Tiotropium Once Daily 18 Mcg Versus Salmeterol Twice Daily 50 Mcg on Time to First Exacerbation in COPD Patients.
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Pulmonary Disease, Chronic Obstructive
Intervention: Tiotropium bromide; Salmeterol; Placebo Salmeterol; Placebo Tiotropium
Intervention description: 18 mcg/daily; 100 mcg/daily; Placebo identical to Salmeterol device; Placebo identical to Tiotropium device
Intervention MeSH terms: Bromides; Tiotropium Bromide; Salmeterol Xinafoate
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Enrollment: 7376.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No

Summary:

      This is a randomised, double-blind, double-dummy, multinational, multicentre, parallel group
      trial comparing tiotropium (18 mcg) inhalation capsule via HandiHaler and salmeterol (50 mcg)
      via MDI in patients with COPD. There will be a two-week run-in period followed by a 52-week
      randomised treatment phase. Patients who withdraw prematurely from trial medication will be
      encouraged to remain in the trial and participate in follow-up telephone contacts until their
      predicted normal exit date from the trial (i.e. 52 weeks after taking the first dose of
      randomised treatment). The phone calls will be made at all scheduled visits.

      The primary objective of this study is to compare the effect of tiotropium (18 mcg)
      inhalation capsule via HandiHaler with that of salmeterol (50 mcg) via MDI on COPD
      exacerbations.

      The primary endpoint is time to first COPD exacerbation during the 52 week randomised
      treatment period. A COPD exacerbation will be defined as a complex of respiratory events /
      symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing,
      dyspnoea or chest tightness with at least one symptom lasting at least three days requiring
      treatment with antibiotics and/or systemic steroids and/or hospitalisation.

      The onset of an exacerbation is defined as the onset of the first new or increased reported
      symptom. The end of the exacerbation should be recorded as defined by the investigator.

      Only COPD exacerbations with onset during randomised treatment will be included in the
      analysis.
    

Eligibility criteria:

        Inclusion Criteria:

          1. All patients must have a diagnosis of chronic obstructive pulmonary disease (COPD) and
             must meet the following criteria at Visit 1:

             Patients must have relatively stable, moderate to very severe airway obstruction with
             a post-bronchodilator FEV1 <=70% of predicted normal and FEV1 <=70% of FVC
             post-bronchodilator (i.e. 30 minutes after inhalation of 4 puffs of 100 µg salbutamol
             or equivalent SABA). Predicted normal values will be calculated according to ECSC.

             For Height measured in inches Males: FEV1 predicted (L) = 4.30 x (height (inches) /
             39.37)-0.029 x age (yrs) - 2.49 Females:FEV1 predicted (L) = 3.95 x (height (inches) /
             39.37)-0.025 x age (yrs) - 2.60 For Height measured in metres Males: FEV1 predicted
             (L) = 4.30 x (height (metres)) - 0.029 x age (years) - 2.49 Females: FEV1 predicted
             (L) = 3.95 x (height (metres)) - 0.025 x age (years) - 2.60

          2. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to
             participation in the trial.

          3. Male or female patients 40 years of age or older.

          4. Patients with a history of at least one exacerbation within the past year requiring
             treatment with either antibiotics and/or systemic steroids and/or hospitalisation.

          5. Patients must be current or ex-smokers with a smoking history of >= 10 pack-years.
             (Patients who have never smoked cigarettes must be excluded.)

          6. Patients must be able to perform all study-related procedures including technically
             acceptable pulmonary function tests (PFTs).

          7. Patients must be able to inhale medication in a competent manner from the HandiHaler
             and a metered dose inhaler (MDI).

          8. Patients must be able to maintain records (patient daily diary card) during the study
             period as required in the protocol.

        Exclusion Criteria:

          1. 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 either the results of the study
             or the patients' ability to participate in the study.

          2. Patients with a diagnosis of asthma.

          3. Patients with a life-threatening pulmonary obstruction, or a history of cystic
             fibrosis.

          4. Patients with known active tuberculosis.

          5. Patients with a known symptomatic prostatic hyperplasia or bladder neck obstruction.
             Patients with symptomatically-controlled prostatic hyperplasia on medication may be
             included and should continue their medication.

          6. Patients with known narrow-angle glaucoma.

          7. Patients with a history of myocardial infarction within the year prior to Visit 1.

          8. Patients with a history of hospital admission for heart failure within the year prior
             to Visit 1.

          9. Patients with cardiac arrhythmia requiring medical or surgical treatment.

         10. Patients with severe cardiovascular disorders.

         11. Patients with a known hypersensitivity to anticholinergic drugs, beta-adrenergics,
             lactose or any other component of the medication delivery system.

         12. Patients with known moderate or severe renal insufficiency (known creatinine clearance
             of <= 50 mL/min).

         13. Patients with untreated known hypokalaemia.

         14. Patients with untreated known thyrotoxicosis.

         15. Patients with brittle/unstable diabetes mellitus.

         16. Patients with a history of and/or active significant alcohol or drug abuse. See
             exclusion criterion 1.

         17. Patients who have taken an investigational drug within 30 days or six half-lives
             (whichever is greater) prior to Screening Visit (Visit 1).

         18. Use of systemic corticosteroid medication at unstable doses (i.e less than six weeks
             on stable dose) or at doses in excess of the equivalent of 10 mg prednisolone per day
             or 20 mg every other day.

         19. Pregnant or nursing women or women of childbearing potential not using a medically
             approved means of contraception (i.e oral contraceptives, intrauterine devices,
             diaphragm or subdermal implants e.g Norplant) for at least three months prior to, and
             for the duration of the trial.

         20. Previous participation (receipt of randomised treatment) in this study.

         21. Patients who are currently participating in another study.

         22. Patients with any respiratory infection or COPD exacerbation in the four weeks prior
             to the Screening Visit (Visit 1) or during the run-in period should be postponed. In
             the case of a respiratory infection or COPD exacerbation during the run-in period, the
             latter may be extended up to four weeks.