Pharmacokinetics and Safety of BI 1744 CL Plus Tiotropium Bromide in Chronic Obstructive Pulmonary Disease (COPD)

A Randomised, Double-blind, 3-way Crossover Study to Compare Pharmacokinetics and Safety of 10 μg BI 1744 CL Plus 5 μg Tiotropium Bromide Given as Fixed Dose Combination Via the Respimat® Inhaler With the Pharmacokinetics and the Safety of the Single Agents, i.e. 10 μg BI 1744 CL and 5 μg Tiotropium Bromide, Delivered Via the Respimat® Inhaler Following 21 Day-treatment Periods in Patients With Chronic Obstructive Pulmonary Disease (COPD)

The purpose of this study is to compare the systemic exposure to BI 1744 BS and tiotropium at steady state following inhalation of the fixed dose combination (FDC) of 10 μg BI 1744 CL plus 5 μg tiotropium bromide with the systemic exposure to BI 1744 BS and tiotropium at steady state following inhalation of the single agents, i.e., 10 μg BI 1744 CL and 5 μg tiotropium bromide, when administered once-daily via the Respimat® Inhaler for 21 days.

The secondary objectives were to compare the safety and tolerability (adverse events, 12-lead electrocardiogram recordings, pulmonary function testing) of BI 1744 CL and tiotropium bromide when administered as fixed dose combination or as single-agent therapy.

Inclusion Criteria:

1. All patients must sign an informed consent consistent with International Conference on Harmonisation (ICH) - Good Clinical Practice (GCP) guidelines and local legislations prior to any study-related procedures, which includes medication washout and restrictions
2. All patients must have a diagnosis of COPD and must meet the following spirometric criteria: Patients must have relatively stable airway obstruction with a post-bronchodilator forced expiratory volume in one second (FEV1) ≥ 30 % of predicted normal and < 80% of predicted normal and a post-bronchodilator FEV1 / forced vital capacity (FVC) < 70% at Visit 1
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 during the study period as required in the protocol
6. Patients must be able to inhale medication in a competent manner from the Respimat® inhaler and from a metered dose inhalator (MDI)

Exclusion Criteria:

1. Patients with a significant disease other than COPD; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patient's ability to participate in the study

2. Patients with clinically relevant abnormal baseline haematology, blood chemistry or urinalysis; all patients with a serum glutamic oxaloacetic transaminase (SGOT) > 2.5 x ULN, serum glutamic pyruvic transaminase (SGPT) > 2.5 x ULN, bilirubin >2x upper limit of normal (ULN), creatinine >2 x ULN or creatinine clearance < 50 mL/min (Estimation of Glomerular Filtration Rate (GFR) by using the Cockcroft-Gault Formula) will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients)

3. Patients with a history of asthma or a total blood eosinophil count ≥600/mm3

4. Patients with any of the following conditions:

   • a diagnosis of thyrotoxicosis
   • a diagnosis of paroxysmal tachycardia (>100 beats per minute)
   • a marked baseline prolongation of QT/QTc interval
   • a history of additional risk factors for Torsade de Pointes (TdP) (e.g. heart failure, hypokalaemia, family history of Long QT Syndrome)

5. Patients with any of the following conditions:

   • a history of myocardial infarction within 1 year of screening visit (Visit 1)
   • a diagnosis of cardiac arrhythmia, arterial hypertension or coronary heart disease
   • known active tuberculosis
   • a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed)
   • a history of life-threatening pulmonary obstruction
   • a history of cystic fibrosis
   • clinically evident bronchiectasis
   • a history of significant alcohol or drug abuse

6. Patients who have undergone thoracotomy with pulmonary resection

7. Patients being treated with any of the following concomitant medications:

   • medications that prolong the QT/QTc interval since the effects of BI 1744 CL on QT/QTc interval have yet to be fully characterized
   • oral β-adrenergics
   • β-blockers (topical β -blockers for ocular conditions are allowed)
   • oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day

8. 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 during clinic visits

9. 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

10. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to Screening Visit (Visit 1)

11. Patients with known hypersensitivity to β-adrenergics and/or anticholinergic drugs, benzalkonium chloride, ethylenediaminetetraacetic acid or any other component of the Respimat® inhalation solution delivery system

12. Pregnant or nursing women

13. Women of childbearing potential not using two highly effective methods of birth control (one barrier and one non-barrier). Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years

14. Patients who have previously been randomized in this study or are currently participating in another study

15. Patients who are unable to comply with pulmonary medication restrictions prior to randomization

16. According to Inclusion Criterion No. 2, patients with a post-bronchodilator FEV1 of < 30% of predicted normal will always be excluded. Patients with a post-bronchodilator FEV1 between 30 and 50% of predicted normal will be excluded from the study, if they display additional symptoms of chronic respiratory insufficiency or right ventricular insufficiency

17. Patients with narrow angle glaucoma, prostate hyperplasia, or bladder neck obstruction