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

A Randomised, Double-blind Clinical Efficacy and Safety Comparison of Tiotropium/Salmeterol 7.5/25 Inhalation Powder in the Morning Via Tiotropium/Salmeterol HandiHaler, Tiotropium 18 Mcg Inhalation Powder in the Morning Via Spiriva HandiHaler, Salmeterol 50 Mcg MDPI in the Morning and Evening and the Free Combination Tiotropium 18 Mcg Inhalation Powder in the Morning Via Spiriva HandiHaler Plus Salmeterol 50 Mcg MDPI in the Morning and Evening Following Chronic Administration (6-week Treatment Periods) in Patients With COPD

The primary objective of this trial is to establish superiority of the once-daily Tiotropium plus Salmeterol Inhalation Powder in daytime lung function response and non-inferiority in night-time lung function response over the comparator treatments inhaled in their established dose regimens when administered for 6-week periods to patients with chronic obstructive pulmonary disease (COPD). The main secondary objective is to evaluate the safety of the Tiotropium plus Salmeterol Inhalation Powder versus the comparator treatments.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: Tiotropium (Tio18GEL); Drug: Salmeterol MDPI (Salm50DPI); Drug: Tiotropium (T18GEL) + Salmeterol MDPI (S_DPI); Drug: Tiotropium/Salmeterol (T+S_PE)

• Study Type: Interventional
• Enrollment (Actual): 147
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
    • 1184.13.1302 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1184.13.1309 Boehringer Ingelheim Investigational Site
  • Cottbus, Germany
    • 1184.13.1308 Boehringer Ingelheim Investigational Site
  • Großhansdorf, Germany
    • 1184.13.1311 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1184.13.1312 Boehringer Ingelheim Investigational Site
  • Mainz, Germany
    • 1184.13.1305 Boehringer Ingelheim Investigational Site
  • Mannheim, Germany
    • 1184.13.1301 Boehringer Ingelheim Investigational Site
  • Rodgau-Dudenhofen, Germany
    • 1184.13.1306 Boehringer Ingelheim Investigational Site
  • Rüdersdorf, Germany
    • 1184.13.1310 Boehringer Ingelheim Investigational Site
  • Schwerin, Germany
    • 1184.13.1307 Boehringer Ingelheim Investigational Site
  • Wiesbaden, Germany
    • 1184.13.1304 Boehringer Ingelheim Investigational Site
  • Wiesloch, Germany
    • 1184.13.1303 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. All patients must sign an informed consent consistent with ICH-GCP guidelines and local legislations prior to any study-related procedures, which includes medication washout and restrictions.

2. All patients must have a diagnosis of COPD and must meet the following criteria:

   relatively stable* airway obstruction with a post-bronchodilator FEV1 < 80% of predicted normal and post-bronchodilator FEV1 < 70% of post-bronchodilator FVC at Visit 1 (according to GOLD criteria).

   * The randomisation of patients with any respiratory infection or COPD exacerbation in the 6 weeks prior to the Screening Visit (Visit 1) or during the baseline period should be postponed. Patients may be randomised 6 weeks following recovery from the infection or exacerbation. Predicted normal values will be calculated according to ECSC.

3. Male or female patients 40 years of age or older.
4. Patients must be current or ex-smokers with a smoking history of 10 pack-years.
5. Patients must be able to perform technically acceptable pulmonary function tests
6. Patients must be able to inhale medication in a competent manner.
7. Patients must be able to perform all necessary recordings in the diary.

