Trial Outcomes & Findings for A Study to Assess the Safety, Tolerability and Efficacy of NVA237 Versus Placebo (NCT NCT01005901)

Last Updated: 2012-04-12

Results Overview

Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 hour 15 minute and 23 hour 45 minute post-dose FEV1 readings. Mixed model used baseline FEV1,baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1324 participants

Primary outcome timeframe

12 weeks

Results posted on

2012-04-12

Participant Flow

1324 participants were screened. 822 participants entered the study.

Participant milestones

Participant milestones
Measure	Glycopyrronium Bromide Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Overall Study STARTED	552	270
Overall Study Safety Population	550	267
Overall Study Full Analysis Set	534	260
Overall Study COMPLETED	450	212
Overall Study NOT COMPLETED	102	58

Reasons for withdrawal

Reasons for withdrawal
Measure	Glycopyrronium Bromide Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Overall Study Withdrawal by Subject	38	14
Overall Study Adverse Event	30	16
Overall Study Administrative problems	21	13
Overall Study Unsatisfactory therapeutic effect	5	5
Overall Study Protocol Violation	4	3
Overall Study Death	2	3
Overall Study Lost to Follow-up	1	2
Overall Study Patient's inability to use the device	1	1
Overall Study No longer requires study drug	0	1

Baseline Characteristics

A Study to Assess the Safety, Tolerability and Efficacy of NVA237 Versus Placebo

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Glycopyrronium Bromide n=550 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=267 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Total n=817 Participants Total of all reporting groups
Age, Customized <65 years	278 participants n=5 Participants	134 participants n=7 Participants	412 participants n=5 Participants
Age, Customized 65 to <75 years	199 participants n=5 Participants	98 participants n=7 Participants	297 participants n=5 Participants
Age, Customized >=75 years	73 participants n=5 Participants	35 participants n=7 Participants	108 participants n=5 Participants
Sex: Female, Male Female	96 Participants n=5 Participants	52 Participants n=7 Participants	148 Participants n=5 Participants
Sex: Female, Male Male	454 Participants n=5 Participants	215 Participants n=7 Participants	669 Participants n=5 Participants

PRIMARY outcome

Timeframe: 12 weeks

Population: Full Analysis Set (FAS) The FAS included all randomized patients who received at least one dose of study medication. Patients in this group were analyzed according to the treatment to which they were randomized. Missing trough FEV1 values at week 12 were imputed using LOCF with pre-dose trough FEV1.

Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 hour 15 minute and 23 hour 45 minute post-dose FEV1 readings. Mixed model used baseline FEV1,baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=512 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=243 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Trough Forced Expiratory Volume in 1 Second (FEV1) at 12 Weeks	1.408 Liters Standard Error 0.0105	1.301 Liters Standard Error 0.0137

SECONDARY outcome

Timeframe: 26 weeks

Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. Patients per treatment group with no missing data were included in this analysis.

Transition Dyspnea Index (TDI) captures changes from baseline. The TDI score is based on three domains with each domain scored from -3 (major deterioration) to +3 (major improvement), to give an overall score of -9 to +9, a negative score indicating a deterioration from baseline. A TDI focal score of 1 is considered to be a clinically significant improvement from baseline. Mixed model used baseline TDI, baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=493 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=240 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Transition Dyspnea Index (TDI) Focal Score After 26 Weeks of Treatment	1.84 Units on a scale Standard Error 0.257	0.80 Units on a scale Standard Error 0.294

SECONDARY outcome

Timeframe: 26 weeks

Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. Individual component score was imputed with LOCF (last observation carried forward).

SGRQ is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity, and impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life. Mixed model used baseline SGRQ, baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=502 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=246 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Quality of Life Assessment With St. George's Respiratory Questionnaire (SGRQ) Total Score After 26 Weeks of Treatment	39.50 Units on a scale Standard Error 0.813	42.31 Units on a scale Standard Error 0.992

SECONDARY outcome

Timeframe: 26 weeks

Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. The median values were not estimable.

