Efficacy and Safety Comparison of Tiotropium Daily + Salmeterol Daily or Twice Daily Versus Tiotropium Daily in Patients With COPD

FEV1 AUC was defined as the area under the FEV1 curve normalized for time. It was calculated from time 0 to 12 h (FEV1 AUC0-12), using the trapezoidal rule divided by the corresponding duration (12 h) to give the results in liter (L). FEV1 AUC0-12h response is defined as the change from baseline: FEV1 AUC0-12h response = FEV1 AUC0-12h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

The FEV1 AUC was defined as the area under the FEV1 curve (AUC) normalised for time. It was calculated from time 12 to 24 h (FEV1 AUC12-24), using the trapezoidal rule divided by the corresponding duration (i.e. 12 h) to give the results in L. AUC12-24h response is defined as the change from baseline: FEV1 AUC12-24h response = FEV1 AUC12-24h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit (Visit 2) just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Peak FEV1 was defined as the highest FEV1 reading observed within 3 hours after inhalation of the last morning dose of each randomized treatment. Peak FEV1 response is defined as change from baseline: Peak FEV1 response = Peak FEV1 - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Trough FEV1 is determined at the end of each treatment period and is defined as the pre-dose FEV1 measured just prior to the last administration of the morning dose of randomized treatment. Trough FEV1 response is defined as the change from baseline: Trough FEV1 response = Trough FEV1 - FEV1 (Baseline) The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Number of participants with drug related adverse events.

Time frame: From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.

Population: Treated Set (TS): All randomised patients who took at least one dose of study medication.

Marked changes from baseline in vital signs were defined as followed: Systolic blood pressure * Increase of ≥25 millimetre of mercury (mmHg) above baseline * Decrease below 100 mmHg if not at that level at baseline and a decrease of \>10 mmHg below baseline Diastolic blood pressure * Increase above 90 mmHg and an increase of \>10 mmHg above baseline * Decrease below 60 mmHg if not at that level at baseline and a decrease of \>10 mmHg below baseline Pulse * Increase above 100 bpm if not at that level at baseline and an increase of \>10 bpm above baseline * Decrease below 60 bpm if not at that level at baseline and a decrease of \>10 bpm below baseline Baseline is defined as the pre-dose measurement at randomisation visit.

Time frame: At baseline and 6 hours following the morning dose of study medication after 6 weeks of treatment.

Population: Treated Set (TS): All randomised patients who took at least one dose of study medication and who had available data.

Response in average shortness of breath (SOB) score at night. The SOB measured the shortness of breath, ranging from 1 to 5, where 1 = not at all, 2 = a little bit, 3 = somewhat, 4 = quite a bit and 5 = very much. A higher score indicates a worse outcome. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating the mean.

Time frame: At baseline and last 3 weeks of 6-week treatment period.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

FEV1 AUC was defined as the area under the FEV1 curve normalized for time. It was calculated from time 0 to 24 h (FEV1 AUC0-24), using the trapezoidal rule divided by the corresponding duration (24 h) to give the results in liter (L). FEV1 AUC0-24h response is defined as the change from baseline: FEV1 AUC0-24h response = FEV1 AUC0-24h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

The FVC AUC was defined as the area under the FVC curve (AUC) normalised for time. It was calculated from time 0 to 24 h (FVC AUC0-24), using the trapezoidal rule divided by the corresponding duration (i.e. 24 h) to give the results in L. AUC response was defined as the change from the baseline FVC; baseline was defined as the FVC measured on randomisation visit. Mean is adjusted mean.

Time frame: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hour after inhalation the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

FVC AUC was defined as the area under the FVC curve normalized for time. It was calculated from time 0 to 12 h (FVC AUC0-12), using the trapezoidal rule divided by the corresponding duration (12 h) to give the results in liter (L). FVC AUC0-12h response is defined as the change from baseline: FVC AUC0-12h response = FVC AUC0-12h - FVC (Baseline). The baseline value for FVC based parameters is defined as the pre-dose FVC measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

The FVC AUC was defined as the area under the FVC curve (AUC) normalised for time. It was calculated from time 12 to 24 h (FVC AUC12-24), using the trapezoidal rule divided by the corresponding duration (i.e. 12 h) to give the results in L. AUC12-24h response is defined as the change from baseline: FVC AUC12-24h response = FVC AUC12-24h - FVC (Baseline). The FVC baseline value is defined as the pre-dose FVC measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 10, 11 and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Response in individual forced expiratory volume in 1 second (FEV1) over a 24 hour observation period. Response is defined as change from baseline. Means are adjusted for treatment, centre, treatment period and patient within centre.

Time frame: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23, and 24 hours post morning dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Response in forced vital capacity (FVC) over a 24 hour observation period. Response is defined as change from baseline.

Time frame: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23 and 24 hours post morning dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Response in individual peak expiratory flow (PEF) over a 24 hour observation period. Response is defined as change from baseline. Means are adjusted for treatment, centre, treatment period and patient within centre.

Time frame: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23, and 24 hours post morning dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Response in mean number of days with night-time awakenings. Per treatment period, the mean number days with awakening during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating this mean. Mean number of days with night-time awakenings response is defined as the change from baseline. The baseline value, mean number of days with night-time awakenings (Baseline), is defined as the mean of the number of days with night-time awakenings obtained from the last week preceding the randomization visit.

