Effect of Tiotropium Plus Salmeterol vs. Fluticasone/Salmeterol on Static Lung Volumes and Exercise Endurance in COPD

Study Overview
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Brief Summary
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The primary objective of this study is to demonstrate that treatment with a free combination of tiotropium and salmeterol provides superior improvement in static lung volumes and exercise tolerance compared to a fixed combination of fluticasone and salmeterol in patients with COPD. The secondary objective includes assessment of safety.

Official Title
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Effect of Inhalation of a Free Combination of Tiotropium Once Daily 18 Mcg and Salmeterol Twice Daily 50 Mcg Versus a Fixed Combination of Fluticasone and Salmeterol Twice Daily (500/50 Mcg) on Static Lung Volumes and Exercise Tolerance in COPD Patients (a Randomised, Double-blind, Double Dummy, 16 (2 x 8) Weeks, Crossover Study).

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Tiotropium plus Salmeterol
* Drug: Fluticasone/Salmeterol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient has signed an Informed Consent Form in accordance with GCP and local legislative requirements prior to participation in the trial, i.e., prior to pre-trial washout of any restricted medications. The patient has a clinical diagnosis of chronic obstructive pulmonary disease (COPD). The patient has relatively stable, moderate to severe airway obstruction. The patient has a pre-bronchodilator forced expiratory volume in the first second (FEV1) less than or equal to 65% of predicted normal determined at Visit 1 using the following predicted equations (R94-1408): Males Forced expiratory volume in the first second (FEV1) predicted [Litres (L)] = 4.30 x Height [metres] minus 0.029 x Age [years] minus 2.49 Females Forced expiratory volume in the first second (FEV1) predicted [Litres (L)] = 3.95 x Height [metres] minus 0.025 x Age [years] minus 2.60 and a Thoracic Gas Volume (Functional residual volume) ((TGV)(FRC)) bigger than 120% predicted normal at visit 1 (or historical data not older than 6 month) Males Thoracic Gas Volume (Functional residual volume) ((TGV(FRC)) pred. [Litres (L)] = 2.34 x Height [metres] + 0.009 x Age [years] minus 1.09 Females Thoracic Gas Volume (Functional residual volume) ((TGV(FRC)) pred. [Litres (L)] = 2.24 x Height [metres] + 0.001 x Age [years] minus 1.00 The patient is at least 40 years and less than or equal to 75 years old. The patient has a cigarette smoking history of at least 10 pack-years. A pack-year is defined as the equivalent of smoking one pack of cigarettes per day for a year. The patient is able to perform all specified procedures and able to maintain all necessary records during the study period as required in the protocol. The patient is able to inhale the trial medication from the HandiHaler device. The patient is able to inhale the trial medication from the Diskus/Accuhaler device. Exclusion Criteria: a significant disease other than chronic obstructive pulmonary disease (COPD). (review contraindications for exercise testing), a recent history of myocardial infarction within one year. a recent history of heart failure, pulmonary oedema, or patients with cardiac arrhythmia or any contraindication to exercise described in the CTProtocol within the last 3. daytime supplemental oxygen. a diagnosis of known active tuberculosis. a history of cancer within the last 5 years. a history of life-threatening pulmonary obstruction, or a history of cystic fibrosis or bronchiectasis. thoracotomy with pulmonary resection. an upper respiratory tract infection or an exacerbation of chronic obstructive pulmonary disease (COPD) a known hypersensitivity to anticholinergic drug, ß-adrenergic or corticosteroids, lactose or any other component of the inhalation capsule delivery system. a known symptomatic prostatic hypertrophy or bladder neck obstruction. a known moderate or severe renal insufficiency. a known narrow-angle glaucoma. a known untreated hypokalemia. a known untreated thyrotoxicosis. a history of asthma, allergic rhinitis or atopy, or a total blood eosinophil count larger than 600/mm3. treatment with cromolyn sodium or nedocromil sodium treatment with antihistamines or antileukotrienes. treatment with tiotropium for 1 month before Visit 1. treatment with oral corticosteroid medication. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception a history of or active alcohol or drug abuse. an investigational drug within 1 month or 10 half lives a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnoea. participation in a rehabilitation program for chronic obstructive pulmonary disease (COPD). treatment with monoamine oxidase inhibitors inhibitors or tricyclic antidepressants. participation in another study. more than eight puffs of salbutamol/day during the run-in period