The time to the first moderate or severe COPD exacerbation was the study day on which the patient experienced first moderate or severe COPD exacerbation. COPD exacerbations are considered to be moderate if treatment with systemic corticosteroids and/or antibiotics was required. COPD exacerbations are considered to be severe if treatment for moderate severity and hospitalization were required.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=534 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=260 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation During 26 Weeks of Treatment	NA Days The median values were not estimable because less than 50% of patients had a moderate or severe COPD exacerbation during the study.	NA Days The median values were not estimable because less than 50% of patients had a moderate or severe COPD exacerbation during the study.

SECONDARY outcome

Timeframe: 26 weeks

Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. Patients with observations both at baseline and week 26 were included in this analysis

Participants recorded the number of puffs of rescue medication taken in the previous 12 hours in the morning and evening. The total number of puffs of rescue medication per day over the full 26 weeks was calculated and divided by the total number of days with non-missing rescue medication data to derive the mean daily number of puffs of rescue medication taken for the patient.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=529 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=259 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Change From Baseline in the Mean Number of Puffs Per Day of Rescue Medication Over the Study Duration (Baseline to Week 26)	-1.21 Puffs per day Standard Error 0.122	-0.75 Puffs per day Standard Error 0.156

SECONDARY outcome

Timeframe: Day 1 and Week 26

Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. "n" indicates number of patients with observation at each time-point

Spirometry was conducted according to internationally accepted standards. FEV1 was measured at all time points up to 4 hours post-dose, and at 23 hours 15 min and 23 hours 45 min, by visit. Mixed model used baseline FEV1,baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=519 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=253 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
FEV1 at Each Time-point on Day 1 and Week 26 Day 1: 5 min (n = 497, 240)	1.388 Liters Standard Error 0.0057	1.295 Liters Standard Error 0.0076
FEV1 at Each Time-point on Day 1 and Week 26 Day 1: 15 min (n = 503, 249)	1.435 Liters Standard Error 0.0066	1.292 Liters Standard Error 0.0087
FEV1 at Each Time-point on Day 1 and Week 26 Day 1: 30 min (n = 511, 252)	1.472 Liters Standard Error 0.0070	1.299 Liters Standard Error 0.0093
FEV1 at Each Time-point on Day 1 and Week 26 Day 1: 1 hour (n = 513, 253)	1.493 Liters Standard Error 0.0070	1.296 Liters Standard Error 0.0094
FEV1 at Each Time-point on Day 1 and Week 26 Day 1: 2 hours (n = 514, 251)	1.562 Liters Standard Error 0.0076	1.355 Liters Standard Error 0.0102
FEV1 at Each Time-point on Day 1 and Week 26 Day 1: 3 hours (n = 519, 248)	1.544 Liters Standard Error 0.0079	1.349 Liters Standard Error 0.0108
FEV1 at Each Time-point on Day 1 and Week 26 Day 1: 4 hours (n = 514, 247)	1.548 Liters Standard Error 0.0077	1.365 Liters Standard Error 0.0105
FEV1 at Each Time-point on Day 1 and Week 26 Day 1: 23 hours 15 min (n = 499, 244)	1.400 Liters Standard Error 0.0078	1.289 Liters Standard Error 0.0103
FEV1 at Each Time-point on Day 1 and Week 26 Day 1: 23 hours 45 min (n = 498, 244)	1.428 Liters Standard Error 0.0083	1.328 Liters Standard Error 0.0108
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: pre-dose trough (n = 447, 208)	1.371 Liters Standard Error 0.0100	1.256 Liters Standard Error 0.0140
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: -45 min (n = 447, 208)	1.373 Liters Standard Error 0.0104	1.256 Liters Standard Error 0.0145
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: -15 min (n = 443, 205)	1.368 Liters Standard Error 0.0104	1.252 Liters Standard Error 0.0144
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: 5 min (n = 439, 208)	1.409 Liters Standard Error 0.0106	1.255 Liters Standard Error 0.0147
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: 15 min (n = 435, 205)	1.427 Liters Standard Error 0.0109	1.269 Liters Standard Error 0.0152
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: 30 min (n = 440, 207)	1.433 Liters Standard Error 0.0112	1.259 Liters Standard Error 0.0155
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: 1 hour (n = 438, 206)	1.459 Liters Standard Error 0.0115	1.251 Liters Standard Error 0.0159
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: 2 hours (n = 438, 203)	1.508 Liters Standard Error 0.0114	1.299 Liters Standard Error 0.0160
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: 3 hours (n = 439, 204)	1.504 Liters Standard Error 0.0124	1.299 Liters Standard Error 0.0170
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: 4 hours (n = 438, 205)	1.489 Liters Standard Error 0.0114	1.312 Liters Standard Error 0.0158
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: 23 hours 15 min (n = 434, 206)	1.386 Liters Standard Error 0.0118	1.267 Liters Standard Error 0.0158
FEV1 at Each Time-point on Day 1 and Week 26 Week 26: 23 hours 45 min (n = 434, 206)	1.396 Liters Standard Error 0.0116	1.282 Liters Standard Error 0.0157

