A 24-week (+ 24 Week Extension) Placebo-controlled (Only 1st 12-week Period), Double-Blind, Parallel-group, Efficacy and Safety Comparison of Fixed-dose Combination (FDC) Tiotropium/Salmeterol, Tiotropium, Salmeterol and FDC Tiotropium/Salmeterol Plus Salmeterol in Chronic Obstructive Pulmonary Disease (COPD) Patients
Trial Snapshot
- Phase
- Phase 3
- Status
- Terminated
- Sponsor
- Boehringer Ingelheim
- Enrollment
- 207
- Locations
- 79
- Primary Endpoint
- Trough FEV1 response
Study Overview
Brief Summary
The primary objectives of this study are to assess bronchodilator efficacy as determined by forced expiratory volume in one second (FEV1), the effect on dyspnoea as determined by the Baseline Dyspnoea Index (BDI)/Transition Dyspnoea Index (TDI), the effect on health status as determined by the St George Respiratory Questionnaire (SGRQ) and the effect on chronic obstructive pulmonary disease (COPD) exacerbations
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Care Provider, Investigator)
Masking Description
double-blind
Eligibility Criteria
- Ages
- 40 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Diagnosis of chronic obstructive pulmonary disease (COPD)
- •Post-bronchodilator forced expiratory volume in one second (FEV1) <80% predicted and FEV1/forced vital capacity (FVC) <70% predicted
Exclusion Criteria
- •Significant other diseases then COPD
- •Recent myocardial infarction (MI)
- •Any unstable or life-threatening cardiac arrythmia requiring intervention or change in drug therapy during the past year
- •Hospitalisation for cardiac failure during the past year
- •History of asthma
Arms & Interventions
Tiotropium QD
Tiotropium Inhalation Powder, hard gelatine capsule (Spiriva®)
Intervention: Tiotropium (Drug)
Salmeterol BID
Salmeterol Inhalation Powder, hard PE capsule
Intervention: Salmeterol (Drug)
Tiotropium/Salmeterol QD + Salmeterol
Tiotropium/Salmeterol Inhalation Powder, Hard Polyethylene Capsule, plus Salmeterol Inhalation Powder, hard PE capsule
Intervention: Tiotropium/Salmeterol QD + Salmeterol (Drug)
Placebo
One capsule of inhalation powder of placebo was administered daily in the morning from the blue and grey HandiHaler® device and in the evening from the blue HandiHaler® device for treatment duration of 12 weeks (Patients randomized into the placebo group will be re-assigned at random to one of the four active treatments (T+S_PE, Tio18GEL, Salm25PE, T+S_PE/S25PE) for the remaining 36 weeks of the 48-week study period.). The morning and evening dose of study medication had to be taken at approximately the same time, the evening dose had to be taken approximately 12 hours after the morning dose. All medications were self-administered by patients.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Trough FEV1 response
Time Frame: 12 Weeks, 24 Weeks and 48 Weeks
FEV1AUC 0 8hr response
Time Frame: 12 Weeks, 24 Weeks and 48 Weeks
SGRQ total score
Time Frame: 12 Weeks, 24 Weeks and 48 Weeks
Mahler TDI focal score
Time Frame: 12 Weeks, 24 Weeks and 48 Weeks
Time to first moderate to severe COPD exacerbation
Time Frame: 12 Weeks, 24 Weeks and 48 Weeks
Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at the End of the 12-week Treatment Period
Time Frame: At baseline and week 12
Change from baseline in trough Forced Expiratory Volume in one second (FEV1) at the end of the 12-week treatment period is presented. FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. It is measured by a spirometer. Trough FEV1 is defined as the pre-dose FEV1 measured in the clinic at the -10 minutes time point just prior to inhalation of the morning dose of randomised treatment. Trough FEV1 response is defined as the change from baseline: Trough FEV1 response = Trough FEV1 - FEV1 (Baseline)
Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at the End of the 24-week Treatment Period
Time Frame: At baseline and week 24
Change from baseline in trough Forced Expiratory Volume in one second (FEV1) at the end of the 24-week treatment period is presented. FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is defined as the pre-dose FEV1 measured in the clinic at the -10 min time point just prior to inhalation of the morning dose of randomised treatment.
Forced Expiratory Volume in One Second (FEV1) Area Under the Concentration-time Curve From 0 to 8h (AUC0-8h) Response at the End of the 12-week Treatment Period
Time Frame: At baseline and at week 12: 10 minutes (min) prior to inhalation, and 30min, 60min, 2hours (hrs), 3hrs, 4hrs, 6hrs and 8hrs after inhalation of the morning drug dose.
