Pharmacokinetics and Safety of BI 1744 CL Plus Tiotropium Bromide in Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: BI 1744 CL; BI 1744 CL/Tiotropium FDC; Tiotropium
Intervention MeSH terms: Tiotropium Bromide; Olodaterol
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double
Enrollment: 47.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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