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Crossover Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Tiotropium plus Salmeterol|nan|
|Drug: Fluticasone/Salmeterol|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-dose TGV(FRC) (After 8 Weeks) | Post-dose TGV(FRC) (Thoracic Gas Volume; co-primary endpoint) after 8 weeks | 8 weeks | 
| Endurance Time (After 8 Weeks) | Endurance time to the point of symptom limitation after 8 weeks during a constant work rate exercise test at 75% Wcap (co-primary endpoint) | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-dose TGV(FRC) (After 4 Weeks) | Post-dose TGV(FRC) (Thoracic Gas Volume) after 4 weeks | 4 weeks | 
| Endurance Time (After 4 Weeks) | Endurance time to the point of symptom limitation after 4 weeks during a constant work rate exercise test at 75% Wcap (co-primary endpoint) | 4 weeks | 
| Static Lung Volumes | Trough TGV(FRC) (Thoracic Gas Volume) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes | Trough TGV(FRC) (Thoracic Gas Volume) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes | Trough RV (Residual Volume) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes | Trough RV (Residual Volume) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes | Post-dose RV (Residual Volume) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes | Post-dose RV (Residual Volume) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes | Trough IC (Inspiratory Capacity) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes | Trough IC (Inspiratory Capacity) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes | Post-dose IC (Inspiratory Capacity) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes | Post-dose IC (Inspiratory Capacity) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes | Trough IRV (Inspiratory Reserve Volume) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes | Trough IRV (Inspiratory Reserve Volume) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes | Post-dose IRV (Inspiratory Reserve Volume) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes | Post-dose IRV (Inspiratory Reserve Volume) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes | Trough TLC (Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes | Trough TLC (Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes | Post-dose TLC (Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes | Post-dose TLC (Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes (Percent) | Trough RV/TLC (Residual Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes (Percent) | Trough RV/TLC (Residual Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes (Percent) | Post-dose RV/TLC (Residual Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes (Percent) | Post-dose RV/TLC (Residual Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes (Percent) | Trough TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes (Percent) | Trough TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Static Lung Volumes (Percent) | Post-dose TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography) | 8 weeks | 
| Static Lung Volumes (Percent) | Post-dose TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography) | 4 weeks | 
| Slow Vital Capacity (SVC) | Trough SVC (Slow Vital Capacity) after 8 weeks (measured by spirometry) | 8 weeks | 
| Slow Vital Capacity (SVC) | Trough SVC (Slow Vital Capacity) after 4 weeks (measured by spirometry) | 4 weeks | 
| Slow Vital Capacity (SVC) | Post-dose SVC (Slow Vital Capacity) after 8 weeks (measured by spirometry) | 8 weeks | 
| Slow Vital Capacity (SVC) | Post-dose SVC (Slow Vital Capacity) after 4 weeks (measured by spirometry) | 4 weeks | 
| Forced Expiratory Volume in 1 Second (FEV1) | Trough FEV1 (Forced Expiratory Volume in 1 second) after 8 weeks (measured by spirometry) | 8 weeks | 
| Forced Expiratory Volume in 1 Second (FEV1) | Trough FEV1 (Forced Expiratory Volume in 1 second) after 4 weeks (measured by spirometry) | 4 weeks | 
| Forced Expiratory Volume in 1 Second (FEV1) | Post-dose FEV1 (Forced Expiratory Volume in 1 second) after 8 weeks (measured by spirometry) | 8 weeks | 
| Forced Expiratory Volume in 1 Second (FEV1) | Post-dose FEV1 (Forced Expiratory Volume in 1 second) after 4 weeks (measured by spirometry) | 4 weeks | 
| Forced Expiratory Volume in 1 Second (FEV1) | Trough percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 8 weeks (measured by spirometry) | 8 weeks | 
| Forced Expiratory Volume in 1 Second (FEV1) | Trough percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 4 weeks (measured by spirometry) | 4 weeks | 
| Forced Expiratory Volume in 1 Second (FEV1) | Post-dose percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 8 weeks (measured by spirometry) | 8 weeks | 
| Forced Expiratory Volume in 1 Second (FEV1) | Post-dose percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 4 weeks (measured by spirometry) | 4 weeks | 
| Forced Vital Capacity (FVC) | Trough FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry) | 8 weeks | 
| Forced Vital Capacity (FVC) | Trough FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry) | 4 weeks | 
| Forced Vital Capacity (FVC) | Post-dose FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry) | 8 weeks | 
| Forced Vital Capacity (FVC) | Post-dose FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry) | 4 weeks | 
| FEV1 Over FVC (Percent) | Trough FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry) | 8 weeks | 
| FEV1 Over FVC (Percent) | Trough FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry) | 4 weeks | 
| FEV1 Over FVC (Percent) | Post-dose FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry) | 8 weeks | 
| FEV1 Over FVC (Percent) | Post-dose FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry) | 4 weeks | 
| Symptom Intensity During Exercise | Isotime Borg dyspnea scale after 8 weeks, Unit on a Scale (min. 0, max 10), 0 = no dyspnea, 10 = worst imaginable dyspnea | 8 weeks | 
| Symptom Intensity During Exercise | Isotime Borg dyspnea scale after 4 weeks, Unit on a Scale (min. 0, max. 10), 0 = no dyspnea, 10 = worst imaginable dyspnea | 4 weeks | 
| Symptom Intensity During Exercise | Isotime Borg leg discomfort scale after 8 weeks, Unit on a Scale (min. 0, max. 10), 0 = no leg dyscomfort, 10 = worst imaginable leg dyscomfort | 8 weeks | 
| Symptom Intensity During Exercise | Isotime Borg leg discomfort scale after 4 weeks, Unit on a Scale (min. 0, max. 10), 0 = no leg dyscomfort, 10 = worst imaginable leg dyscomfort | 4 weeks | 
| Dyspnea and Leg Discomfort | Peak Borg dyspnea scale after 8 weeks, Unit on a Scale (min. 0, max 10) | 8 weeks | 
| Dyspnea and Leg Discomfort | Peak Borg leg discomfort scale after 8 weeks, Unit on a Scale (min. 0, max 10) | 8 weeks | 
| Locus of Symptom Limitation at Peak Exercise During Exercise | Reason for stopping exercise at baseline (leg discomfort, breathing discomfort, both or none) | baseline | 
| Locus of Symptom Limitation at Peak Exercise During Exercise | Reason for stopping exercise after 4 weeks (leg discomfort, breathing discomfort, both or none) | 4 weeks | 
| Locus of Symptom Limitation at Peak Exercise During Exercise | Reason for stopping exercise after 8 weeks (leg discomfort, breathing discomfort, both or none) | 8 weeks |