Efficacy, Safety, and Tolerability of NVA237 Compared to Tiotropium in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The trough in FEV1 was defined as the mean of two measurements at 23hours 15min and 23 hours 45min post dosing. ANCOVA model: Trough FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center (region). This analysis excluded values within 6 hours of rescue medication use or 7 days of systemic corticosteroid use.

Time frame: Week 12

Population: The per-protocol set included all randomized patients who received at least one dose of study drug, with available data and without any major protocol deviations or who did not take study drug as per protocol in the 14 day period prior to trough.

A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours. Baseline mean daily, daytime and nighttime (combined) number of puffs is defined as the average of the respective number of puffs. Only patients with a value at both baseline and post-baseline visits were included.

Time frame: Baseline and Day 1 to Week 12

Population: The per-protocol set included all randomized patients who received at least one dose of study drug, with a value at both baseline and post-baseline visits were included.

Event free rate was calculated as a percentage of participants who did not experience any moderate or severe COPD exacerbation leading to hospitalization/treatment with systemic corticosteroids/treatment with antibiotics. The event free rate reflects the percent of patients who did NOT have an exacerbation by 4, 8 and 12 weeks. Event-free rates are calculated at the end of the specified weeks (i.e. Day 29, Day 57 and Day 85) by the Kaplan Meier method.

Time frame: Weeks 4, 8 and 12

Population: The per-protocol set included all randomized patients who received at least one dose of study drug, with available data and without any major protocol deviations and described as patients with moderate to severe exacerbations were included in this analysis.

Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEV1 was analyzed using Analysis of Covariance (ANCOVA) model: FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region.

Time frame: (5,15,30 min, 1, 2,3,4 h, 23h 15 min and 23h 45 min postdose of Day 1), (-45, -15 min predose, 5,15,30 min, 1h, 23h 15 min and 23h 45 min postdose of Week 4), (-45, -15 min predose, 5,15,30 min, 1, 2, 3,4 h, 23h 15 min and 23h 45 min postdose of Week 12)

Population: The per-protocol set included all randomized patients who received at least one dose of study drug, with available data and without any major protocol deviations

Forced Vital Capacity (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. ANCOVA model: FVC = treatment + baseline FVC + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region.

Time frame: (5,15,30 min, 1, 2,3,4 h, 23h 15 min and 23h 45 min postdose of Day 1), (-45, -15 min predose, 5,15,30 min, 1h, 23h 15 min and 23h 45 min postdose of Week 4), (-45, -15 min predose, 5,15,30 min, 1, 2, 3,4 h, 23h 15 min and 23h 45 min postdose of Week 12)

Population: The per-protocol set included all randomized patients who received at least one dose of study drug, with available data and without any major protocol deviations

IC was measured with spirometry conducted according to internationally accepted standards. ANCOVA model: IC = treatment + baseline IC + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region.

Time frame: (25 min, 1 h 55 min, 3 h 55 min, 23 h 40 min Day 1), (-20 min, 25 min, 23 h 40 min Week 4),(-20 min, 25 min, 1 h 55 min, 3 h 55 min, 23 h 40 min Week 12)

Population: The per-protocol set included all randomized patients who received at least one dose of study drug, with available data and without any major protocol deviations

Participants completed eDiaries providing scores 0 to 3 for symptoms: Cough and wheeze (none, mild, moderate, severe); sputum volume (none, less than 5 mL, 5-25 mL, \>25 mL); sputum color (none, white-grey, yellow, green); lowest level of activity causing breathlessness (never or only when running, when walking uphill or upstairs, when walking on flat ground, at rest). Symptoms in the morning, for the previous night (no waking due to symptoms, woke up once due to symptoms, woke up more than once due to symptoms, woke up frequently or could not sleep due to symptoms). Symptoms experienced during the day that had prevented them for performing normal activities (not at all, a little, quite a lot, completely). The mean change from baseline in the total scores and in the individual scores was summarized by treatment. Only participants with a value at both baseline and post-baseline were included. Possible total scores 0-18 (night); 0-36 (day). A higher score means worsening of symptoms.

Time frame: 12 weeks

Population: The per-protocol set included all randomized patients who received at least one dose of study drug. Only patients with a value at both baseline and post-baseline are included.

Spirometry was conducted according to internationally accepted standards. Peak FEV1 is the maximum FEV1 recorded during first 4 hours post dose. ANCOVA model: Peak FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center (region). Center is included as a random effect nested within region. This analysis excludes values within 6 hours of rescue medication use or 7 days of systemic corticosteroid use.

Time frame: 5 min to 4 hours post-dose at Day 1 and Week 12

Population: The per-protocol set included all randomized patients who received at least one dose of study drug, with available data and without any major protocol deviations

Forced Expiratory Volume in one second (FEV1) was measured with spirometry conducted according to internationally accepted standards. Area Under the Curve (AUC) is calculated using the trapezoidal rule using the existing FEV1 measurements (i.e., the missing FEV1 measurements are not interpolated). ANCOVA model: FEV1 AUC = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region.

Time frame: Day 1 and week 12

Population: The per-protocol set included all randomized patients who received at least one dose of study drug, with available data and without any major protocol deviations.

St. George's Respiratory Questionnaire (SGRQ) is a health related quality of life questionnaire consisting of 51 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. ANCOVA model: SGRQ total score = treatment + baseline SGRQ score + baseline ICS use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center (region).

Time frame: Week 12

Population: The per-protocol set included all randomized patients who received at least one dose of study drug, with available data and without any major protocol deviations.

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. ANCOVA model: TDI focal score = treatment + Baseline dyspnea index (BDI) + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region.

Time frame: Weeks 4 and 12

Population: The per-protocol set included all randomized patients who received at least one dose of study drug, with available data and without any major protocol deviations.

FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The trough in FEV1 was defined as the mean of two measurements at 23h 15min and 23h 45min post dosing. ANCOVA model: Trough FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). This analysis excluded values within 6 hours of rescue medication use or 7 days of systemic corticosteroid.

Time frame: Week 12

Population: The Full Analysis Set (FAS) includes all randomized patients who received at least one dose of study drug and had available data for analysis.

FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. Trough FEV1 is defined as the average of the post-dose 23 h 15 min and the 23 h 45 min FEV1 values. Trough assessments taken outside 22 h 45 min - 24 h 15 min are excluded from this analysis. ANCOVA model: Trough FEV1 = treatment + baseline FEV1 + baseline Inhaled corticosteroid (ICS) use (Yes/No) + FEV1 reversibility components + baseline smoking status + region + center(region). Center is included as a random effect nested within region.

Time frame: Day 1 and Week 4

Population: The per-protocol set included all randomized patients who received at least one dose of study drug, with available data and without any major protocol deviations or who did not take study drug as per protocol in the 14 day period prior to trough.