Tiotropium Once Daily 18 Mcg Versus Salmeterol Twice Daily 50 Mcg on Time to First Exacerbation in COPD Patients.

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.

• Drug: Tiotropium bromide
  18 mcg/daily
• Drug: Salmeterol
  100 mcg/daily
• Drug: Placebo Salmeterol
  Placebo identical to Salmeterol device
• Drug: Placebo Tiotropium
  Placebo identical to Tiotropium device

• Active Comparator: Tiotropium + Placebo
  patients inhale Tiotropium 18mcg once daily via HandiHaler and Placebo MDI twice daily
  Interventions:

  • Drug: Tiotropium bromide
  • Drug: Placebo Salmeterol
• Active Comparator: Salmeterol + Placebo
  patients inhale Salmeterol 50mcg twice daily via MDI and Placebo HandiHaler once daily
  Interventions:

  • Drug: Salmeterol
  • Drug: Placebo Tiotropium

• Vogelmeier CF, Asijee GM, Kupas K, Beeh KM. Tiotropium and Salmeterol in COPD Patients at Risk of Exacerbations: A Post Hoc Analysis from POET-COPD(®). Adv Ther. 2015 Jun;32(6):537-47. doi: 10.1007/s12325-015-0216-2. Epub 2015 Jun 23.
• Rabe KF, Fabbri LM, Israel E, Kögler H, Riemann K, Schmidt H, Glaab T, Vogelmeier CF. Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial. Lancet Respir Med. 2014 Jan;2(1):44-53. doi: 10.1016/S2213-2600(13)70248-0. Epub 2013 Dec 5.
• Beeh KM, Glaab T, Stowasser S, Schmidt H, Fabbri LM, Rabe KF, Vogelmeier CF. Characterisation of exacerbation risk and exacerbator phenotypes in the POET-COPD trial. Respir Res. 2013 Oct 29;14:116. doi: 10.1186/1465-9921-14-116.
• Rabe KF, Fabbri LM, Vogelmeier C, Kögler H, Schmidt H, Beeh KM, Glaab T. Seasonal distribution of COPD exacerbations in the Prevention of Exacerbations with Tiotropium in COPD trial. Chest. 2013 Mar;143(3):711-719. doi: 10.1378/chest.12-1277.
• Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Mölken MP, Beeh KM, Rabe KF, Fabbri LM; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011 Mar 24;364(12):1093-1103. doi: 10.1056/NEJMoa1008378.
• Beeh KM, Hederer B, Glaab T, Müller A, Rutten-van Moelken M, Kesten S, Vogelmeier C. Study design considerations in a large COPD trial comparing effects of tiotropium with salmeterol on exacerbations. Int J Chron Obstruct Pulmon Dis. 2009;4:119-25. Epub 2009 Apr 15.

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.