SECONDARY outcome

Timeframe: Day 1 and Week 26

Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. "n" indicates number of patients with observation at each time-point.

Spirometry was conducted according to internationally accepted standards. FVC was calculated at each time point up to 4 hours post-dose and at 23 hours 15 min and 23 hours 45 min, by visit. Mixed model used baseline FVC, baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=534 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=260 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Day 1: 5 min (n = 497, 240)	2.887 Liters Standard Error 0.0132	2.675 Liters Standard Error 0.0173
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Day 1: 15 min (n = 503, 249)	2.943 Liters Standard Error 0.0147	2.660 Liters Standard Error 0.0188
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Day 1: 30 min (n = 511, 252)	2.948 Liters Standard Error 0.0155	2.637 Liters Standard Error 0.0199
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Day 1: 1hour (n = 513, 253)	3.019 Liters Standard Error 0.0148	2.669 Liters Standard Error 0.0198
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Day 1: 2 hours (n = 514, 251)	3.086 Liters Standard Error 0.0166	2.754 Liters Standard Error 0.0219
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Day 1: 3 hours (n = 519, 248)	3.096 Liters Standard Error 0.0168	2.783 Liters Standard Error 0.0227
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Day 1: 4 hours (n = 514, 247)	3.064 Liters Standard Error 0.0161	2.760 Liters Standard Error 0.0217
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Day 1: 23 hours 15 min (n = 499, 244)	2.895 Liters Standard Error 0.0169	2.693 Liters Standard Error 0.0221
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Day 1: 23 hours 45 min (n = 498, 244)	2.907 Liters Standard Error 0.0169	2.718 Liters Standard Error 0.0219
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: Pre-dose trough (n = 447, 208)	2.827 Liters Standard Error 0.0238	2.623 Liters Standard Error 0.0305
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: -45 min (n = 447, 208)	2.859 Liters Standard Error 0.0271	2.658 Liters Standard Error 0.0337
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: -15 min (n = 443, 205)	2.798 Liters Standard Error 0.0235	2.589 Liters Standard Error 0.0306
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: 5 min (n = 439, 208)	2.891 Liters Standard Error 0.0251	2.639 Liters Standard Error 0.0318
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: 15 min (n = 435, 205)	2.895 Liters Standard Error 0.0240	2.660 Liters Standard Error 0.0309
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: 30 min (n = 440, 207)	2.885 Liters Standard Error 0.0239	2.603 Liters Standard Error 0.0310
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: 1 hour (n = 438, 206)	2.938 Liters Standard Error 0.0256	2.625 Liters Standard Error 0.0329
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: 2 hours (n = 438, 203)	2.977 Liters Standard Error 0.0225	2.687 Liters Standard Error 0.0302
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: 3 hours (n = 439, 204)	3.016 Liters Standard Error 0.0270	2.742 Liters Standard Error 0.0345
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: 4 hours (n = 438, 205)	2.962 Liters Standard Error 0.0225	2.709 Liters Standard Error 0.0303
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: 23 hours 15 min (n = 434, 206)	2.884 Liters Standard Error 0.0257	2.673 Liters Standard Error 0.0322
Forced Vital Capacity (FVC) at Each Time-point on Day 1 and Week 26 Week 26: 23 hours 45 min (n = 434, 206)	2.859 Liters Standard Error 0.0234	2.669 Liters Standard Error 0.0306

