Effect of Tiotropium + Olodaterol on Breathlessness in COPD Patients

A Randomised, Double-blind, Cross-over Study to Evaluate the Effect of 6 Weeks Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (5/5 µg) Compared With Tiotropium (5 µg), Both Delivered by the Respimat® Inhaler, on Breathlessness During the Three Minute Constant Speed Shuttle Test (3min CSST) in Patients With Chronic Obstructive Pulmonary Disease (COPD). [OTIVATO TM]

The primary objective of the present study is to evaluate the effect of tiotropium + olodaterol fixed dose combination (FDC) compared to tiotropium monotherapy on the intensity of breathlessness during the 3min constant speed shuttle test (CSST).

A secondary objective is to explore the relationship between reductions in breathlessness during the 3min CSST and reductions in breathlessness during activities of everyday living as measured by the dyspnea domain of the Chronic Respiratory Questionnaire (CRQ) following bronchodilator therapy.

Inclusion criteria:

• Patients must sign an informed consent consistent with International Conference on Harmonization Good Clinical Practice guidelines prior to participation in the trial, including medication washout and restrictions
• Diagnosis of Chronic Obstructive Pulmonary Disease and relatively stable airway obstruction: post bronchodilator 30%<= Forced Expiratory Volume in 1st second (FEV1)<80% of predicted normal (European Coal and Steel Community) and a post bronchodilator FEV1/Forced Vital Capacity<0.70 at visit 1
• Male or female patients >=40 and =<75 years of age on day of signing consent.
• Current or ex-smokers with a smoking history > 10 pack-years. Patients who have never smoked cigarettes must be excluded.
• Baseline Dyspnea Index score< 8 at visit 0.
• Hyperinflation at rest, defined as Functional Residual Capacity > 120% predicted at visit 1.
• Borg dyspnea score >=4 at the end of 3min Constant Speed Shuttle Test at visit 2
• Perform technically acceptable pulmonary function tests (spirometry and body plethysmography) and complete multiple shuttle tests during the study period
• Inhale medication in a competent manner from the Respimat® inhaler and from a metered dose inhaler

Exclusion criteria:

• Significant disease other than Chronic Obstructive Pulmonary Disease (COPD); a significant disease which, in the investigator's opinion, may (i) put the patient at risk (ii) influence the study results or (iii) cause concern regarding the patient's ability to participate
• Clinically relevant abnormal baseline haematology, blood chemistry, in the investigator's opinion, or creatinine >x2 Upper Limit Normal will be excluded regardless of clinical condition
• Current documented diagnosis of asthma
• COPD exacerbation in the 6 weeks prior to screening
• Diagnosis of thyrotoxicosis
• History of myocardial infarction within 6 months of screening
• Life-threatening cardiac arrhythmia (investigator judgment)
• Known active tuberculosis
• Any malignancy unless free of disease for at least 5 years (treated basal cell carcinoma or squamous cell skin cancers are allowed)
• History of cystic fibrosis
• Clinically relevant bronchiectasis (investigator judgment)
• Severe emphysema requiring endobronchial interventions within 6 months prior to screening
• History of significant alcohol or drug abuse (investigator judgment)
• Any contraindications for exercise testing
• Patients who have undergone thoracotomy with pulmonary resection
• Treatment with any oral or patch ß-adrenergics
• Treatment with oral corticosteroid medication at unstable doses or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day
• Treatment with antibiotics for any reason within 4 weeks of screening
• Patients being treated with Phosphodiesterase Type 4 (PDE4) inhibitors within 3 months of screening visit should not be enrolled and PDE4 inhibitors should not be withdrawn for the purpose of enrolling in this study
• Regular use of daytime oxygen therapy for >1 hour per day and in the investigator's opinion will be unable to abstain from use during clinic visits
• Completion of a pulmonary rehabilitation program 6 weeks prior to screening or currently in a program
• Limitation of exercise performance as a result of factors other than fatigue or exertional dyspnea, such as arthritis in the leg, angina pectoris, claudication, morbid obesity
• Endurance time >=12 minutes during the incremental shuttle walk test
• Oxygen saturation < 85% (on room air) at rest or during exercise.
• Taken an investigational drug within 1 month or 6 half-lives or in case the investigational drug class is listed within the washout period specified prior to screening visit
• Known hypersensitivity to ß-adrenergics and/or anticholinergic drugs, Benzalkonium Chloride, Ethylenediaminetetraacetic acid or any other component of the Respimat® inhalation solution
• Women who are pregnant, nursing, or who plan to become pregnant while in the trial
• Women of childbearing potential not using a highly effective method of birth control
• Previously been randomized in this study or are currently participating in another study
• Unable to comply with pulmonary medication restrictions prior to randomization