Clinical trial NCT00239421: A Six-week Study Comparing the Efficacy and Safety of Tiotropium Plus Formoterol to Salmeterol Plus Fluticasone in Chronic Obstructive Pulmonary Disease (COPD)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Disease, Chronic Obstructive
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2005-10-17
Enrollment: 605
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. All patients must sign an informed consent prior to participation in the trial, which includes medication washout and restrictions.
2. 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 2.
3. Male or female patients 40 years of age or older.
4. Patients must be current or ex-smokers with a smoking history of more than 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 from the HandiHaler® device, the Blue Inhaler device, and from a metered dose inhaler (MDI).

Exclusion Criteria:

1. Patients with significant diseases other than COPD.
2. Patients with a recent history (i.e., six months or less) of myocardial infarction.
3. Patients who have been hospitalized for heart failure (NYHA class III or IV) within the past year.
4. Any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
5. Patients with a history of cancer within the last five years.
6. Patients with known narrow-angle glaucoma.
7. Patients with a history of asthma, allergic rhinitis or atopy 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. Patients with known active tuberculosis.
10. Patients with significant alcohol or drug abuse within the past two years.
11. Patients who have undergone thoracotomy with pulmonary resection.
12. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the Screening Visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program that will not be maintained throughout the study.
13. Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy.
14. Patients who are being treated with antihistamines (H1 receptor antagonists) for asthma or excluded allergic conditions.
15. Patients who have taken an investigational drug within one month or six half lives prior to Visit 1.
16. Patients who have been treated with oral beta-adrenergics within one month prior to Visit 1.
17. Patients who have been treated with antileukotrienes or leukotriene receptor antagonists for any disease within one month prior to Visit 1.
18. Patients who have been treated with oral steroids within six weeks prior to Visit 1.
19. Patients who have been treated with monoamine oxidase inhibitors or tricyclic antidepressants within one month prior to Visit 1.
20. Patients who have been treated with cromolyn sodium or nedocromil sodium within one month prior to Visit 1.
21. Patients who have been treated with inhaled steroids within two months prior to Visit 1, including combinations of inhaled steroids and long-acting beta-adrenergics.
22. Patients with known hypersensitivity to anticholinergic drugs, beta adrenergics, lactose or any other components of the inhalation capsule delivery system or any other components of the aerosol delivery systems.
23. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception for the previous three months.
24. Patients with any respiratory infections in the six weeks prior to the Screening Visit (Visit 1) or during the run-in period.
25. Patients who are currently participating in another study.
26. Patients requiring more than eight puffs of salbutamol on three or more consecutive days during the run-in period.

Primary outcomes:
measure: 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:
measure: 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.
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Med. Uni.-Klinik Graz
city: Wels
country: Austria
facility: Klinikum Kreuzschwestern Wels
city: Wien
country: Austria
facility: Boehringer Ingelheim Investigational Site
city: Antwerpen
country: Belgium
facility: Sint-Vincentius Ziekenhuis
city: Chênée
country: Belgium
facility: CHU Notre Dame des Bruyères
city: Menen
country: Belgium
facility: Heilig Hartziekenhuis Campus Menen
city: Vosselaar
country: Belgium
facility: Boehringer Ingelheim Investigational Site
city: Aarhus
country: Denmark
facility: Lungemedicinsk Forskning 2B
city: Copenhagen NV
country: Denmark
facility: Bispebjerg Hospital
city: Hellerup
country: Denmark
facility: Amtssygehuset i Gentofte
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital
city: Odense C
country: Denmark
facility: Odense Universitetshospital
city: Beuvry
country: France
facility: Centre Hospitalier Germon et Gauthier
city: Clermont Ferrand cedex 1
country: France
facility: Hôpital Gabriel Montpied
city: Grenoble
country: France
facility: Boehringer Ingelheim Investigational Site
city: Lagord
country: France
facility: Boehringer Ingelheim Investigational Site
city: Lille Cedex
country: France
facility: Clinique de la Louvière
city: Berlin
country: Germany
facility: Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: MEDARS GmbH
city: Bochum
country: Germany
facility: Klinikum der Ruhr-Universität Bochum
city: Dortmund
country: Germany
facility: ClinGuard GmbH
city: Frankfurt/Main
country: Germany
facility: Boehringer Ingelheim Investigational Site
city: Gauting
country: Germany
facility: Inamed Research GmbH & Co. KG
city: Gelnhausen
country: Germany
facility: Boehringer Ingelheim Investigational Site
city: Großhansdorf
country: Germany
facility: am Krankenhaus Großhansdorf
city: Hamburg
country: Germany
facility: Pneumologisches Forschungsinstitut GmbH
city: Hannover
country: Germany
facility: Boehringer Ingelheim Investigational Site
city: Kiel
country: Germany
facility: Boehringer Ingelheim Investigational Site
city: Köln
country: Germany
facility: Klinikum der Universität zu Köln
city: Leipzig
country: Germany
facility: ClinPharm International GmbH & Co. KG
city: Magdeburg
country: Germany
facility: Otto-von-Guericke-Universtität Magdeburg
city: Minden
country: Germany
facility: Boehringer Ingelheim Investigational Site
city: München
country: Germany
facility: Boehringer Ingelheim Investigational Site
city: Almelo
country: Netherlands
facility: Poli Longziekten
city: Breda
country: Netherlands
facility: lokatie Langendijk
city: Eindhoven
country: Netherlands
facility: Catharina Hospital
city: Heerlen
country: Netherlands
facility: Polikliniek Longziekten
city: Hengelo
country: Netherlands
facility: Poli Longziekten
city: Nijmegen
country: Netherlands
facility: UMC St Radboud ziekenhuis
city: Rotterdam
country: Netherlands
facility: Sint Franciscus Gasthuis
city: Veldhoven
country: Netherlands
facility: Afdeling CardioSearch
city: Bellville
country: South Africa
facility: Tiervlei Trial Centre
city: Bloemfontein
country: South Africa
facility: Boehringer Ingelheim Investigational Site
city: Cape Town
country: South Africa
facility: UCT Lung Institute
city: Cape Town
country: South Africa
facility: Boehringer Ingelheim Investigational Site
city: Durban
country: South Africa
facility: Boehringer Ingelheim Investigational Site
city: Durban
country: South Africa
facility: St. Augustine Hospital
city: George
country: South Africa
facility: QdotPharma
city: Johannesburg
country: South Africa
facility: Boehringer Ingelheim Investigational Site
city: Paarl
country: South Africa
facility: Boehringer Ingelheim Investigational Site
city: Pretoria
country: South Africa
facility: Boehringer Ingelheim Investigational Site
city: Jönköping
country: Sweden
facility: Lung- och allergikliniken, Länssjukhuset Ryhov
city: Motala
country: Sweden
facility: Endokrinologmott/Medicinkliniken
city: Stockholm
country: Sweden
facility: Lung och allergikliniken
city: Stockholm
country: Sweden
facility: Lung och allergikliniken
city: Umeå
country: Sweden
facility: Lung- och allergikliniken, Universitetssjukhuset
Study officials:
affiliation: B.I. Pharma GmbH & Co. KG
name: Boehringer Ingelheim Study Coordinator
role: STUDY_CHAIR
References:
citation: Rabe KF, Timmer W, Sagkriotis A, Viel K. Comparison of a combination of tiotropium plus formoterol to salmeterol plus fluticasone in moderate COPD. Chest. 2008 Aug;134(2):255-262. doi: 10.1378/chest.07-2138. Epub 2008 Apr 10.