A Phase 2 interventional study of NVA237 12.5 µg once daily and NVA237 25.0 µg once daily in Chronic Obstructive Pulmonary Disease, sponsored by Novartis Pharmaceuticals. Completed at 29 sites in 7 countries. Open to participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2015-03-23.
Sponsored by Novartis Pharmaceuticals · Phase 2, Interventional, and Treatment
This study was designed to investigate the efficacy and safety of NVA237, a long-acting muscarinic antagonist, in patients with moderate to severe COPD.
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This study's enrollment of 388 is above the median of 72 across 2,118 interventional studies indexed under Lung Diseases.
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Exclusion Criteria:
NVA237 12.5 µg once daily
Drug: NVA237 12.5 µg once daily
NVA237 25.0 µg once daily
Drug: NVA237 25.0 µg once daily
NVA237 12.5 µg twice daily
Drug: NVA237 12.5 µg twice daily
NVA237 50.0 µg once daily
Drug: NVA237 50.0 µg once daily
NVA237 25.0 µg twice daily
Drug: NVA237 25.0 µg twice daily
NVA237 100.0 µg once daily
Drug: NVA237 100.0 µg once daily
NVA237 50.0 µg twice daily
Drug: NVA237 50.0 µg twice daily
Placebo to NVA237 once daily
Drug: Placebo to NVA237 once daily
NVA237 12.5 µg via dry powder inhaler once daily for 28 days during either period 1 or during period 2.
NVA237 25.0 µg via dry powder inhaler once daily for 28 days during either period 1 or during period 2.
NVA237 12.5 µg via dry powder inhaler twice daily for 28 days during either period 1 or during period 2.
NVA237 50.0 µg via dry powder inhaler once daily for 28 days during either period 1 or during period 2.
NVA237 25.0 µg via dry powder inhaler twice daily for 28 days during either period 1 or during period 2.
NVA237 100.0 µg via dry powder inhaler once daily for 28 days during either period 1 or during period 2.
NVA237 50.0 µg via dry powder inhaler twice daily for 28 days during either period 1 or during period 2.
Placebo to NVA237 via dry powder inhaler once daily for 28 days during either period 1 or during period 2.
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
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
Trough Forced Expiratory Volume in One Second for Once and Twice Daily Regimens of NVA237 for the Same Total Daily Dose of NVA237
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
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
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
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
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
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
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
Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second at 12 Hours at Day 28 of Treatment
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
Percentage of the Maximal Response of NVA237 Doses on Peak Forced Expiratory Volume in One Second at Day 28 of Treatment
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
Percentage of the Maximal Response of NVA237 Doses on Forced Vital Capacity at Day 28 of Treatment
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
Percentage of the Maximal Response of NVA237 Doses on Trough Forced Expiratory Volume in One Second at 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.
Time frame: Days 1, 7 and 14
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
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
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
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
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
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
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
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
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
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
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
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
Percentage of the Maximal Response of NVA237 Doses on Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment
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
Percentage of the Maximal Response of NVA237 Doses on Trough Forced Vital Capacity on 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.
Time frame: Days 1, 7 and 14
Mean Daily Use of Rescue Medication by Treatment at Different Time Points
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
Trough Forced Expiratory Volume in One Second by Treatment at 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.
Time frame: Day 28
Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours at Day 28 of Treatment
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
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)
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
Forced Expiratory Volume in One Second at 12 Hours on Day 28 of Treatment
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
Peak Forced Expiratory Volume in One Second at Day 28 of Treatment
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
Trough Forced Vital Capacity After 28 Days of Treatment
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
Trough Forced Expiratory Volume in One Second at 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.
Time frame: 23 hours 15 mins and 23 hours 45 mins post-dose on Days 1, 7 and 14
Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours on Days 1 and 14 of Treatment
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
Forced Expiratory Volume in One Second Area Under the Curve 0-4 Hours on Days 1, 7 and 14 of Treatment
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
Forced Expiratory Volume in One Second of Area Under the Curve 0-8 Hours 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.