Time frame: At baseline and last 3 weeks of 6-week treatment period.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Per treatment period, the mean number days with awakening (only chronic obstructive pulmonary disease (COPD) related awakenings) during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating the mean. Mean number of days with COPD related awakenings response is defined as the change from baseline. The baseline value, mean number of days with COPD related awakenings (Baseline), is defined as the mean of the number of days with COPD related awakenings obtained from the last week preceding the randomization visit.

Time frame: At baseline and last 3 weeks of 6-week treatment period.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Response (change from baseline) in mean number of days with rescue medication use in day-time, night-time and 24-hours. Per treatment period, the response in mean number of days using rescue medication was calculated for day-time (from inhalation of morning dose until 12 hours thereafter), night-time (from inhalation of evening dose until 12 hours thereafter) and 24h-total (from inhalation of morning dose until 24 hours thereafter) separately. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating means. Mean is adjusted mean.

Time frame: At baseline and last 3 weeks of 6-week treatment period.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Response in mean number of puffs of rescue medication. Per treatment period, the response in mean number of puffs rescue medication used was calculated, for day-time (from inhalation of morning dose until 12 hours thereafter), night-time (from inhalation of evening dose until 12 hours thereafter) and 24h-total (from inhalation of morning dose until 24 hours thereafter) separately. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating means. Night-time, day-time and 24h-total mean number of puffs rescue medication used responses are defined as the change from night-time, day-time and 24h-total baseline, respectively. The baseline values, night-time, day-time and 24h-total mean mean number of puffs rescue medication used (Baseline), are defined as the mean of the night-time, day-time and 24h-total values, respectively obtained from the last week preceding the randomisation visit.

Time frame: At baseline and last 3 weeks of 6-week treatment period.

Population: Full Analysis Set (FAS): All patients where baseline data any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Per treatment period, the mean number of awakening (only chronic obstructive pulmonary disease (COPD) related awakenings) during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating this mean. Mean number of COPD related awakenings response is defined as the change from baseline. The baseline value, mean number of COPD related awakenings (Baseline), is defined as the mean of the number of days with COPD related awakenings obtained from the last week preceding the randomization visit.

Time frame: At baseline and last 3 weeks of 6-week treatment period.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Per treatment period, the morning mean FEV1 (mean of the pre-dose morning FEV1 measurements) and evening mean FEV1 (mean of the pre-dose evening FEV1 measurement) were calculated. Per treatment period the data obtained after the first 3 weeks were used for calculating these means. Morning and evening mean FEV1 responses are defined as the change from morning and evening baseline, respectively. The baseline values, morning and evening mean FEV1(Baseline), are defined as the mean of the morning and evening values, respectively obtained from the last week preceding the randomization visit . Mean is adjusted for treatment, centre, treatment period and patient within centre.

Time frame: At baseline and last 3 weeks of 6-week treatment period.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-Treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

The mean PEF is defined as the mean of the values obtained during the weeks after the first three weeks of treatment. Morning and evening mean PEF were calculated and analyzed separately. PEF was measured twice daily (in the morning prior to inhalation of study medication and in the evening prior to inhalation of study medication). Morning and evening mean PEF response are defined as the change from morning and evening baseline, respectively. Morning and evening mean PEF baseline are defined as the mean of the morning and evening values, respectively obtained from the last week preceding the randomization visit. Mean is adjusted for treatment, center, treatment period and patient within center.

Time frame: At baseline and last 3 weeks of 6-week treatment period.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-Treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints

PEF(L/min) AUC0-12(h) response is defined as the change from baseline. AUC0-12(h) was calculated as the area under the curve from 0 to 12 hours using the trapezoidal rule, divided by the full duration (12 hours) to report in liter/minutes. PEF AUC0-12h response = PEF AUC0-12h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and 10 minutes (min) prior and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

PEF(L/min) AUC0-24(h) response is defined as the change from baseline. AUC0-24(h) was calculated as the area under the curve from 0 to 24 hours using the trapezoidal rule, divided by the full duration (24 hours) to report in liter/minutes. PEF AUC0-24h response = PEF AUC0-24h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

PEF(L/min) AUC12-24(h) response is defined as the change from baseline. AUC12-24(h) was calculated as the area under the curve from 12 to 24 hours using the trapezoidal rule, divided by the full duration (12 hours) to report in liter/minutes. PEF AUC12-24h response = PEF AUC12-24h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and 10 minutes (min) prior and 30 min, 60 min, 2, 10, 11 and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Peak FEV1 was defined as the highest FEV1 reading observed within 3 hours after inhalation of the last morning dose of each randomized treatment. Peak FEV1 response is defined as change from baseline: Peak FEV1 response = Peak FEV1 - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analyzed may vary across endpoints.

Peak PEF was defined as the highest PEF reading observed within 3 hours after inhalation of the last morning dose of randomized treatment. Peak PEF response is defined as change from baseline: Peak PEF response = Peak PEF - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Trough FVC1 is determined at the end of each 6-week treatment period and is defined as the pre-dose FVC1 measured just prior to the last administration of the morning dose of randomized treatment. Trough FVC1 response is defined as the change from baseline: Trough FVC1 response = Trough FVC1 - FVC1 (Baseline) The FVC1 baseline value is defined as the pre-dose FVC1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.

Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.

Trough PEF is determined at the end of each treatment period and is defined as the pre-dose PEF measured just prior to the last administration of the morning dose of randomized treatment. Trough PEF response is defined as the change from baseline: Trough PEF response = Trough PEF - PEF (Baseline) The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Time frame: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.

Population: Full Analysis Set: All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.