A Six-Week, Randomized, Double-Blind, Quadruple-Dummy Parallel Group Multiple Dose Study Comparing the Efficacy and Safety of Tiotropium Inhalation Capsules Plus Formoterol Inhalation Capsules to Salmeterol Inhalation Aerosol Plus Fluticasone Inhalation Aerosol in Patients With Chronic Obstructive Pulmonary Disease (COPD)
Overview
- Phase
- Phase 4
- Intervention
- Not specified
- Conditions
- Pulmonary Disease, Chronic Obstructive
- Sponsor
- Boehringer Ingelheim
- Enrollment
- 605
- Locations
- 38
- Primary Endpoint
- The primary efficacy variable was forced expiratory volume in one second (FEV1). There were two co-primary endpoints: FEV1 area under the curve for the time period 0 to 12 hours [FEV1 AUC (0-12)] and peak FEV1 measured after 6 weeks of treatment.
- Status
- Completed
- Last Updated
- 12 years ago
Overview
Brief Summary
To compare the efficacy and safety of tiotropium plus formoterol in comparison to salmeterol plus fluticasone in COPD patients.
Detailed Description
Tiotropium (Spiriva®) is a once-daily inhaled anticholinergic for the treatment of COPD. A six-week, multicentre, randomized, double-blind, parallel group study was conducted to compare the efficacy and safety of the free combination of tiotropium 18 µg once daily plus formoterol 12 µg b.i.d. \[Tio+For\] to salmeterol 50 µg b.i.d. plus fluticasone 500 µg b.i.d. \[Sal+Flu\] in COPD patients. Information regarding the differential efficacy and safety of the two different combinations may be essential for physicians to make informed choices of therapy for COPD patients considered candidates for combination therapy. Following an initial screening visit, subjects entered a two or four-week run-in period in which they received ipratropium (Atrovent®) on a regular basis. At the second visit (Baseline), subjects were randomized into the six-week, double blind portion of the study in which they received either Tio+For or Sal+Flu. After three weeks of treatment, an interim visit was scheduled. After six weeks of treatment, a 12-hour profile of pulmonary function testings (FEV1, FVC) was obtained. Spirometric measurements were performed at pre-dose and 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dosing. There were two co-primary endpoints: FEV1 area under the curve for the time period 0 to 12 hours (FEV1 AUC0-12) and peak FEV1. The efficacy evaluation (intention-to-treat) comprised 592 patients \[Tio+For: N=297, Sal+Flu: N=295\]. The two treatment groups were comparable with regard to demographic data and baseline disease characteristics \[Baseline FEV1 (±SE): Tio+For: 1.310 L (±0.026 L); Sal+Flu: 1.325 L (±0.025 L)\]. Adjustment was done for baseline and centre-effects. Study Hypothesis: The following primary hypotheses (one-sided) were tested with regard to superiority (all means are adjusted means): H01: FEV1AUC(0-12 hours) (tiotropium+formoterol) \<= FEV1AUC (0-12 hours) (salmeterol+fluticasone) versus H11: FEV1AUC(0-12 hours) (tiotropium+formoterol) \> FEV1AUC 0-12 hours(salmeterol+fluticasone) It was stipulated in the protocol that, if the null hypothesis H01 was rejected in favour of H11, then the following hypothesis would be tested: H01: Peak FEV1 (tiotropium+formoterol) \<= Peak FEV1 (salmeterol+fluticasone) versus H11: Peak FEV1 (tiotropium+formoterol) \> Peak FEV1 (salmeterol+fluticasone) Each step was only considered confirmatory providing all previous steps were successful. If any of the previous steps were not successful, any analysis of the current step would have been considered descriptive. Comparison(s): Test therapy: Test product: Tiotropium inhalation capsules plus formoterol inhalation capsules Dose: 18 µg tiotropium per day (one capsule), 12 µg formoterol twice daily (two times one capsule) Mode of administration: inhalation via the Handihaler device (tiotropium), inhalation via the Blue Inhaler device (formoterol) Reference therapy: Test product: Salmeterol plus fluticasone propionate Dose: Salmeterol 50 µg (2 puffs of 25 µg each) b.i.d., fluticasone propionate 500 µg (2 puffs of 250 µg each) b.i.d. Mode of administration: inhalation via MDI The treatment duration was 42 days each. Primary endpoint measurements were performed on the last treatment day.
Investigators
Eligibility Criteria
Inclusion Criteria
- •All patients must sign an informed consent prior to participation in the trial, which includes medication washout and restrictions.
- •All patients must have a diagnosis of chronic obstructive pulmonary disease according to the GOLD criteria and must meet the following spirometric criteria:
- •a post-bronchodilator FEV1 \< 80% of predicted normal, a post-bronchodilator FEV1/FVC \< 70% at Visit 1, and a morning FEV1 \<= 65% predicted at Visit
- •Male or female patients 40 years of age or older.
- •Patients must be current or ex-smokers with a smoking history of more than 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 from the HandiHaler® device, the Blue Inhaler device, and from a metered dose inhaler (MDI).
Exclusion Criteria
- •Patients with significant diseases other than COPD.
- •Patients with a recent history (i.e., six months or less) of myocardial infarction.
- •Patients who have been hospitalized for heart failure (NYHA class III or IV) within the past year.
- •Any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
- •Patients with a history of cancer within the last five years.
- •Patients with known narrow-angle glaucoma.
- •Patients with a history of asthma, allergic rhinitis or atopy or who have a total blood eosinophil count \>= 600/mm
- •Patients with a history of life threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis.
- •Patients with known active tuberculosis.
- •Patients with significant alcohol or drug abuse within the past two years.
Outcomes
Primary Outcomes
The primary efficacy variable was forced expiratory volume in one second (FEV1). There were two co-primary endpoints: FEV1 area under the curve for the time period 0 to 12 hours [FEV1 AUC (0-12)] and peak FEV1 measured after 6 weeks of treatment.
Secondary Outcomes
- Secondary endpoints were trough FEV1, trough FVC, peak FVC and FVC AUC (0-12) measured at the same times as FEV1 after six weeks of treatment, individual FEV1 and FVC profiles, rescue medication use, peak expiratory flow, results of safety measurements.