A Six-Week Study Comparing the Efficacy and Safety of Tiotropium Plus Formoterol to Salmeterol Plus Fluticasone in COPD

Condition(s) targeted: Pulmonary Disease, Chronic Obstructive

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

Phase: Phase 4

Status: Completed

Sponsored by: Boehringer Ingelheim Pharmaceuticals

Official(s) and/or principal investigator(s):
Boehringer Ingelheim Study Coordinator, Study Chair, Affiliation: B.I. Pharma GmbH & Co. KG

This was a six-week, randomized, double-blind, quadruple-dummy parallel group multiple dose study comparing the efficacy and safety of tiotropium inhalation capsules (18 µg per day) plus formoterol inhalation capsules (12 µg twice daily) to salmeterol inhalation aerosol (50 µg b. i.d.) plus fluticasone inhalation aerosol (500 µg b. i.d.) in patients with chronic obstructive pulmonary disease (COPD). Diagnosis and main criteria for inclusion were the following: Outpatients of either sex, aged >= 40 years with a diagnosis of COPD (GOLD criteria); post-bronchodilator FEV1 < 80% predicted [ECSC criteria] and post-bronchodilator FEV1/FVC < 70% at Visit 1, pre-bronchodilator FEV1 <= 65% [ECSC criteria] at Visit 2, smoking history of > 10 pack-years, no history of asthma. Duration of treatment was 42 days. Criteria for evaluation were the following: FEV1AUC(0-12) and peak FEV1 (obtained within the first three hours of testing) after six weeks, FEV1, FVC, PEFR, rescue medication use, adverse events, pulse rate, blood pressure, physical examination. Statistical methods: Analysis of covariance with terms for treatment, pooled centre (country) and baseline reading. Descriptive statistics..

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 P

Study design: Treatment, Randomized, Double-Blind, Active Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: 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 outcome: 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.

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(0-12h) (tiotropium+formoterol) <= FEV1AUC(0-12h) (salmeterol+fluticasone) versus H11: FEV1AUC(0-12h) (tiotropium+formoterol) > FEV1AUC0-12h (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.

Minimum age: 40 Years. Maximum age: N/A. Gender(s): Both.

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.

Boehringer Ingelheim Investigational Site, Wien 1120, Austria

Med. Uni.-Klinik Graz, Graz 8036, Austria

Klinikum Kreuzschwestern Wels, Wels 4600, Austria

Boehringer Ingelheim Investigational Site, Vosselaar 2350, Belgium

Sint-Vincentius Ziekenhuis, Antwerpen 2018, Belgium

CHU Notre Dame des Bruyères, Chênée 4032, Belgium

Heilig Hartziekenhuis Campus Menen, Menen 8930, Belgium

Hvidovre Hospital, Hvidovre DK-2650, Denmark

Bispebjerg Hospital, Copenhagen NV DK-2400, Denmark

Lungemedicinsk Forskning 2B, Aarhus DK-8000, Denmark

Amtssygehuset i Gentofte, Hellerup DK-2900, Denmark

Odense Universitetshospital, Odense C DK-5000, Denmark

Boehringer Ingelheim Investigational Site, Grenoble 38100, France

Centre Hospitalier Germon et Gauthier, Beuvry 62660, France

Clinique de la Louvière, Lille Cedex 59042, France

Hôpital Gabriel Montpied, Clermont Ferrand cedex 1 63003, France

Boehringer Ingelheim Investigational Site, Lagord 17140, France

MEDARS GmbH, Berlin 14057, Germany

Boehringer Ingelheim Investigational Site, Kiel 24105, Germany

Otto-von-Guericke-Universtität Magdeburg, Magdeburg 39120, Germany

am Krankenhaus Großhansdorf, Großhansdorf 22927, Germany

Pneumologisches Forschungsinstitut GmbH, Hamburg 20535, Germany

ClinPharm International GmbH & Co. KG, Leipzig 04229, Germany

Boehringer Ingelheim Investigational Site, Gelnhausen 63571, Germany

Klinikum der Ruhr-Universität Bochum, Bochum 44791, Germany

Boehringer Ingelheim Investigational Site, Minden 32423, Germany

Klinikum der Universität zu Köln, Köln 50931, Germany

Boehringer Ingelheim Investigational Site, Hannover 30176, Germany

Boehringer Ingelheim Investigational Site, München 80634, Germany

Boehringer Ingelheim Investigational Site, Berlin 13597, Germany

Boehringer Ingelheim Investigational Site, Frankfurt/Main 60323, Germany

ClinGuard GmbH, Dortmund 44263, Germany

Inamed Research GmbH & Co. KG, Gauting 82131, Germany

lokatie Langendijk, Breda 4819 EV, Netherlands

UMC St Radboud ziekenhuis, Nijmegen 6525 GA, Netherlands

Catharina Hospital, Eindhoven 5623 EJ, Netherlands

Polikliniek Longziekten, Heerlen 6419 PC, Netherlands

Sint Franciscus Gasthuis, Rotterdam 3045 PM, Netherlands

Poli Longziekten, Almelo 7609 PP, Netherlands

Poli Longziekten, Hengelo 7555 DL, Netherlands

Afdeling CardioSearch, Veldhoven 5504 DB, Netherlands

Boehringer Ingelheim Investigational Site, Pretoria 0083, South Africa

QdotPharma, George 6529, South Africa

Boehringer Ingelheim Investigational Site, Durban 4001, South Africa

Tiervlei Trial Centre, Bellville 7530, South Africa

Boehringer Ingelheim Investigational Site, Paarl 7646, South Africa

St. Augustine Hospital, Durban 4001, South Africa

Boehringer Ingelheim Investigational Site, Cape Town 8001, South Africa

Boehringer Ingelheim Investigational Site, Johannesburg 2193, South Africa

UCT Lung Institute, Cape Town 7700, South Africa

Boehringer Ingelheim Investigational Site, Bloemfontein 9301, South Africa

Lung och allergikliniken, Stockholm 141 86, Sweden

Lung- och allergikliniken, Universitetssjukhuset, Umeå S-901 85, Sweden

Lung och allergikliniken, Stockholm 171 76, Sweden

Endokrinologmott/Medicinkliniken, Motala 591 85, Sweden

Lung- och allergikliniken, Länssjukhuset Ryhov, Jönköping S-551 85, Sweden

Starting date: November 2003
Ending date: September 2004
Last updated: April 3, 2008