SECONDARY outcome

Timeframe: Day 1, Week 12 and Week 26

Population: Serial spirometry group, a sub-set of the full analysis set of patients. Twelve hour serial spirometry was conducted in this subset of patients in selected centers at Day 1. At week 12/13 and week 26/27 a 24 hour serial spirometry was performed. "n" is the number of patients with non-missing observations at each time point.

The standardized (with respect to the length of time) area under the curve (AUC) for FEV1 was calculated using trapezoidal rule between 5 min and 12 h post dose at Week 1 Day 1, Week 12 and Week 26 for every patient in the serial spirometry subgroup. Mixed model used baseline FEV1,baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=169 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=83 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
FEV1 Area Under the Curve (AUC) (5 Min - 12 Hour) at Day 1, Week 12 and Week 26 Day 1 (n = 169, 83)	1.475 Liters Standard Error 0.0129	1.320 Liters Standard Error 0.0173
FEV1 Area Under the Curve (AUC) (5 Min - 12 Hour) at Day 1, Week 12 and Week 26 Week 12 (n = 153, 75)	1.433 Liters Standard Error 0.0179	1.284 Liters Standard Error 0.0244
FEV1 Area Under the Curve (AUC) (5 Min - 12 Hour) at Day 1, Week 12 and Week 26 Week 26 (n = 149, 70)	1.445 Liters Standard Error 0.0199	1.238 Liters Standard Error 0.0274

SECONDARY outcome

Timeframe: Week 12 and Week 26

The standardized (with respect to the length of time) area under the curve (AUC) for FEV1 was calculated using trapezoidal rule between 5 min and 23 h 45 min post dose at week12/week 13and week 26/week 27 where available for every patient in the serial spirometry subgroup. Mixed model used baseline FEV1,baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=169 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=83 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
FEV1 Area Under Curve (AUC) (5 Min - 23 Hour 45 Min) at Week 12 and Week 26 Week 12 (n = 153, 75)	1.401 Liters Standard Error 0.0167	1.268 Liters Standard Error 0.0228
FEV1 Area Under Curve (AUC) (5 Min - 23 Hour 45 Min) at Week 12 and Week 26 Week 26 (n = 149, 70)	1.412 Liters Standard Error 0.0185	1.213 Liters Standard Error 0.0254

SECONDARY outcome

Timeframe: Day 1 and Week 26

Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. If one of the 23 h 15 min or 23 h 45 min values are missing then the remaining non-missing value is taken as trough FEV1 or trough FVC. If both values are missing, then their trough FEV1 or trough FVC is regarded as missing

Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 hour 15 minute and 23 hour 45 minute post-dose FEV1 readings. Mixed model used baseline FEV1, baseline ICS use, FEV1 prior to inhalation of SABA, and FEV1 45 minutes post-inhalation of SABA as covariates. Trough FVC was defined as the average of the 23 hour 15 minute and 23 hour 45 minute post-dose FVC readings. Mixed model used baseline FVC, baseline ICS use, FEV1 prior to inhalation of SABA, and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=534 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=260 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Trough FEV1 and FVC at Day 1 and Week 26 Day 1: FEV1 (n = 508, 248)	1.414 Liters Standard Error 0.0075	1.309 Liters Standard Error 0.0099
Trough FEV1 and FVC at Day 1 and Week 26 Week 26: FEV1 (n = 461, 217)	1.387 Liters Standard Error 0.0112	1.275 Liters Standard Error 0.0150
Trough FEV1 and FVC at Day 1 and Week 26 Day 1: FVC (n = 508, 248)	2.901 Liters Standard Error 0.0154	2.705 Liters Standard Error 0.0202
Trough FEV1 and FVC at Day 1 and Week 26 Week 26: FVC (n = 438, 208)	2.867 Liters Standard Error 0.0236	2.668 Liters Standard Error 0.0300