Time frame: 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 Area Under the Curve 0-12 Hours at Day 1 and 14 of Treatment
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
Forced Expiratory Volume in One Second of Area Under the Curve 12-24 Hours Over Days 1, and 14 of Treatment
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
Forced Expiratory Volume in One Second at 12 Hours on Days 1 and 14 of Treatment
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
Peak Forced Expiratory Volume in One Second on Days 1, 7 and 14 of Treatment
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
Trough Forced Vital Capacity on 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.
Time frame: Days 1, 7 and 14
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.
| Milestone | 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 |
| Withdrew: Adverse event | 25 |
| Withdrew: Withdrawal by subject | 9 |
| Withdrew: Protocol violation | 5 |
| Withdrew: Lost to follow-up | 4 |
| Withdrew: Administrative | 2 |
| Withdrew: Abnormal lab value | 1 |
| Withdrew: Death | 1 |
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.
| Liters | Overall Study |
|---|---|
| Total daily dose 20 ug | 0.037 (0.013 to 0.053) |
| Total daily dose 25 ug | 0.037 (0.013 to 0.052) |
| Total daily dose 30 ug | 0.036 (0.013 to 0.051) |
| Total daily dose 35 ug | 0.035 (0.013 to 0.050) |
| Total daily dose 40 ug | 0.034 (0.013 to 0.049) |
| Total daily dose 45 ug | 0.033 (0.013 to 0.047) |
| Total daily dose 50 ug | 0.032 (0.012 to 0.046) |
| Total daily dose 55 ug | 0.031 (0.012 to 0.045) |
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.
| Percentage of maximal response * hours | 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. |
|---|---|---|---|---|---|---|---|
| Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours at Day 28 of Treatment | 28.9 (18.7 to 41.6) | 44.8 (31.6 to 58.8) | 49.0 (34.1 to 64.1) | 61.9 (48.0 to 74.0) | 65.7 (50.9 to 78.1) | 76.4 (64.8 to 85.1) | 79.3 (67.5 to 87.7) |
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.
| Liters | Overall Study |
|---|---|
| Total daily dose 20 ug | 0.008 (-0.008 to 0.023) |
| Total daily dose 25 ug | 0.008 (-0.008 to 0.024) |
| Total daily dose 30 ug | 0.008 (-0.008 to 0.024) |
| Total daily dose 35 ug | 0.008 (-0.008 to 0.023) |
| Total daily dose 40 ug | 0.008 (-0.008 to 0.023) |
| Total daily dose 45 ug | 0.008 (-0.008 to 0.022) |
| Total daily dose 50 ug | 0.008 (-0.008 to 0.022) |
| Total daily dose 55 ug | 0.007 (-0.007 to 0.021) |
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.
| Percentage of maximal response* hours | 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. |
|---|---|---|---|---|---|---|---|
| AUC 0-4h (n=82,90,91,89,92,91,82) | 50.8 (38.7 to 63.6) | 66.9 (53.7 to 77.7) | 58.9 (45.9 to 71.5) | 79.7 (67.4 to 87.4) | 73.7 (60.6 to 83.4) | 88.3 (77.8 to 93.3) | 84.4 (73.0 to 91.0) |
| AUC 0-8h (n=82,90,91,90,92,91,82) | 45.8 (33.2 to 58.8) | 62.8 (49.9 to 74.1) | 55.5 (42.0 to 68.4) | 77.1 (66.6 to 85.1) | 71.4 (59.1 to 81.2) | 87.1 (79.9 to 91.9) | 83.3 (74.3 to 89.7) |
| AUC 0-12h (n=82,90,91,90,92,91,82) | 41.1 (28.8 to 54.5) | 58.3 (44.7 to 70.6) | 50.5 (37.0 to 64.1) | 73.6 (61.8 to 82.8) | 67.1 (54.0 to 78.1) | 84.8 (76.4 to 90.6) | 80.3 (70.1 to 87.7) |
| AUC 12-24h (n=82,90,91,89,92,91,81) | 25.6 (15.5 to 42.5) | 40.1 (24.2 to 59.6) | 56.6 (31.4 to 78.2) | 56.4 (33.0 to 74.7) | 71.4 (41.5 to 87.8) | 71.2 (42.6 to 85.5) | 82.4 (51.2 to 93.5) |
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.
