0.483)

20. Other Pre-specified Outcome

Title	Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours at Day 28 of Treatment
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	82	90	91	90	92	91	82	82
Mean (Standard Deviation) [Liters]	1.307 (0.469)	1.351 (0.392)	1.321 (0.469)	1.317 (0.390)	1.339 (0.462)	1.395 (0.496)	1.457 (0.453)	1.247 (0.467)

21. Other Pre-specified Outcome

Title	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)
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	82	90	91	90	92	91	82	82
AUC 0-4h (n=82,90,91,89,92,91,82,82)	1.415 (0.494)	1.478 (0.439)	1.414 (0.489)	1.431 (0.411)	1.417 (0.487)	1.490 (0.532)	1.553 (0.504)	1.315 (0.490)
AUC 0-8h (n=82,90,91,90,92,91,82,82)	1.386 (0.477)	1.447 (0.423)	1.392 (0.491)	1.397 (0.411)	1.397 (0.476)	1.461 (0.520)	1.527 (0.495)	1.305 (0.485)
AUC 0-12h (n=82,90,91,90,92,91,82,82)	1.364 (0.480)	1.416 (0.416)	1.362 (0.487)	1.377 (0.408)	1.375 (0.469)	1.442 (0.515)	1.505 (0.480)	1.285 (0.476)
AUC 12-24h (n=82,90,91,89,92,91,81,82)	1.251 (0.464)	1.287 (0.382)	1.280 (0.458)	1.264 (0.378)	1.299 (0.459)	1.350 (0.480)	1.421 (0.426)	1.208 (0.461)

22. Other Pre-specified Outcome

Title	Forced Expiratory Volume in One Second at 12 Hours on Day 28 of Treatment
Description	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.
Time Frame	12 hours on day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	79	88	91	85	87	88	78	80
Mean (Standard Deviation) [Liters]	1.272 (0.471)	1.330 (0.415)	1.279 (0.476)	1.330 (0.384)	1.320 (0.466)	1.391 (0.498)	1.429 (0.449)	1.256 (0.472)

23. Other Pre-specified Outcome

Title	Peak Forced Expiratory Volume in One Second at Day 28 of Treatment
Description	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.
Time Frame	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 Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	82	90	91	89	92	91	82	82
Mean (Standard Deviation) [Liters]	1.500 (0.516)	1.563 (0.453)	1.494 (0.507)	1.514 (0.432)	1.504 (0.516)	1.570 (0.546)	1.630 (0.513)	1.397 (0.515)

24. Other Pre-specified Outcome

Title	Trough Forced Vital Capacity After 28 Days of Treatment
Description	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.
Time Frame	23 hours 15 mins and 23 hours 45 mins post-dose on Day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	81	88	90	88	87	90	81	82
Mean (Standard Deviation) [Liters]	2.939 (0.878)	3.007 (0.910)	2.954 (0.849)	2.973 (0.825)	3.041 (0.770)	2.974 (0.999)	3.080 (0.913)	2.703 (0.857)

25. Other Pre-specified Outcome

Title	Trough Forced Expiratory Volume in One Second at Days 1, 7 and 14
Description	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.
Time Frame	23 hours 15 mins and 23 hours 45 mins post-dose on Days 1, 7 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	88	92	91	91	95	94	87	87
Day 1 (n= 88,92,91, 90, 94, 94, 87, 86)	1.299 (0.490)	1.387 (0.477)	1.375 (0.477)	1.371 (0.406)	1.355 (0.503)	1.367 (0.514)	1.492 (0.483)	1.290 (0.471)
Day 7 (n= 87,92,90, 91, 95, 93, 85, 87)	1.332 (0.499)	1.422 (0.432)	1.349 (0.467)	1.391 (0.392)	1.375 (0.486)	1.372 (0.501)	1.480 (0.474)	1.294 (0.491)
Day 14 (n= 85,90,91, 88, 94, 93, 81, 84)	1.336 (0.442)	1.349 (0.446)	1.335 (0.444)	1.356 (0.391)	1.359 (0.479)	1.375 (0.519)	1.500 (0.455)	1.284 (0.471)

26. Other Pre-specified Outcome

Title	Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours on Days 1 and 14 of Treatment
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	89	94	93	92	96	96	87	90
Day 1 (n= 89,94,93,92,96,96,87,90)	1.318 (0.470)	1.370 (0.444)	1.354 (0.462)	1.361 (0.393)	1.336 (0.460)	1.376 (0.526)	1.466 (0.471)	1.256 (0.469)
Day 14 (n= 86,92,91,91,95,93,84,86)	1.306 (0.427)	1.353 (0.420)	1.324 (0.430)	1.348 (0.372)	1.335 (0.460)	1.386 (0.493)	1.449 (0.453)	1.253 (0.473)