Forced Expiratory Volume in one second (FEV1) area under the concentration-time curve from 0 to 8 hours (AUC0-8h) response at the end of the 12-week treatment period is presented. FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The FEV1 AUC0-8h is defined as the area under the FEV1 curve (AUC) normalized for time. It was calculated as area under the curve from zero time to 8 h using the trapezoidal rule divided by the corresponding duration (i.e. 8 h) to give the results in litres. The trough FEV1 was assigned to zero time. Trough FEV1 at baseline is defined as the pre-dose FEV1 measured in the clinic at the -10 minutes time point just prior to inhalation of the first morning dose of randomised treatment at the randomisation visit. Response = FEV1 AUC0-8h at week 12 - trough FEV1 at baseline.
Forced Expiratory Volume in One Second (FEV1) Area Under the Concentration-time Curve From 0 to 8h (AUC0-8h) Response at the End of the 24-week Treatment Period
Time Frame: At baseline and at week 24: 10 minutes (min) prior to inhalation, and 30min, 60min, 2hours (hrs), 3hrs, 4hrs, 6hrs and 8hrs after inhalation of the morning drug dose.
Forced Expiratory Volume in one second (FEV1) area under the concentration-time curve from 0 to 8h (AUC0-8h) response at the end of the 24-week treatment period is presented. FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The FEV1 AUC0-8h is defined as the area under the FEV1 curve (AUC) normalized for time. It was calculated as area under the curve from zero time to 8 h using the trapezoidal rule divided by the corresponding duration (i.e. 8 h) to give the results in litres. The trough FEV1 was assigned to zero time. Trough FEV1 at baseline is defined as the pre-dose FEV1 measured in the clinic at the -10 minutes time point just prior to inhalation of the first morning dose of randomised treatment at the randomisation visit. Response = FEV1 AUC0-8h at week 24 - trough FEV1 at baseline.
Mahler Transition Dyspnoea Index (TDI) Focal Score at the End of the 12-week Treatment Period
Time Frame: At the end of week 12
The Mahler Dyspnoea questionnaire is an instrument which measures change from baseline state in the severity of breathlessness (shortness of breath). It is based on the criteria of the various grades for change in functional impairment (any activities started or stopped?), change in magnitude of task (What activities cause breathlessness now?) and change in magnitude of effort (Need to pause while performing activities?), which causes breathlessness, each ranging from grade -3 (major deterioration) to +3 (major improvement). The Transition Dyspnoea Index (TDI) focal score was calculated as the sum of these three components of the TDI, i.e. change in Functional Impairment, in Magnitude of Task and in Magnitude of Effort. Consequently, TDI ranges from -9 to +9 with a higher score indicating improvement.
Mahler Transition Dyspnoea Index (TDI) Focal Score at the End of the 24-week Treatment Period
Time Frame: At the end of week 24
The Mahler Dyspnoea questionnaire is an instrument which measures the severity of breathlessness (shortness of breath) change from the baseline state. It is based on the criteria of the various grades for change in functional impairment (any activities started or stopped?), change in magnitude of task (What activities cause breathlessness now?) and change in magnitude of effort (Need to pause while performing activities?), which causes breathlessness, each ranging from grade -3 (major deterioration) to +3 (major improvement). The Transition Dyspnoea Index (TDI) focal score was calculated as the sum of these three components of the TDI, i.e. change in Functional Impairment, in Magnitude of Task and in Magnitude of Effort. Consequently, TDI ranges from -9 to +9 with a higher score indicating improvement.
St George Respiratory Questionnaire (SGRQ) Total Score at the End of the 24-week Treatment Period (Based Upon Pooled Data From 48-week Sister Studies 1184.14 and 1184.15)
Time Frame: At the end of week 24
The St George Respiratory Questionnaire (SGRQ) is designed as a supervised self-administered questionnaire that determines the impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Scores range from 0 to 100, with higher scores indicating more limitations. The evaluation SGRQ was planned to be based upon pooled data from 48-week sister studies 1184.14 and 1184.15.
Time to First Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Within 48 Weeks
Time Frame: Up to 12 weeks
Time from start of treatment to first moderate to severe chronic obstructive pulmonary disease (COPD) exacerbation within 48 weeks is presented.
Number of Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Within 48 Weeks
Time Frame: Up to 12 weeks.
Number of patients with moderate to severe chronic obstructive pulmonary disease (COPD) exacerbations within 48 weeks is presented.