| Percentage of maximal response | 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. |
|---|---|---|---|---|---|---|---|
| Percentage of the Maximal Response of NVA237 Doses on Forced Expiratory Volume in One Second at 12 Hours at Day 28 of Treatment | 27.1 (14.7 to 44.6) | 42.7 (25.7 to 61.7) | 35.5 (20.4 to 54.0) | 59.8 (40.9 to 76.3) | 52.4 (33.9 to 70.2) | 74.9 (58.0 to 86.6) | 68.7 (50.7 to 82.5) |
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.
| Percentage of maximal response | 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. |
|---|---|---|---|---|---|---|---|
| Percentage of the Maximal Response of NVA237 Doses on Peak Forced Expiratory Volume in One Second at Day 28 of Treatment | 53.3 (41.2 to 65.5) | 69.2 (56.7 to 79.2) | 61.1 (48.2 to 73.4) | 81.5 (71.1 to 88.4) | 75.6 (63.4 to 84.7) | 89.6 (82.4 to 93.9) | 85.8 (76.5 to 91.7) |
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.
| Percentage of maximal response | 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. |
|---|---|---|---|---|---|---|---|
| Percentage of the Maximal Response of NVA237 Doses on Forced Vital Capacity at Day 28 of Treatment | 23.3 (11.3 to 45.3) | 37.4 (19.8 to 62.7) | 53.6 (26.5 to 81.2) | 54.0 (30.9 to 77.2) | 69.3 (38.6 to 89.7) | 69.7 (43.6 to 87.2) | 81.4 (52.5 to 94.6) |
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.
| Percentage of maximal response | 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. |
|---|---|---|---|---|---|---|---|
| Day 1 (n= 88,92,91, 90, 94, 94, 87) | 28.5 (17.5 to 45.3) | 43.8 (27.8 to 62.3) | 63.3 (37.9 to 82.5) | 60.1 (38.2 to 76.8) | 76.7 (49.3 to 90.5) | 74.3 (48.6 to 86.9) | 86.2 (59.8 to 95.0) |
| Day 7 (n= 87,92,90, 91, 95, 93, 85) | 27.1 (16.3 to 44.3) | 42.0 (26.3 to 61.4) | 61.6 (36.4 to 82.1) | 58.5 (37.3 to 76.1) | 75.5 (48.3 to 90.1) | 73.0 (48.7 to 86.4) | 85.4 (59.8 to 94.8) |
| Day 14 (n= 85,90,91, 88, 94, 93, 81) | 27.1 (16.4 to 44.3) | 42.0 (26.4 to 61.4) | 61.6 (36.6 to 82.1) | 58.5 (37.4 to 76.1) | 75.5 (48.5 to 90.2) | 73.0 (48.8 to 86.5) | 85.4 (60.1 to 94.8) |
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.
| Percentage of maximal response* hours | 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. |
|---|---|---|---|---|---|---|---|
| Day 1 (n= 89,94,93,92,96,96,87) | 38.3 (25.3 to 53.4) | 55.4 (40.4 to 69.6) | 59.5 (42.8 to 74.2) | 71.3 (57.5 to 82.1) | 74.6 (60.0 to 85.2) | 83.2 (73.0 to 90.2) | 85.4 (75.0 to 92.0) |
| Day 14 (n= 86,92,91,91,95,93,84) | 28.9 (18.7 to 41.6) | 44.8 (31.6 to 58.8) | 49.0 (34.1 to 64.1) | 61.9 (48.0 to 74.0) | 65.7 (50.9 to 78.1) | 76.4 (64.8 to 85.1) | 79.3 (67.5 to 87.7) |
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.