Exclusion Criteria:

1. Significant diseases other than COPD
2. Patients with clinically significant abnormal baseline haematology, blood chemistry or urinalysis, if the abnormality defines a significant disease as defined in exclusion criterion No. 1.
3. Patients with a recent history of myocardial infarction.
4. Patients with any unstable or life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the past year.
5. Hospitalisation for cardiac failure during the past year.
6. Malignancy within the last five years excluded basal cell carcinoma.
7. Patients with a history of asthma or who have a total blood eosinophil count 600/mm3.
8. Patients with a history of life threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis.
9. Known active tuberculosis.
10. Patients with a history of alcohol or drug abuse.
11. Thoracotomy with pulmonary resection.
12. Rehabilitation program within the last six weeks
13. Patients who regularly use daytime oxygen therapy
14. Patients who have taken an investigational drug within 30 days
15. Use of not allowed medications
16. Known hypersensitivity to used drugs or other components of the study medication.
17. Pregnant or nursing women
18. Women of childbearing potential not using a highly effective method of birth control. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years.
19. Patients who are currently participating in another study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: T+S_PE/ Tio18GEL / Salm50DPI / T18GEL+S_DPI; 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S_PE)/ 18 µg Tiotropium (Tio18GEL) / 50 µg Salmeterol MDPI (Salm50DPI) / 18 µg Tiotropium (T18GEL) plus 50 µg Salmeterol MDPI (S_DPI) BID	Drug: Tiotropium (Tio18GEL); 18 µg Tiotropium (Tio18GEL) inhalation powder; Drug: Salmeterol MDPI (Salm50DPI); 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID); Drug: Tiotropium (T18GEL) + Salmeterol MDPI (S_DPI); 18 µg Tiotropium (T18GEL) inhalation powder plus 50 µg Salmeterol MDPI (S_DPI) twice daily (BID); Drug: Tiotropium/Salmeterol (T+S_PE); Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S_PE) inhalation powder
Experimental: Tio18GEL/ T18GEL+S_DPI/ T+S_PE/ Salm50DPI; 18 µg Tiotropium (Tio18GEL) / 18 µg Tiotropium (T18GEL) + 50 µg Salmeterol MDPI (S_DPI) BID / 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S_PE) / 50 µg Salmeterol MDPI (Salm50DPI)	Drug: Tiotropium (Tio18GEL); 18 µg Tiotropium (Tio18GEL) inhalation powder; Drug: Salmeterol MDPI (Salm50DPI); 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID); Drug: Tiotropium (T18GEL) + Salmeterol MDPI (S_DPI); 18 µg Tiotropium (T18GEL) inhalation powder plus 50 µg Salmeterol MDPI (S_DPI) twice daily (BID); Drug: Tiotropium/Salmeterol (T+S_PE); Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S_PE) inhalation powder
Experimental: Salm50DPI/ T+S_PE/ T18GEL+S_DPI/ Tio18GEL; 50 µg Salmeterol MDPI (Salm50DPI) / 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S_PE) / 18 µg Tiotropium (T18GEL) + 50 µg Salmeterol MDPI (S_DPI) BID / 18 µg Tiotropium (Tio18GEL)	Drug: Tiotropium (Tio18GEL); 18 µg Tiotropium (Tio18GEL) inhalation powder; Drug: Salmeterol MDPI (Salm50DPI); 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID); Drug: Tiotropium (T18GEL) + Salmeterol MDPI (S_DPI); 18 µg Tiotropium (T18GEL) inhalation powder plus 50 µg Salmeterol MDPI (S_DPI) twice daily (BID); Drug: Tiotropium/Salmeterol (T+S_PE); Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S_PE) inhalation powder
Experimental: T18GEL+S_DPI/ Salm50DPI/ Tio18GEL/ T+S_PE; 18 µg Tiotropium (T18GEL) + 50 µg Salmeterol MDPI (S_DPI) BID / 50 µg Salmeterol MDPI (Salm50DPI) / 18 µg Tiotropium (Tio18GEL) / 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S_PE)	Drug: Tiotropium (Tio18GEL); 18 µg Tiotropium (Tio18GEL) inhalation powder; Drug: Salmeterol MDPI (Salm50DPI); 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID); Drug: Tiotropium (T18GEL) + Salmeterol MDPI (S_DPI); 18 µg Tiotropium (T18GEL) inhalation powder plus 50 µg Salmeterol MDPI (S_DPI) twice daily (BID); Drug: Tiotropium/Salmeterol (T+S_PE); Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S_PE) inhalation powder