SECONDARY outcome

Timeframe: Baseline, Day 1, Week 12 and Week 26

Population: The safety set included all patients who received at least one dose of study medication whether or not being randomized. A sub-set of the safety population had 24 hour Holter monitoring. "n" indicates patients with observations both at baseline and each endpoint.

The mean heart rate was collected with a 24 hour Holter monitor in a sub-set of the safety population. The change between baseline and day 1, week 12 and week 26 was calculated. The analysis of the Holter recordings was performed by a central facility. Data on heart rate, heart rate variability, supraventricular and ventricular ectopy were collected and assessed.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=42 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=23 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Change in 24-hourly Mean Heart Rate at Day 1, Week 12 and Week 26 Day 1: (n = 42, 23)	-1.77 beats per minute Standard Deviation 7.583	-1.28 beats per minute Standard Deviation 8.676
Change in 24-hourly Mean Heart Rate at Day 1, Week 12 and Week 26 Week 12: (n = 42, 20)	-1.99 beats per minute Standard Deviation 7.489	-1.70 beats per minute Standard Deviation 7.230
Change in 24-hourly Mean Heart Rate at Day 1, Week 12 and Week 26 Week 26: (n = 37, 22)	-4.40 beats per minute Standard Deviation 9.347	-2.60 beats per minute Standard Deviation 9.349

SECONDARY outcome

Timeframe: 26 Weeks and 30 Day follow-up

Population: The safety set included all patients who received at least one dose of study medication whether or not being randomized. Patients were randomized according to the treatment they received.

Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=550 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=267 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations Participants with at least one AE	317 participants	174 participants
Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations Death	3 participants	3 participants
Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations SAE(s)	41 participants	24 participants
Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations Discontinuation due to AE(s)	32 participants	19 participants
Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations Discontinuation due to SAE(s)	15 participants	8 participants
Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations Discontinuation due to non-SAE(s)	18 participants	11 participants
Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations AE leading to dose interruption	12 participants	8 participants
Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations AE requiring significant additional therapy	246 participants	155 participants
Number of Participants With Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations AE leading to new or prolonged hospitalization	35 participants	21 participants

SECONDARY outcome

Timeframe: 26 weeks

Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication.

One overall rate is calculated for the entire study population. Rate is the number of moderate or severe exacerbations per year = total number of moderate or severe exacerbations for all participants/total number of treatment years for all participants. COPD exacerbations were considered to be moderate if treatment with systemic corticosteroids and/or antibiotics was required. COPD exacerbations were considered to be severe if treatment for moderate severity and hospitalization were required.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=534 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=260 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Rate of Moderate or Severe COPD Exacerbations Over the 26 Week Treatment Period	0.43 exacerbations per year	0.59 exacerbations per year

SECONDARY outcome

Timeframe: 26 Weeks

Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication. At 26 weeks, the analysis is based on only patients with a value at both baseline and post-baseline.