| Percentage of maximal response* hours | 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. |
|---|---|---|---|---|---|---|---|
| Day 1 (n=89,94,93,91,96,96,86) | 58.4 (44.4 to 71.8) | 73.2 (59.1 to 83.6) | 66.1 (51.6 to 78.6) | 84.1 (72.0 to 91.1) | 79.1 (65.6 to 88.0) | 91.1 (81.5 to 95.3) | 88.0 (77.1 to 93.6) |
| Day 7 (n=87,93,90,92,95,94,85) | 50.8 (38.7 to 63.6) | 66.9 (53.7 to 77.7) | 58.9 (45.9 to 71.5) | 79.7 (67.4 to 87.4) | 73.7 (60.6 to 83.4) | 88.3 (77.8 to 93.3) | 84.4 (73.0 to 91.0) |
| Day 14 (n=86,92,91,91,95,93,84) | 50.8 (38.7 to 63.6) | 66.9 (53.7 to 77.7) | 58.9 (45.9 to 71.5) | 79.7 (67.4 to 87.4) | 73.7 (60.6 to 83.4) | 88.3 (77.8 to 93.3) | 84.4 (73.0 to 91.0) |
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.
| Percentage of maximal response* hours | 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. |
|---|---|---|---|---|---|---|---|
| Day 1 (n=89, 94, 93, 91, 96, 96, 87) | 54.2 (40.1 to 67.8) | 70.3 (57.2 to 80.8) | 63.6 (49.0 to 76.3) | 82.6 (72.8 to 89.4) | 77.8 (65.8 to 86.5) | 90.5 (84.3 to 94.4) | 87.5 (79.4 to 92.8) |
| Day 7 (n= 87, 93, 91, 92, 95, 94, 85) | 45.8 (33.2 to 58.8) | 62.8 (49.9 to 74.1) | 55.5 (42.0 to 68.4) | 77.1 (66.6 to 85.1) | 71.4 (59.1 to 81.2) | 87.1 (79.9 to 91.9) | 83.3 (74.3 to 89.7) |
| Day 14 (n=86, 92, 91, 91, 95, 93, 84) | 45.8 (33.2 to 58.8) | 62.8 (49.9 to 74.1) | 55.5 (42.0 to 68.4) | 77.1 (66.6 to 85.1) | 71.4 (59.1 to 81.2) | 87.1 (79.9 to 91.9) | 83.3 (74.3 to 89.7) |
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.
| Percentage of maximal response* hours | 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. |
|---|---|---|---|---|---|---|---|
| Day 1 (n=89, 94, 93, 91, 96, 96, 87) | 49.5 (35.5 to 63.6) | 66.2 (52.4 to 77.8) | 58.8 (44.0 to 72.3) | 79.6 (68.7 to 87.5) | 74.1 (61.1 to 83.9) | 88.7 (81.5 to 93.3) | 85.1 (75.9 to 91.3) |
| Day 14 (n=86, 92, 91, 91, 95, 93, 84) | 41.1 (28.8 to 54.5) | 58.3 (44.7 to 70.6) | 50.5 (37.0 to 64.1) | 73.6 (61.8 to 82.8) | 67.1 (54.0 to 78.1) | 84.8 (76.4 to 90.6) | 80.3 (70.1 to 87.7) |
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.
| Percentage of maximal response* hours | 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. |
|---|---|---|---|---|---|---|---|
| Day 1 (n=89, 94, 93, 92, 96, 96, 87) | 23.9 (1.2 to 90.7) | 37.9 (2.4 to 95.2) | 54.4 (4.5 to 97.8) | 54.1 (4.7 to 97.6) | 69.5 (8.6 to 98.9) | 69.3 (9.0 to 98.8) | 81.1 (15.5 to 99.5) |
| Day 14 (n= 86, 92, 91, 91, 95, 93, 84) | 25.6 (15.5 to 42.5) | 40.1 (24.2 to 59.6) | 56.6 (31.3 to 78.2) | 56.4 (32.9 to 74.7) | 71.4 (41.4 to 87.8) | 71.2 (42.5 to 85.5) | 82.4 (51.2 to 93.5) |
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.