Secondary Outcomes
- Concomitant medications (for instance antibiotics and systemic steroids)(48 weeks)
- Weekly mean number of COPD related night time awakenings(1 week)
- Individual FEV1, FVC and PEF measurements(48 weeks)
- Trough FEV1 response(4, 36 and 48 weeks)
- Peak FEV1 response(12, 24, 36 and 48 weeks)
- Mahler TDI focal score(4, 36 and 48 weeks)
- Mahler Dyspnoea Indices (Functional Impairment, Magnitude of Task and Magnitude of Effort)(4, 12, 24, 36 and 48 weeks)
- SGRQ total score, and the impact, activity and symptoms domain scores from the SGRQ(4, 12, 36 and 48 weeks)
- All adverse events(48 weeks)
- FEV1 AUC0-8h response(4, 36 and 48 weeks)
- Use of rescue medication (weekly mean number of puffs of as-needed salbutamol/albuterol per day, daytime and night-time)(24 hours)
- FVC (forced vital capacity) AUC0-8h and trough FVC response(48 weeks)
- Weekly mean morning pre-dose and evening pre-dose PEFs (peak expiratory flow) and FEV1 (recorded by AM2+); PEFs determined by spirometry ](48 weeks)
- Vital signs: pulse rate and blood pressure(Baseline and 4 weeks)
- Routine blood chemistry, haematology and urinalysis(Baseline and 48 weeks)
- Vital status of randomised patients(48 weeks)
- Number of days in hospital (including ambulance transportation(48 weeks)
- Number of unscheduled health care provider visits(48 weeks)
- Number of visits in emergency room (including ambulance transportation)(48 weeks)
- Number of days in intensive care unit(48 weeks)
- Forced Expiratory Volume in One Second (FEV1) Area Under the Concentration-time Curve From 0 to 8h (AUC0-8h) Response After 4, 36 and 48 Weeks Treatment Period(At baseline and at week 4: 10 minutes (min) prior to inhalation, and 30min, 60min, 2hours (hrs), 3hrs, 4hrs, 6hrs and 8hrs after inhalation of the morning drug dose.)
- Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) After 4, 36 and 48 Weeks Treatment Period(At baseline and week 4.)
- Change From Baseline in Peak Forced Expiratory Volume in One Second (FEV1) at Week 4, 12, 18, 24, 36 and 48(At baseline and at week 4 and 12: within 3h after inhalation of the morning dose of randomised treatment.)
- The Forced Vital Capacity (FVC) Area Under the Concentration-time Curve From 0 to 8h (AUC0-8h) Response After 4, 12, 24, 36 and 48 Weeks Treatment Period(At baseline and at week 4 and 12: 10 minutes (min) prior to inhalation, and 30min, 60min, 2hours (hrs), 3hrs, 4hrs, 6hrs and 8hrs after inhalation of the morning drug dose.)
- Change From Baseline in Trough Forced Vital Capacity (FVC) After 4, 12, 24, 36 and 48 Weeks Treatment Period(At baseline and week 4 and 12.)
- Change From Baseline in Peak Forced Vital Capacity (FVC) at Week 4, 12, 18, 24, 36 and 48(At baseline and at week 4 and 12: within 3 hours after inhalation of the morning dose of randomised treatment.)
- Forced Expiratory Volume in One Second (FEV1) at Clinic Visits at the Individual Times on Week 4(At week 4: 10 minutes (min) prior to inhalation, and 30min, 60min, 2hours (hrs), 3hrs, 4hrs, 6hrs and 8hrs after inhalation of the morning drug dose.)
- Forced Expiratory Volume in One Second (FEV1) at Clinic Visits at the Individual Times on Week 12(At week 12: 10 minutes (min) prior to inhalation, and 30min, 60min, 2hours (hrs), 3hrs, 4hrs, 6hrs and 8hrs after inhalation of the morning drug dose.)
- Forced Vital Capacity (FVC) at Clinic Visits at the Individual Times on Week 4(At week 4: 10 minutes (min) prior to inhalation, and 30min, 60min, 2hours (hrs), 3hrs, 4hrs, 6hrs and 8hrs after inhalation of the morning drug dose.)
- Forced Vital Capacity (FVC) at Clinic Visits at the Individual Times on Week 12(At week 12, at 10 min prior and 0 hours (hrs), 30 minutes (min), 1hrs, 2hrs, 3hrs, 4hrs, 6hrs and 8hrs after inhalation of the morning drug dose.)
- Peak Expiratory Flow (PEF) Rate at Clinic Visits at the Individual Times on Week 4(At week 4, at 0 hours (hrs), 30 minutes (min), 1hrs, 2hrs, 3hrs, 4hrs, 6hrs and 8hrs after inhalation of the morning drug dose.)
- Peak Expiratory Flow (PEF) Rate at Clinic Visits at the Individual Times on Week 12(At week 12, at 0 hours (hrs), 30 minutes (min), 1hrs, 2hrs, 3hrs, 4hrs, 6hrs and 8hrs after inhalation of the morning drug dose.)