27. Other Pre-specified Outcome

Title	Forced Expiratory Volume in One Second Area Under the Curve 0-4 Hours on Days 1, 7 and 14 of Treatment
Description	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.
Time Frame	5 min,15 min, 1,2,3,4 hours (postdose) on Days 1, 7 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	89	94	93	92	96	96	86	89
Day 1 (n=89,94,93,91,96,96,86,89)	1.428 (0.492)	1.483 (0.485)	1.421 (0.489)	1.469 (0.428)	1.411 (0.483)	1.453 (0.551)	1.533 (0.501)	1.312 (0.494)
Day 7 (n=87,93,90,92,95,94,85,89)	1.403 (0.468)	1.483 (0.463)	1.397 (0.478)	1.432 (0.407)	1.390 (0.472)	1.453 (0.505)	1.537 (0.494)	1.310 (0.491)
Day 14 (n=86,92,91,91,95,93,84,86)	1.451 (0.456)	1.473 (0.456)	1.390 (0.471)	1.468 (0.409)	1.429 (0.503)	1.460 (0.514)	1.545 (0.485)	1.314 (0.500)

28. Other Pre-specified Outcome

Title	Forced Expiratory Volume in One Second of Area Under the Curve 0-8 Hours Days 1, 7, and 14
Description	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.
Time Frame	at 5 min,15 min, 1,2,3,4,6,8 hours (postdose) on days 1, 7 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	89	94	93	92	96	96	87	90
Day 1 (n=89, 94, 93, 91, 96, 96, 87, 90)	1.400 (0.486)	1.450 (0.476)	1.401 (0.483)	1.451 (0.426)	1.390 (0.476)	1.446 (0.548)	1.519 (0.493)	1.301 (0.488)
Day 7 (n= 87, 93, 91, 92, 95, 94, 85, 89)	1.386 (0.471)	1.462 (0.455)	1.375 (0.464)	1.409 (0.397)	1.373 (0.470)	1.433 (0.503)	1.516 (0.481)	1.293 (0.489)
Day 14 (n=86, 92, 91, 91, 95, 93, 84, 86)	1.381 (0.453)	1.441 (0.452)	1.375 (0.463)	1.435 (0.398)	1.400 (0.486)	1.442 (0.508)	1.514 (0.479)	1.293 (0.498)

29. Other Pre-specified Outcome

Title	Forced Expiratory Volume in One Second Area Under the Curve 0-12 Hours at Day 1 and 14 of Treatment
Description	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.
Time Frame	5 min,15 min, 1,2,3,4,6,8,10 hours, 11h 55 min (postdose) on days 1 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	89	94	93	91	96	96	87	90
Day 1 (n=89, 94, 93, 91, 96, 96, 87, 90)	1.382 (0.488)	1.425 (0.465)	1.379 (0.474)	1.430 (0.421)	1.364 (0.470)	1.431 (0.544)	1.498 (0.484)	1.289 (0.482)
Day 14 (n=86, 92, 91, 91, 95, 93, 84, 86)	1.360 (0.447)	1.416 (0.445)	1.357 (0.452)	1.406 (0.388)	1.378 (0.480)	1.427 (0.503)	1.494 (0.472)	1.281 (0.493)

30. Other Pre-specified Outcome

Title	Forced Expiratory Volume in One Second of Area Under the Curve 12-24 Hours Over Days 1, and 14 of Treatment
Description	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.
Time Frame	11 hours 55 min, 14,20,22 hours; 23 hours 15 min, 23 hours 45 min (postdose) on Days 1 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	89	94	93	92	96	96	87	90
Day 1 (n=89, 94, 93, 92, 96, 96, 87, 90)	1.257 (0.459)	1.315 (0.432)	1.329 (0.455)	1.295 (0.375)	1.306 (0.454)	1.322 (0.512)	1.437 (0.461)	1.224 (0.459)
Day 14 (n= 86, 92, 91, 91, 95, 93, 84, 86)	1.251 (0.417)	1.289 (0.405)	1.290 (0.415)	1.291 (0.366)	1.291 (0.450)	1.344 (0.488)	1.406 (0.437)	1.225 (0.459)