| Percentage of maximal response | 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. |
|---|---|---|---|---|---|---|---|
| Day 1 (n=83, 90, 91, 85, 89, 90, 83) | 35.1 (19.1 to 55.7) | 52.0 (32.0 to 71.6) | 44.4 (25.7 to 64.7) | 68.4 (48.5 to 83.4) | 61.5 (41.0 to 78.5) | 81.2 (65.3 to 91.0) | 76.1 (58.1 to 88.0) |
| Day 14 (n=84, 91, 88, 90, 90, 92, 78) | 27.1 (14.7 to 44.6) | 42.7 (25.7 to 61.7) | 35.5 (20.4 to 54.0) | 59.8 (40.9 to 76.3) | 52.4 (33.9 to 70.2) | 74.9 (58.0 to 86.6) | 66.7 (50.7 to 82.5) |
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.
| Percentage of maximal response | 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. |
|---|---|---|---|---|---|---|---|
| Day 1 (n=89, 94, 93, 91, 96, 96, 86) | 61.7 (47.4 to 74.7) | 76.0 (62.5 to 85.5) | 68.9 (54.1 to 81.1) | 86.1 (75.8 to 92.2) | 81.3 (68.7 to 89.6) | 92.3 (85.6 to 96.0) | 89.5 (80.6 to 94.5) |
| Day 7 (n=87, 93, 90, 92, 95, 94, 85) | 53.3 (41.2 to 65.5) | 69.2 (56.7 to 79.2) | 61.1 (48.2 to 73.4) | 81.5 (71.1 to 88.4) | 75.6 (63.4 to 84.7) | 89.6 (82.4 to 93.9) | 85.8 (76.5 to 91.7) |
| Day 14 (n=86, 92, 91, 91, 95, 93, 84) | 53.3 (41.2 to 65.5) | 69.2 (56.7 to 79.2) | 61.1 (48.2 to 73.4) | 81.5 (71.1 to 88.4) | 75.6 (63.4 to 84.7) | 89.6 (82.4 to 93.9) | 85.8 (76.5 to 91.7) |
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.
| Percentage of maximal response | 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. |
|---|---|---|---|---|---|---|---|
| Day 1 (n=88, 92, 91, 90, 94, 94, 87) | 22.8 (11.3 to 43.5) | 36.8 (19.6 to 60.9) | 52.9 (26.2 to 79.9) | 53.4 (30.7 to 75.8) | 68.7 (38.3 to 88.9) | 69.1 (43.4 to 86.3) | 81.0 (52.3 to 94.1) |
| Day 7 (n=87, 92, 90, 91, 95, 93, 85, 87) | 23.3 (11.2 to 45.2) | 37.4 (19.6 to 62.5) | 53.6 (26.3 to 81.2) | 54.0 (30.7 to 77.1) | 69.3 (38.3 to 89.7) | 69.7 (43.3 to 87.1) | 81.4 (52.0 to 94.6) |
| Day 14 (n= 85, 90, 91, 88, 94, 93, 81, 84) | 23.3 (11.3 to 45.3) | 37.4 (19.7 to 65.5) | 53.6 (26.4 to 81.2) | 54.0 (30.8 to 77.1) | 69.3 (38.5 to 89.7) | 69.7 (43.5 to 87.2) | 81.4 (52.2 to 94.6) |
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.
