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

Pulmonary Disease, Chronic Obstructive Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00239421
• Other study ID #: 205.287
• Status: Completed
• Phase: Phase 4
• First received: October 14, 2005
• Last updated: October 31, 2013
• Start date: November 2003
• Est. completion date: September 2004

Study information

• Verified date: October 2013
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)Austria: Federal Ministry for Health and WomenBelgium: Institutional Review BoardDenmark: Danish Medicines AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)South Africa: Medicines Control Council
• Study type: Interventional

Clinical Trial Summary

To compare the efficacy and safety of tiotropium plus formoterol in comparison to salmeterol plus fluticasone in COPD patients.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 605
• Est. completion date: September 2004
• Est. primary completion date: September 2004
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

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

• 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.

Locations

Country	Name	City	State
Austria	Med. Uni.-Klinik Graz	Graz
Austria	Klinikum Kreuzschwestern Wels	Wels
Austria	Boehringer Ingelheim Investigational Site	Wien
Belgium	Sint-Vincentius Ziekenhuis	Antwerpen
Belgium	CHU Notre Dame des Bruyères	Chênée
Belgium	Heilig Hartziekenhuis Campus Menen	Menen
Belgium	Boehringer Ingelheim Investigational Site	Vosselaar
Denmark	Lungemedicinsk Forskning 2B	Aarhus
Denmark	Bispebjerg Hospital	Copenhagen NV
Denmark	Amtssygehuset i Gentofte	Hellerup
Denmark	Hvidovre Hospital	Hvidovre
Denmark	Odense Universitetshospital	Odense C
France	Centre Hospitalier Germon et Gauthier	Beuvry
France	Hôpital Gabriel Montpied	Clermont Ferrand cedex 1
France	Boehringer Ingelheim Investigational Site	Grenoble
France	Boehringer Ingelheim Investigational Site	Lagord
France	Clinique de la Louvière	Lille Cedex
Germany	Boehringer Ingelheim Investigational Site	Berlin
Germany	MEDARS GmbH	Berlin
Germany	Klinikum der Ruhr-Universität Bochum	Bochum
Germany	ClinGuard GmbH	Dortmund
Germany	Boehringer Ingelheim Investigational Site	Frankfurt/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	Hannover
Germany	Boehringer Ingelheim Investigational Site	Kiel
Germany	Klinikum der Universität zu Köln	Köln
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
Netherlands	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
South Africa	Tiervlei Trial Centre	Bellville
South Africa	Boehringer Ingelheim Investigational Site	Bloemfontein
South Africa	Boehringer Ingelheim Investigational Site	Cape Town
South Africa	UCT Lung Institute	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
Sweden	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

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.

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