Back to resultsEfficacy and Safety Comparison of Tiotropium Daily + Salmeterol Daily or Twice Daily Versus Tiotropium Daily in Patients With COPD
Primary Purpose
Pulmonary Disease, Chronic Obstructive
Status
Completed
Phase
Phase 3
Locations
Germany
Study Type
Interventional
Intervention
Tiotropium (Tio18GEL)
Salmeterol MDPI (Salm50DPI)
Tiotropium (T18GEL) + Salmeterol MDPI (S_DPI)
Tiotropium/Salmeterol (T+S_PE)
Sponsored by
About this trial
This is an interventional treatment trial for Pulmonary Disease, Chronic Obstructive
Eligibility Criteria
Inclusion Criteria:
- 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.
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.
- Male or female patients 40 years of age or older.
- Patients must be current or ex-smokers with a smoking history of 10 pack-years.
- Patients must be able to perform technically acceptable pulmonary function tests
- Patients must be able to inhale medication in a competent manner.
- Patients must be able to perform all necessary recordings in the diary.
Exclusion Criteria:
- Significant diseases other than COPD
- 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.
- Patients with a recent history of myocardial infarction.
- Patients with any unstable or life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the past year.
- Hospitalisation for cardiac failure during the past year.
- Malignancy within the last five years excluded basal cell carcinoma.
- Patients with a history of asthma or who have a total blood eosinophil count 600/mm3.
- Patients with a history of life threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis.
- Known active tuberculosis.
- Patients with a history of alcohol or drug abuse.
- Thoracotomy with pulmonary resection.
- Rehabilitation program within the last six weeks
- Patients who regularly use daytime oxygen therapy
- Patients who have taken an investigational drug within 30 days
- Use of not allowed medications
- Known hypersensitivity to used drugs or other components of the study medication.
- Pregnant or nursing women
- 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.
- Patients who are currently participating in another study.
Sites / Locations
- 1184.13.1302 Boehringer Ingelheim Investigational Site
- 1184.13.1309 Boehringer Ingelheim Investigational Site
- 1184.13.1308 Boehringer Ingelheim Investigational Site
- 1184.13.1311 Boehringer Ingelheim Investigational Site
- 1184.13.1312 Boehringer Ingelheim Investigational Site
- 1184.13.1305 Boehringer Ingelheim Investigational Site
- 1184.13.1301 Boehringer Ingelheim Investigational Site
- 1184.13.1306 Boehringer Ingelheim Investigational Site
- 1184.13.1310 Boehringer Ingelheim Investigational Site
- 1184.13.1307 Boehringer Ingelheim Investigational Site
- 1184.13.1304 Boehringer Ingelheim Investigational Site
- 1184.13.1303 Boehringer Ingelheim Investigational Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
T+S_PE/ Tio18GEL / Salm50DPI / T18GEL+S_DPI
Tio18GEL/ T18GEL+S_DPI/ T+S_PE/ Salm50DPI
Salm50DPI/ T+S_PE/ T18GEL+S_DPI/ Tio18GEL
T18GEL+S_DPI/ Salm50DPI/ Tio18GEL/ T+S_PE
Arm Description
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
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)
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)
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)
Outcomes
Primary Outcome Measures
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.
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.
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.
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Number of Participants With Drug Related Adverse Events
Number of participants with drug related adverse events.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00662792
Brief Title
Efficacy and Safety Comparison of Tiotropium Daily + Salmeterol Daily or Twice Daily Versus Tiotropium Daily in Patients With COPD
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
April 15, 2008 (Actual)
Primary Completion Date
July 22, 2009 (Actual)
Study Completion Date
July 22, 2009 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Boehringer Ingelheim
4. Oversight
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Disease, Chronic Obstructive
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
147 (Actual)
8. Arms, Groups, and Interventions
Arm Title
T+S_PE/ Tio18GEL / Salm50DPI / T18GEL+S_DPI
Arm Type
Experimental
Arm Description
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
Arm Title
Tio18GEL/ T18GEL+S_DPI/ T+S_PE/ Salm50DPI
Arm Type
Experimental
Arm Description
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)
Arm Title
Salm50DPI/ T+S_PE/ T18GEL+S_DPI/ Tio18GEL
Arm Type
Experimental
Arm Description
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)
Arm Title
T18GEL+S_DPI/ Salm50DPI/ Tio18GEL/ T+S_PE
Arm Type
Experimental
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Tiotropium (Tio18GEL)
Intervention Description
18 µg Tiotropium (Tio18GEL) inhalation powder
Intervention Type
Drug
Intervention Name(s)
Salmeterol MDPI (Salm50DPI)
Intervention Description
50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID)
Intervention Type
Drug
Intervention Name(s)
Tiotropium (T18GEL) + Salmeterol MDPI (S_DPI)
Intervention Description
18 µg Tiotropium (T18GEL) inhalation powder plus 50 µg Salmeterol MDPI (S_DPI) twice daily (BID)
Intervention Type
Drug
Intervention Name(s)
Tiotropium/Salmeterol (T+S_PE)
Intervention Description
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S_PE) inhalation powder
Primary Outcome Measure Information:
Title
Response in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 - 12 Hours (AUC0-12)
Description
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.
Title
Response in Forced Expiratory Volume in Second (FEV1) Area Under the Curve From 12 - 24 Hours (AUC12 -24)
Description
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.