| Number of Puffs | 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 |
|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| Percentage of maximal response | 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. |
|---|---|---|---|---|---|---|---|
| Maximal Response of Incremental Once Daily and Twice Daily Doses of NVA237 That Each Dose Achieves in Relation to the Maximal Effect of NVA237 on Trough Forced Expiratory Volume in One Second at Day 28 | 27.1 ± 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| Trough Forced Expiratory Volume in One Second by Treatment at Day 28 | 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| Forced Expiratory Volume in One Second Area Under the Curve 0-24 Hours at Day 28 of Treatment | 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| Forced Expiratory Volume in One Second at 12 Hours on Day 28 of Treatment | 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| Peak Forced Expiratory Volume in One Second at Day 28 of Treatment | 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| Trough Forced Vital Capacity After 28 Days of Treatment | 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| 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 |
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.
| Liters | 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 |
|---|---|---|---|---|---|---|---|---|
| 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 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| NVA237 12.5 ug q.d. | — | 2/89 (2.2%) | 9/89 (10.1%) |
| NVA237 25 ug q.d. | — | 2/96 (2.1%) | 11/96 (11.5%) |
| NVA237 12.5 ug b.i.d. | — | 1/96 (1%) | 5/96 (5.2%) |
| NVA237 50 ug q.d. | — | 3/92 (3.3%) | 7/92 (7.6%) |
| NVA237 25 ug b.i.d. | — | 4/96 (4.2%) | 8/96 (8.3%) |
| NVA237 100 ug q.d. | — | 3/96 (3.1%) | 9/96 (9.4%) |
| NVA237 50 ug b.i.d. | — | 1/87 (1.1%) | 9/87 (10.3%) |
| Placebo | — | 3/91 (3.3%) | 14/91 (15.4%) |
| Event | 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 |
|---|---|---|---|---|---|---|---|---|
| Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders | 1/89 | 0/96 | 1/96 | 0/92 | 2/96 | 1/96 | 0/87 | 0/91 |
| Ventricular extrasystolesCardiac disorders | 0/89 | 0/96 | 0/96 | 0/92 | 0/96 | 0/96 | 1/87 | 0/91 |
| EpididymitisReproductive system and breast disorders | 1/89 | 0/96 | 0/96 | 0/92 | 0/96 | 0/96 | 0/87 | 0/91 |
| Angina pectorisCardiac disorders | 0/89 | 0/96 | 0/96 | 0/92 | 0/96 | 0/96 | 0/87 | 1/91 |
| Herpes zosterInfections and infestations | 0/89 | 0/96 | 0/96 | 0/92 | 0/96 | 0/96 | 0/87 | 1/91 |
| Respiratory tract infectionInfections and infestations | 0/89 | 0/96 | 0/96 | 0/92 | 0/96 | 0/96 | 0/87 | 1/91 |
| Sudden deathGeneral disorders | 0/89 | 0/96 | 0/96 | 1/92 | 0/96 | 0/96 | 0/87 | 0/91 |
| GastroenteritisInfections and infestations | 0/89 | 0/96 | 0/96 | 1/92 | 0/96 | 0/96 | 0/87 | 0/91 |
| Cerebrovascular accidentNervous system disorders | 0/89 | 0/96 | 0/96 | 1/92 | 0/96 | 0/96 | 0/87 | 0/91 |
| Gastrooesophageal reflux diseaseGastrointestinal disorders | 0/89 | 0/96 | 0/96 | 0/92 | 1/96 | 0/96 | 0/87 | 0/91 |
| Event | 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 |
|---|---|---|---|---|---|---|---|---|
| NasopharyngitisInfections and infestations | 4/89 | 8/96 | 2/96 | 4/92 | 3/96 | 4/96 | 5/87 | 6/91 |
| Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders | 6/89 | 3/96 | 1/96 | 0/92 | 3/96 | 2/96 | 1/87 | 4/91 |
| HeadacheNervous system disorders | 1/89 | 1/96 | 2/96 | 3/92 | 3/96 | 4/96 | 3/87 | 6/91 |
Baseline/demographic measures are based on safety set
| Age, Continuous(Years) | All Participants |
|---|---|
| Mean | 61.2 ± 7.91 |
| Sex: Female, Male(Participants) | All Participants |
|---|---|
| Female | 251 |
| Male | 135 |
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