Comparison of Tiotropium in the HandiHaler Versus the Respimat in Chronic Obstructive Pulmonary Disease

Study Overview
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Brief Summary
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Direct comparison studies of the tiotropium HandiHaler® 18 µg and Respimat® 5 µg formulations have been limited to 4-week crossover studies. Therefore, prospective data from a trial of adequate size and duration is required to establish that compared to tiotropium HandiHaler®, tiotropium Respimat® will have (a) similar effects on safety and (b) similar or superior effects on exacerbations.

Official Title
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A Randomized, Active-controlled, Double-blind, Double-dummy, Parallel Group Design, Multi-center Trial to Compare the Efficacy and Safety of 2.5 µg and 5 µg Tiotropium Inhalation Solution Delivered by the Respimat Inhaler With Tiotropium Inhalation Capsules 18 µg Delivered by the HandiHaler (TIOSPIR)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: tiotropium 18 mcg
* Drug: tiotropium 1.25 mcg (2 actuations/day)
* Drug: tiotropium 2.5 mcg (2 actuations/day)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: All patients must sign an informed consent consistent with International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions. Male or female patients 40 years of age or older. Patients must be current or ex-smokers with a smoking history of ≥10 pack-years. (Patients who have never smoked cigarettes must be excluded) All patients must have a diagnosis of COPD (P06-12085), and must meet the following criteria: Relatively stable airway obstruction with a post-bronchodilator FEV1 ≤ 70% of predicted normal and post-bronchodilator FEV1 / FVC ≤70%. Pulmonary function tests (PFTs) were conducted after the inhalation of 400 μg salbutamol / albuterol (preferred), however testing with either 200 μg salbutamol/albuterol or a combination of salbutamol / albuterol with ipratropium bromide (2 to 4 actuations) was acceptable. Other short-acting beta agonists, such as terbutaline, may have been used for the testing. The medication used for the testing was documented. Further, historical data from measurements within the past 6 months either at the site or at a referral site may have been used (see Section 6.2.1 of the CTP, located in Appendix 16.1.1). Subjects were not to have been randomized to the study without the availability of spirometry data at the actual study site. Eligibility for PFT sub-study: For subjects participating in the spirometry sub-study, historical data may not have been used for inclusion. These subjects must have qualified in the clinic at Visit 1 after performing a baseline measurement. These subjects performed a pre-dose PFT which was followed by the administration of 400 μg salbutamol / albuterol only (no other short-acting beta agonist was allowed), followed by a post-dose PFT for qualification. Able to inhale from the HandiHaler® and the Respimat® devices. Exclusion criteria: Significant diseases other than COPD. A significant disease is defined as a disease or condition which, in the opinion of the investigator, may put the patient at risk because of participation in the study or may influence the patients ability to participate in the study. Patients with a recent history (i.e., six months or less) of myocardial infarction. Patients with any unstable or life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the last year. Hospitalisation for cardiac failure (New York Heart Association (NYHA) Class III or IV) during the past year. Known active tuberculosis. Patients with a history of asthma, cystic fibrosis, clinically evident bronchiectasis, interstitial lung disease, or pulmonary thromboembolic disease. History of thoracotomy with pulmonary resection. Subjects with a history of thoracotomy for other reasons were to have been evaluated per exclusion criterion 1. Subject was planning to undergo lung transplant or lung volume reduction surgery (LVRS). Malignancy for which the subject had undergone resection, radiation, chemotherapy or biological treatments within the last 5 years. Subjects with treated basal cell carcinoma were allowed. Known respiratory infection or exacerbation of COPD in the 4 weeks prior to randomization. Known hypersensitivity to anticholinergic drugs, lactose, benzalkonium chloride (BAC), ethylenediaminetetraacetic acid (EDTA), or any other components of the HandiHaler® or Respimat® inhalation solution delivery system. Known moderate to severe renal impairment (as judged by the investigator). Known narrow angle glaucoma. Known significant symptomatic prostatic hyperplasia or bladder-neck obstruction. Subjects whose symptoms were controlled on treatment may have been included. Use of systemic corticosteroid medication at unstable doses (i.e., less than 6 weeks on stable dose) or at doses in excess of the equivalent of 10 mg prednisolone per day. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception for at least 3 months prior to and for the duration of the trial. Significant alcohol or drug abuse within the past 12 months. Subjects requiring the use of supplemental oxygen therapy for > 12 hours per day. Subjects who had completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit or subjects who were currently in a pulmonary rehabilitation program that was not maintained throughout the duration of the study. Subjects who had taken an investigational drug within 30 days prior to the Screening Visit. Previous participation (receipt of randomized treatment) in this study. Subjects who were currently participating in an interventional study.

Ages Eligible for Study
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Minimum Age: 40 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tiotropium 2.5 mcg and placebo<br>Patients receive one of the active tiotropium arms daily | Drug: tiotropium 1.25 mcg (2 actuations/day)<br>* soft mist inhaler 2 actuations=2 puffs/day<br>|
| Active Comparator: tiotropium 18 mcg and placebo<br>Patients receive one of the active tiotropium arms daily | Drug: tiotropium 18 mcg<br>* HandiHaler<br>|
| Experimental: tiotropium 5 mcg and placebo<br>Patients receive one of the active tiotropium arms daily | Drug: tiotropium 2.5 mcg (2 actuations/day)<br>* soft mist inhaler (2 actuations=2 puffs/day)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to All-Cause Mortality | Number of patients with all-cause mortality | Up to 3 years | 
| Time to First COPD Exacerbation | Defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines). Onset of exacerbation was defined by the onset of first recorded symptom. The end of exacerbation was decided by the investigator based on clinical judgement. Exacerbations were classified as follows: Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 Over 120 Weeks (in a Substudy of 1370 Patients) | Trough forced expiratory volume in one second (FEV1) over 120 weeks (in a substudy of 1370 patients) | Up to 3 years | 
| Number of COPD Exacerbations | The number of COPD exacerbations. COPD exacerbation defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines). | Up to 3 years | 
| Time to First Hospitalization Associated With COPD Exacerbation | The results presented below are for the patients with hospitalizations due to COPD exacerbations. | Up to 3 years | 
| Number of Hospitalizations Associated With COPD Exacerbation | Total number of hospitalizations associated with COPD exacerbation. | Up to 3 years | 
| Time to First Moderate to Severe COPD Exacerbation | COPD exacerbation defined as a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment where a complex of lower respiratory event/symptoms was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where a required change in treatment includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines). Exacerbations classified as follows: Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization. Results presented below are number of patients with moderate to severe exacerbations. | Up to 3 years | 
| Time to Onset of First Major Adverse Cardiovascular Event (MACE) | Time to onset of first major adverse cardiovascular event (MACE). MACE was defined as: Fatal event in the system organ classes of cardiac and vascular disorders, Preferred terms: sudden death, cardiac death, sudden cardiac death, Outcome events of myocardial infarction (serious and non-serious), Outcome events of stroke (serious and non-serious) and Outcome events of TIA (serious and non-serious). The results presented below are for the number of patients with MACE. | Up to 3 years | 
| Time to Death From Major Adverse Cardiovascular Event (MACE) | The results presented below are number of patients with death from MACE. | Up to 3 years |