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 - 12 Hours (AUC0-12)	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.	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.
Response in Forced Expiratory Volume in Second (FEV1) Area Under the Curve From 12 - 24 Hours (AUC12 -24)	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.	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.
Response in Peak Forced Expiratory Volume in 1 Second (FEV1)	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.	At baseline and within 3 hours post-morning dose after 6 weeks of treatment.
Response in Trough Forced Expiratory Volume in 1 Second (FEV1)	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.	At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0-24 Hours (AUC0-24)	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.	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.
Response in Forced Vital Capacity (FVC) Area Under the Curve From 0 to 12 Hours (AUC0-12)	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.	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.
Response in Forced Vital Capacity (FVC) Area Under the Curve From 12 to 24 Hours (AUC12-24)	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.	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.
Response in Forced Vital Capacity (FVC) Area Under the Curve From 0 - 24 Hours (AUC0-24)	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.	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.
Response in Peak Forced Vital Capacity (FVC)	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.	At baseline and within 3 hours post-morning dose after 6 weeks of treatment.
Response in Trough Forced Vital Capacity (FVC)	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.	At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.
Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve Form 0 to 12 Hours (AUC0-12)	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.	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.
Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve From 12 to 24 Hours (AUC12-24)	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.	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.
Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve From 0 to 24 Hours (AUC0-24)	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.	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.
Response in Peak PEF (Peak Expiratory Flow Rate)	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.	At baseline and within 3 hours post-morning dose after 6 weeks of treatment.
Response in Trough Peak Expiratory Flow Rate (PEF)	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.	At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period	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.	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.
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period	Response in forced vital capacity (FVC) over a 24 hour observation period. Response is defined as change from baseline.	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.
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period	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.	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.
Response in Morning and Evening Peak Expiratory Flow Rate (PEF), Recorded by Patients at Home	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.	At baseline and last 3 weeks of 6-week treatment period.
Response in Morning and Evening Forced Expiratory Volume in 1 Second (FEV1) Recorded by Participants at Home	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.	At baseline and last 3 weeks of 6-week treatment period.
Response in Mean Number of Days With Rescue Medication Use	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.	At baseline and last 3 weeks of 6-week treatment period.
Response in Mean Number of Puffs of Rescue Medication	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.	At baseline and last 3 weeks of 6-week treatment period.
Response in Mean Number of Days With Night-time Awakenings	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.	At baseline and last 3 weeks of 6-week treatment period.
Response in Mean Number of Days With Night-time Awakenings Due to Shortness of Breath (SOB)	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.	At baseline and last 3 weeks of 6-week treatment period.
Response in Means Number of Awakenings Due to Shortness of Breath (SOB)	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.	At baseline and last 3 weeks of 6-week treatment period.
Response in Average Shortness of Breath (SOB) Score at Night	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.	At baseline and last 3 weeks of 6-week treatment period.
Number of Participants With Drug Related Adverse Events	Number of participants with drug related adverse events.	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.
Number of Patients With Marked Changes in Vital Signs	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.	At baseline and 6 hours following the morning dose of study medication after 6 weeks of treatment.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2008
• Primary Completion (Actual): July 22, 2009
• Study Completion (Actual): July 22, 2009

Study Registration Dates

• First Submitted: April 17, 2008
• First Submitted That Met QC Criteria: April 18, 2008
• First Posted (Estimate): April 21, 2008

Study Record Updates

• Last Update Posted (Actual): June 28, 2022
• Last Update Submitted That Met QC Criteria: June 27, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Salmeterol Xinafoate; Tiotropium Bromide
• Other Study ID Numbers: 1184.13