Title
Response in Peak Forced Expiratory Volume in 1 Second (FEV1)
Description
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.
Title
Response in Trough Forced Expiratory Volume in 1 Second (FEV1)
Description
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.
Secondary Outcome Measure Information:
Title
Response in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0-24 Hours (AUC0-24)
Description
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.
Title
Response in Forced Vital Capacity (FVC) Area Under the Curve From 0 to 12 Hours (AUC0-12)
Description
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.
Title
Response in Forced Vital Capacity (FVC) Area Under the Curve From 12 to 24 Hours (AUC12-24)
Description
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.
Title
Response in Forced Vital Capacity (FVC) Area Under the Curve From 0 - 24 Hours (AUC0-24)
Description
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.
Title
Response in Peak Forced Vital Capacity (FVC)
Description
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.
Title
Response in Trough Forced Vital Capacity (FVC)
Description
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.
Title
Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve Form 0 to 12 Hours (AUC0-12)
Description
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.
Title
Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve From 12 to 24 Hours (AUC12-24)
Description
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.
Title
Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve From 0 to 24 Hours (AUC0-24)
Description
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.
Title
Response in Peak PEF (Peak Expiratory Flow Rate)
Description
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.
Title
Response in Trough Peak Expiratory Flow Rate (PEF)
Description
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.
Title
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
Description
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.
Title
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
Description
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.
Title
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
Description
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.
Title
Response in Morning and Evening Peak Expiratory Flow Rate (PEF), Recorded by Patients at Home
Description
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.
Title
Response in Morning and Evening Forced Expiratory Volume in 1 Second (FEV1) Recorded by Participants at Home
Description
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.
Title
Response in Mean Number of Days With Rescue Medication Use
Description
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.
Title
Response in Mean Number of Puffs of Rescue Medication
Description
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.
Title
Response in Mean Number of Days With Night-time Awakenings
Description
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.
Title
Response in Mean Number of Days With Night-time Awakenings Due to Shortness of Breath (SOB)
Description
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.
Title
Response in Means Number of Awakenings Due to Shortness of Breath (SOB)
Description
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.
Title
Response in Average Shortness of Breath (SOB) Score at Night
Description
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.
Title
Number of Participants With Drug Related Adverse Events
Description
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.
Title
Number of Patients With Marked Changes in Vital Signs
Description
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.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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.
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.
Male or female patients 40 years of age or older.
Patients must be current or ex-smokers with a smoking history of 10 pack-years.
Patients must be able to perform technically acceptable pulmonary function tests
Patients must be able to inhale medication in a competent manner.
Patients must be able to perform all necessary recordings in the diary.
Exclusion Criteria:
Significant diseases other than COPD
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.
Patients with a recent history of myocardial infarction.
Patients with any unstable or life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the past year.
Hospitalisation for cardiac failure during the past year.
Malignancy within the last five years excluded basal cell carcinoma.
Patients with a history of asthma or who have a total blood eosinophil count 600/mm3.
Patients with a history of life threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis.
Known active tuberculosis.
Patients with a history of alcohol or drug abuse.
Thoracotomy with pulmonary resection.
Rehabilitation program within the last six weeks
Patients who regularly use daytime oxygen therapy
Patients who have taken an investigational drug within 30 days
Use of not allowed medications
Known hypersensitivity to used drugs or other components of the study medication.
Pregnant or nursing women
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.
Patients who are currently participating in another study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Boehringer Ingelheim
Organizational Affiliation
Boehringer Ingelheim
Official's Role
Study Chair
Facility Information:
Facility Name
1184.13.1302 Boehringer Ingelheim Investigational Site
City
Berlin
Country
Germany
Facility Name
1184.13.1309 Boehringer Ingelheim Investigational Site
City
Berlin
Country
Germany
Facility Name
1184.13.1308 Boehringer Ingelheim Investigational Site
City
Cottbus
Country
Germany
Facility Name
1184.13.1311 Boehringer Ingelheim Investigational Site
City
Großhansdorf
Country
Germany
Facility Name
1184.13.1312 Boehringer Ingelheim Investigational Site
City
Hamburg
Country
Germany
Facility Name
1184.13.1305 Boehringer Ingelheim Investigational Site
City
Mainz
Country
Germany
Facility Name
1184.13.1301 Boehringer Ingelheim Investigational Site
City
Mannheim
Country
Germany
Facility Name
1184.13.1306 Boehringer Ingelheim Investigational Site
City
Rodgau-Dudenhofen
Country
Germany
Facility Name
1184.13.1310 Boehringer Ingelheim Investigational Site
City
Rüdersdorf
Country
Germany
Facility Name
1184.13.1307 Boehringer Ingelheim Investigational Site
City
Schwerin
Country
Germany
Facility Name
1184.13.1304 Boehringer Ingelheim Investigational Site
City
Wiesbaden
Country
Germany
Facility Name
1184.13.1303 Boehringer Ingelheim Investigational Site
City
Wiesloch
Country
Germany
12. IPD Sharing Statement
Links:
URL
http://www.mystudywindow.com/
Description
Related Info
Learn more about this trial
Efficacy and Safety Comparison of Tiotropium Daily + Salmeterol Daily or Twice Daily Versus Tiotropium Daily in Patients With COPD
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