31. Other Pre-specified Outcome

Title	Forced Expiratory Volume in One Second at 12 Hours on Days 1 and 14 of Treatment
Description	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.
Time Frame	Days 1 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	84	91	91	90	90	92	83	83
Day 1 (n=83, 90, 91, 85, 89, 90, 83, 81)	1.319 (0.502)	1.364 (0.452)	1.327 (0.465)	1.345 (0.405)	1.299 (0.457)	1.374 (0.549)	1.439 (0.459)	1.244 (0.449)
Day 14 (n=84, 91, 88, 90, 90, 92, 78, 83)	1.290 (0.431)	1.356 (0.431)	1.303 (0.428)	1.329 (0.368)	1.329 (0.455)	1.389 (0.506)	1.469 (0.436)	1.268 (0.477)

32. Other Pre-specified Outcome

Title	Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment
Description	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.
Time Frame	Days 1, 7, and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	89	94	93	92	96	96	86	89
Day 1 (n=89, 94, 93, 91, 96, 96, 86, 89)	1.503 (0.515)	1.558 (0.497)	1.494 (0.507)	1.541 (0.442)	1.483 (0.495)	1.521 (0.567)	1.597 (0.510)	1.378 (0.504)
Day 7 (n=87, 93, 90, 92, 95, 94, 85, 89)	1.459 (0.477)	1.540 (0.474)	1.455 (0.496)	1.501 (0.426)	1.448 (0.491)	1.513 (0.524)	1.598 (0.510)	1.364 (0.504)
Day 14 (n=86, 92, 91, 91, 95, 93, 84, 86)	1.487 (0.471)	1.547 (0.465)	1.465 (0.484)	1.537 (0.429)	1.506 (0.513)	1.528 (0.529)	1.615 (0.497)	1.380 (0.509)

33. Other Pre-specified Outcome

Title	Trough Forced Vital Capacity on Days 1, 7 and 14
Description	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.
Time Frame	Days 1, 7 and 14

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NVA237 12.5 µg q.d.	NVA237 25.0 µg q.d.	NVA237 12.5 µg b.i.d.	NVA237 50.0 µg q.d.	NVA237 25.0 µg b.i.d.	NVA237 100.0 µg q.d.	NVA237 50.0 µg b.i.d.	Placebo
Arm/Group Description	NVA237 12.5 µg once daily	NVA237 25.0 µg once daily	NVA237 12.5 µg twice daily	NVA237 50.0 µg once daily	NVA237 25.0 µg twice daily	NVA237 100.0 µg once daily	NVA237 50.0 µg twice daily	Placebo to NVA237 once daily
Measure Participants	88	92	91	91	95	94	87	87
Day 1 (n=88, 92, 91, 90, 94, 94, 87, 86)	2.895 (0.830)	3.063 (0.967)	2.997 (0.835)	3.017 (0.820)	2.956 (0.810)	2.944 (1.001)	3.088 (0.961)	2.779 (0.838)
Day 7 (n=87, 92, 90, 91, 95, 93, 85, 87)	2.982 (0.833)	3.135 (0.928)	2.991 (0.873)	3.072 (0.833)	2.993 (0.798)	2.977 (0.987)	3.114 (0.975)	2.759 (0.875)
Day 14 (n= 85, 90, 91, 88, 94, 93, 81, 84)	2.958 (0.772)	3.000 (0.934)	2.965 (0.862)	3.003 (0.812)	2.960 (0.763)	2.941 (0.987)	3.113 (0.941)	2.744 (0.841)