The percentage of nights with no nighttime awakenings is defined as the total number of nights with no nighttime awakenings over the 26 week treatment period divided by the total number of night where diary recordings have been made. Mixed model used baseline nighttime awakenings, baseline ICS use, FEV1 prior to inhalation of SABA, and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=527 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=258 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Percentage of Nights With no Nighttime Awakenings Over the 26 Week Treatment Period	55.96 percentage of nights with no awakenings Standard Error 1.537	54.37 percentage of nights with no awakenings Standard Error 1.970

SECONDARY outcome

Timeframe: 26 Weeks

The percentage of days with no daytime symptoms is defined as the total number of days with no daytime symptoms over the 26 week treatment period divided by the total number of days where diary recordings have been made. Mixed model used baseline daytime symptoms, baseline ICS use, FEV1 prior to inhalation of SABA, and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=528 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=258 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Percentage of Days With no Daytime Symptoms Over the 26 Week Treatment Period	5.70 percentage of days with no symptoms Standard Error 0.799	5.78 percentage of days with no symptoms Standard Error 1.076

SECONDARY outcome

Timeframe: 26 Weeks

The percentage of days able to perform usual daily activities is defined as the total number of days able to perform usual activities over the 26 week treatment period divided by the total number of days where diary recordings have been made. Mixed model used baseline ability to perform usual daily activities, baseline ICS use, FEV1 prior to inhalation of SABA, and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=528 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=258 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Percentage of Days Able to Perform Usual Daily Activities Over the 26 Week Treatment Period	40.31 percentage of days Standard Error 1.473	35.19 percentage of days Standard Error 1.907

SECONDARY outcome

Timeframe: 26 Weeks

Population: Full Analysis Set (FAS) included all randomized patients who received at least one dose of study medication.

The daily symptom score was calculated as the sum of the worst of the morning and evening assessments for each symptom (symptoms, cough, wheeze, sputum color/production, and breathlessness). The score can range from 0 to 18 with 0 indicating no symptoms. The higher the score, the worse the symptomatic status. A negative change (lower number) indicates improvement. Mixed model used baseline symptom variables, baseline inhaled corticosteroid (ICS) use, FEV1 prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates.

Outcome measures

Outcome measures
Measure	Glycopyrronium Bromide n=534 Participants Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=260 Participants Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Mean Daily Total Symptom Score Over the 26 Week Treatment Period	-1.54 units on a scale Standard Error 0.097	-1.18 units on a scale Standard Error 0.129

