A Six-week Study Comparing the Efficacy and Safety of Tiotropium Plus Formoterol to Salmeterol Plus Fluticasone in Chronic Obstructive Pulmonary Disease (COPD)

NCT ID: NCT00239421

Last Updated: 2013-11-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 605 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-11-30
• Study Completion Date: 2004-09-30

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.

Conditions

Pulmonary Disease, Chronic Obstructive

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Interventions

Test: Tiotropium 18 µg per day (one inhalation capsule) plus 12 µg formoterol twice daily (two times one inhalation capsule)

Intervention Type: DRUG

Reference: Salmeterol MDI 50 µg (2 puffs of 25 µg each) b.i.d., plus fluticasone propionate MDI 500 µg (2 puffs of 250 µg each) b.i.d.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boehringer Ingelheim

INDUSTRY

Sponsor Role: lead

Principal Investigators

Boehringer Ingelheim Study Coordinator

Role: STUDY_CHAIR

B.I. Pharma GmbH & Co. KG

Locations

Med. Uni.-Klinik Graz

Graz, , Austria

Boehringer Ingelheim Investigational Site

Vienna, , Austria

Klinikum Kreuzschwestern Wels

Wels, , Austria

Sint-Vincentius Ziekenhuis

Antwerp, , Belgium

CHU Notre Dame des Bruyères

Chênée, , Belgium

Heilig Hartziekenhuis Campus Menen

Menen, , Belgium

Boehringer Ingelheim Investigational Site

Vosselaar, , Belgium

Lungemedicinsk Forskning 2B

Aarhus, , Denmark

Bispebjerg Hospital

Copenhagen NV, , Denmark

Amtssygehuset i Gentofte

Hellerup, , Denmark

Hvidovre Hospital

Hvidovre, , Denmark

Odense Universitetshospital

Odense C, , Denmark

Centre Hospitalier Germon et Gauthier

Beuvry, , France

Hôpital Gabriel Montpied

Clermont-Ferrand, , France

Boehringer Ingelheim Investigational Site

Grenoble, , France

Boehringer Ingelheim Investigational Site

Lagord, , France

Clinique de la Louvière

Lille, , France

Boehringer Ingelheim Investigational Site

Berlin, , Germany

MEDARS GmbH

Berlin, , Germany

Klinikum der Ruhr-Universität Bochum

Bochum, , Germany

Klinikum der Universität zu Köln

Cologne, , Germany

ClinGuard GmbH

Dortmund, , Germany

Boehringer Ingelheim Investigational Site

Frankfurt am Main, , Germany

Inamed Research GmbH & Co. KG

Gauting, , Germany

Boehringer Ingelheim Investigational Site

Gelnhausen, , Germany

am Krankenhaus Großhansdorf

Großhansdorf, , Germany

Pneumologisches Forschungsinstitut GmbH

Hamburg, , Germany

Boehringer Ingelheim Investigational Site

Hanover, , Germany

Boehringer Ingelheim Investigational Site

Kiel, , Germany

ClinPharm International GmbH & Co. KG

Leipzig, , Germany

Otto-von-Guericke-Universtität Magdeburg

Magdeburg, , Germany

Boehringer Ingelheim Investigational Site

Minden, , Germany

Boehringer Ingelheim Investigational Site

München, , Germany

Poli Longziekten

Almelo, , Netherlands

lokatie Langendijk

Breda, , Netherlands

Catharina Hospital

Eindhoven, , Netherlands

Polikliniek Longziekten

Heerlen, , Netherlands

Poli Longziekten

Hengelo, , Netherlands

UMC St Radboud ziekenhuis

Nijmegen, , Netherlands

Sint Franciscus Gasthuis

Rotterdam, , Netherlands

Afdeling CardioSearch

Veldhoven, , Netherlands

Tiervlei Trial Centre

Bellville, , South Africa

Boehringer Ingelheim Investigational Site

Bloemfontein, , South Africa

UCT Lung Institute

Cape Town, , South Africa

Boehringer Ingelheim Investigational Site

Cape Town, , South Africa

Boehringer Ingelheim Investigational Site

Durban, , South Africa

St. Augustine Hospital

Durban, , South Africa

QdotPharma

George, , South Africa

Boehringer Ingelheim Investigational Site

Johannesburg, , South Africa

Boehringer Ingelheim Investigational Site

Paarl, , South Africa

Boehringer Ingelheim Investigational Site

Pretoria, , South Africa

Lung- och allergikliniken, Länssjukhuset Ryhov

Jönköping, , Sweden

Endokrinologmott/Medicinkliniken

Motala, , Sweden

Lung och allergikliniken

Stockholm, , Sweden

Lung och allergikliniken

Stockholm, , Sweden

Lung- och allergikliniken, Universitetssjukhuset

Umeå, , Sweden

Countries

Austria; Belgium; Denmark; France; Germany; Netherlands; South Africa; Sweden

References

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.

Reference Type: DERIVED

PMID: 18403672 (View on PubMed)

Other Identifiers

205.287

Identifier Type: -

Identifier Source: org_study_id