Adverse Events

Arm/Group Title	NVA237 12.5 ug q.d.		NVA237 25 ug q.d.		NVA237 12.5 ug b.i.d.		NVA237 50 ug q.d.		NVA237 25 ug b.i.d.		NVA237 100 ug q.d.		NVA237 50 ug b.i.d.		Placebo
Arm/Group Description	NVA237 12.5 ug q.d.		NVA237 25 ug q.d.		NVA237 12.5 ug b.i.d.		NVA237 50 ug q.d.		NVA237 25 ug b.i.d.		NVA237 100 ug q.d.		NVA237 50 ug b.i.d.		Placebo
All Cause Mortality
	NVA237 12.5 ug q.d.		NVA237 25 ug q.d.		NVA237 12.5 ug b.i.d.		NVA237 50 ug q.d.		NVA237 25 ug b.i.d.		NVA237 100 ug q.d.		NVA237 50 ug b.i.d.		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	NVA237 12.5 ug q.d.		NVA237 25 ug q.d.		NVA237 12.5 ug b.i.d.		NVA237 50 ug q.d.		NVA237 25 ug b.i.d.		NVA237 100 ug q.d.		NVA237 50 ug b.i.d.		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/89 (2.2%)		2/96 (2.1%)		1/96 (1%)		3/92 (3.3%)		4/96 (4.2%)		3/96 (3.1%)		1/87 (1.1%)		3/91 (3.3%)
Cardiac disorders
Angina pectoris	0/89 (0%)		0/96 (0%)		0/96 (0%)		0/92 (0%)		0/96 (0%)		0/96 (0%)		0/87 (0%)		1/91 (1.1%)
Ventricular extrasystoles	0/89 (0%)		0/96 (0%)		0/96 (0%)		0/92 (0%)		0/96 (0%)		0/96 (0%)		1/87 (1.1%)		0/91 (0%)
Gastrointestinal disorders
Gastrooesophageal reflux disease	0/89 (0%)		0/96 (0%)		0/96 (0%)		0/92 (0%)		1/96 (1%)		0/96 (0%)		0/87 (0%)		0/91 (0%)
Pancreatitis acute	0/89 (0%)		1/96 (1%)		0/96 (0%)		0/92 (0%)		0/96 (0%)		0/96 (0%)		0/87 (0%)		0/91 (0%)
General disorders
Non-cardiac chest pain	0/89 (0%)		0/96 (0%)		0/96 (0%)		0/92 (0%)		1/96 (1%)		1/96 (1%)		0/87 (0%)		0/91 (0%)
Sudden death	0/89 (0%)		0/96 (0%)		0/96 (0%)		1/92 (1.1%)		0/96 (0%)		0/96 (0%)		0/87 (0%)		0/91 (0%)
Infections and infestations
Gastroenteritis	0/89 (0%)		0/96 (0%)		0/96 (0%)		1/92 (1.1%)		0/96 (0%)		0/96 (0%)		0/87 (0%)		0/91 (0%)
Herpes zoster	0/89 (0%)		0/96 (0%)		0/96 (0%)		0/92 (0%)		0/96 (0%)		0/96 (0%)		0/87 (0%)		1/91 (1.1%)
Pneumonia	0/89 (0%)		0/96 (0%)		0/96 (0%)		0/92 (0%)		1/96 (1%)		0/96 (0%)		0/87 (0%)		0/91 (0%)
Respiratory tract infection	0/89 (0%)		0/96 (0%)		0/96 (0%)		0/92 (0%)		0/96 (0%)		0/96 (0%)		0/87 (0%)		1/91 (1.1%)
Injury, poisoning and procedural complications
Incisional hernia	0/89 (0%)		1/96 (1%)		0/96 (0%)		0/92 (0%)		0/96 (0%)		0/96 (0%)		0/87 (0%)		0/91 (0%)
Injury	0/89 (0%)		0/96 (0%)		0/96 (0%)		0/92 (0%)		1/96 (1%)		0/96 (0%)		0/87 (0%)		0/91 (0%)
Nervous system disorders
Cerebrovascular accident	0/89 (0%)		0/96 (0%)		0/96 (0%)		1/92 (1.1%)		0/96 (0%)		0/96 (0%)		0/87 (0%)		0/91 (0%)
Reproductive system and breast disorders
Epididymitis	1/89 (1.1%)		0/96 (0%)		0/96 (0%)		0/92 (0%)		0/96 (0%)		0/96 (0%)		0/87 (0%)		0/91 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/89 (1.1%)		0/96 (0%)		1/96 (1%)		0/92 (0%)		2/96 (2.1%)		1/96 (1%)		0/87 (0%)		0/91 (0%)
Vascular disorders
Hypertensive crisis	0/89 (0%)		0/96 (0%)		0/96 (0%)		0/92 (0%)		0/96 (0%)		1/96 (1%)		0/87 (0%)		0/91 (0%)
Other (Not Including Serious) Adverse Events
	NVA237 12.5 ug q.d.		NVA237 25 ug q.d.		NVA237 12.5 ug b.i.d.		NVA237 50 ug q.d.		NVA237 25 ug b.i.d.		NVA237 100 ug q.d.		NVA237 50 ug b.i.d.		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/89 (10.1%)		11/96 (11.5%)		5/96 (5.2%)		7/92 (7.6%)		8/96 (8.3%)		9/96 (9.4%)		9/87 (10.3%)		14/91 (15.4%)
Infections and infestations
Nasopharyngitis	4/89 (4.5%)		8/96 (8.3%)		2/96 (2.1%)		4/92 (4.3%)		3/96 (3.1%)		4/96 (4.2%)		5/87 (5.7%)		6/91 (6.6%)
Nervous system disorders
Headache	1/89 (1.1%)		1/96 (1%)		2/96 (2.1%)		3/92 (3.3%)		3/96 (3.1%)		4/96 (4.2%)		3/87 (3.4%)		6/91 (6.6%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	6/89 (6.7%)		3/96 (3.1%)		1/96 (1%)		0/92 (0%)		3/96 (3.1%)		2/96 (2.1%)		1/87 (1.1%)		4/91 (4.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.