Adverse Events

Glycopyrronium Bromide

Serious events: 41 serious events

Other events: 132 other events

Deaths: 0 deaths

Placebo

Serious events: 24 serious events

Other events: 85 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Glycopyrronium Bromide n=550 participants at risk Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=267 participants at risk Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Blood and lymphatic system disorders Anaemia	0.00% 0/550	0.37% 1/267
Cardiac disorders Atrial fibrillation	0.55% 3/550	0.00% 0/267
Cardiac disorders Bradycardia	0.18% 1/550	0.00% 0/267
Cardiac disorders Cardiac arrest	0.00% 0/550	0.37% 1/267
Cardiac disorders Cardiac failure congestive	0.36% 2/550	0.00% 0/267
Cardiac disorders Myocardial infarction	0.36% 2/550	0.37% 1/267
Cardiac disorders Myocardial ischaemia	0.00% 0/550	0.75% 2/267
Eye disorders Cataract	0.18% 1/550	0.00% 0/267
Gastrointestinal disorders Abdominal pain	0.00% 0/550	0.37% 1/267
Gastrointestinal disorders Colonic polyp	0.18% 1/550	0.00% 0/267
Gastrointestinal disorders Diverticulum intestinal haemorrhagic	0.00% 0/550	0.37% 1/267
Gastrointestinal disorders Dyspepsia	0.18% 1/550	0.00% 0/267
Gastrointestinal disorders Gastric ulcer	0.18% 1/550	0.00% 0/267
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.18% 1/550	0.00% 0/267
Gastrointestinal disorders Vomiting	0.00% 0/550	0.37% 1/267
General disorders Death	0.00% 0/550	0.37% 1/267
General disorders Pyrexia	0.00% 0/550	0.37% 1/267
Hepatobiliary disorders Hepatic cirrhosis	0.18% 1/550	0.00% 0/267
Infections and infestations Lower respiratory tract infection bacterial	0.00% 0/550	0.37% 1/267
Infections and infestations Pneumonia	0.73% 4/550	0.75% 2/267
Infections and infestations Respiratory tract infection	0.00% 0/550	0.37% 1/267
Infections and infestations Tracheobronchitis	0.18% 1/550	0.00% 0/267
Infections and infestations Upper respiratory tract infection	0.00% 0/550	0.75% 2/267
Infections and infestations Upper respiratory tract infection bacterial	0.55% 3/550	0.75% 2/267
Infections and infestations Urinary tract infection bacterial	0.00% 0/550	0.37% 1/267
Injury, poisoning and procedural complications Fall	0.18% 1/550	0.00% 0/267
Injury, poisoning and procedural complications Pelvic fracture	0.18% 1/550	0.00% 0/267
Injury, poisoning and procedural complications Rib fracture	0.18% 1/550	0.37% 1/267
Injury, poisoning and procedural complications Spinal compression fracture	0.18% 1/550	0.00% 0/267
Injury, poisoning and procedural complications Traumatic brain injury	0.18% 1/550	0.00% 0/267
Metabolism and nutrition disorders Dehydration	0.00% 0/550	0.37% 1/267
Metabolism and nutrition disorders Type 2 diabetes mellitus	0.18% 1/550	0.00% 0/267
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.18% 1/550	0.00% 0/267
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder neoplasm	0.00% 0/550	0.37% 1/267
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic neoplasm malignant	0.18% 1/550	0.00% 0/267
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lipoma	0.18% 1/550	0.00% 0/267
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm	0.36% 2/550	0.00% 0/267
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.18% 1/550	0.37% 1/267
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastasis	0.18% 1/550	0.00% 0/267
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-Hodgkin's lymphoma	0.18% 1/550	0.00% 0/267
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.00% 0/550	0.37% 1/267
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid cancer	0.00% 0/550	0.37% 1/267
Nervous system disorders Cerebrovascular accident	0.18% 1/550	0.00% 0/267
Nervous system disorders Syncope	0.36% 2/550	0.00% 0/267
Psychiatric disorders Confusional state	0.18% 1/550	0.00% 0/267
Psychiatric disorders Depression	0.18% 1/550	0.00% 0/267
Psychiatric disorders Suicidal ideation	0.18% 1/550	0.00% 0/267
Renal and urinary disorders Haematuria	0.00% 0/550	0.37% 1/267
Renal and urinary disorders Renal failure acute	0.18% 1/550	0.00% 0/267
Renal and urinary disorders Urinary retention	0.18% 1/550	0.00% 0/267
Reproductive system and breast disorders Prostatomegaly	0.18% 1/550	0.00% 0/267
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.18% 1/550	0.00% 0/267
Respiratory, thoracic and mediastinal disorders Atelectasis	0.18% 1/550	0.00% 0/267
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.6% 9/550	4.1% 11/267
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.36% 2/550	0.00% 0/267
Respiratory, thoracic and mediastinal disorders Hypoxia	0.18% 1/550	0.00% 0/267
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.18% 1/550	0.00% 0/267
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.36% 2/550	0.00% 0/267
Skin and subcutaneous tissue disorders Dermatitis psoriasiform	0.18% 1/550	0.00% 0/267
Vascular disorders Aortic stenosis	0.18% 1/550	0.00% 0/267
Vascular disorders Deep vein thrombosis	0.18% 1/550	0.00% 0/267

Other adverse events

Other adverse events
Measure	Glycopyrronium Bromide n=550 participants at risk Glycopyrronium bromide 50µg delivered once daily via Single Dose Dry Powder Inhaler (SDDPI). At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.	Placebo n=267 participants at risk Placebo delivered once daily via SDDPI. At Visit 1 all patients were provided with a short acting β2-agonist (salbutamol/albuterol) which they were instructed to use throughout the study as rescue medication.
Infections and infestations Nasopharyngitis	5.1% 28/550	7.9% 21/267
Infections and infestations Upper respiratory tract infection	4.2% 23/550	7.5% 20/267
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	19.1% 105/550	25.1% 67/267

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

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

Restriction type: OTHER