- Weekly Mean Morning Pre-dose Peak Expiratory Flows (PEFs)(At week 1 to 14, each morning between 7 a.m. and 10 a.m. (± 30 minutes (min)) at -10 min (± 3 min) prior to the administration of the study medication.)
- Weekly Mean Evening Pre-dose Peak Expiratory Flows (PEFs)(At week 1 to 14, each evening between 7 p.m. and 10 p.m. (± 30 minutes (min)) at -10 min (± 3 min) prior to the administration of the study medication.)
- Peak Expiratory Flow (PEF) Determined by Spirometry at Week 4, 12, 18, 24, 36 and 48(At week 4 and 12: 10 minutes prior to the first dose of study medication, and at 30, 60 minutes, 2, 3, 4, 6 and 8 hours after inhalation of the first dose of randomised treatment.)
- Weekly Mean Morning Pre-dose Forced Expiratory Volume in One Second (FEV1)(At week 1 to 14, each morning between 7 a.m. and 10 a.m. (± 30 minutes (min)) at -10 min (± 3 min) prior to the administration of the study medication.)
- Weekly Mean Evening Pre-dose Forced Expiratory Volume in One Second (FEV1)(At week 1 to 14, each evening between 7 p.m. and 10 p.m. (± 30 minutes (min)) at -10 min (± 3 min) prior to the administration of the study medication.)
- Weekly Mean Number Per Day (24 Hours Period) of Puffs of As-needed Salbutamol/Albuterol Metered Dose Inhaler (MDI)(Weekly up to week 14: per day (24 hours period))
- Weekly Mean Number at Daytime of Puffs of As-needed Salbutamol/Albuterol Metered Dose Inhaler (MDI)(Weekly up to week 14: at daytime (from morning dose till evening dose of study medication))
- Weekly Mean Number at Nighttime of Puffs of As-needed Salbutamol/Albuterol Metered Dose Inhaler (MDI)(Weekly up to week 14: at nighttime (from evening dose till morning dose of study medication))
- Weekly Mean Number of Chronic Obstructive Pulmonary Disease (COPD)-Related Nighttime Awakenings(Per week, up to 14 weeks)
- Mahler Transition Dyspnoea Index (TDI) Focal Score Collected After 4, 36 and 48 Weeks Treatment Period(At week 4.)
- Mahler Transition Dyspnoea Index (TDI) Domain Score - Functional Impairment Collected After 4, 12, 24, 36 and 48 Weeks Treatment Period(At the end of week 4 and 12.)
- Mahler Transition Dyspnoea Index (TDI) Domain Score - Magnitude of Task Collected After 4, 12, 24, 36 and 48 Weeks Treatment Period(At the end of week 4 and 12.)
- Mahler Transition Dyspnoea Index (TDI) Domain Score - Magnitude of Effort Collected After 4, 12, 24, 36 and 48 Weeks Treatment Period(At the end of week 4 and 12.)
- St George Respiratory Questionnaire (SGRQ) Total Score Collected at 4, 12, 36 and 48 Weeks(At week 4 and 12.)
- St George Respiratory Questionnaire (SGRQ) Impact Domain Score Collected at 4, 12, 36 and 48 Weeks(At week 4 and 12.)
- St George Respiratory Questionnaire (SGRQ) Activity Domain Score Collected at 4, 12, 36 and 48 Weeks(At week 4 and 12.)
- St George Respiratory Questionnaire (SGRQ) Symptoms Domain Score Collected at 4, 12, 36 and 48 Weeks(At week 4 and 12.)
- Number of Patients With Adverse Events Within the 48-week Treatment Period(From randomisation till end of treatment, up to 12 weeks.)
- Number of Patients With Marked Changes in Vital Signs (Decrease) by Clinic Visit(At baseline, week 4 and week 12.)
- Number of Patients With Marked Changes in Vital Signs (Increase) by Clinic Visit(At baseline, week 4 and week 12.)
- Number of Patients With Abnormal Haematology at the End of the 12-week Treatment Period(At the end of the 12-week treatment period.)
- Number of Patients With Abnormal Blood Chemistry at the End of the 12-week Treatment Period(At the end of the 12-week treatment period.)
- Number of Patients With Abnormal Urinalysis at the End of the 12-week Treatment Period(At the end of the 12-week treatment period.)
- Vital Status of Randomised Patients(Up to 48 weeks.)
- Number of Days in Hospital Within the 48-week Treatment Period(Up to 12 weeks.)
- Number of Unscheduled Health Care Provider Visits Within the 48-week Treatment Period(Up to 12 weeks.)
- Number of Emergency Room Visits Within the 48-week Treatment Period(Up to 12 weeks.)
- Number of Days in Intensive Care Unit Within the 48-week Treatment Period(Up to 12 weeks.)
- Number of Patients Receiving Concomitant Medication(Up to 12 weeks.)