Effect of Tiotropium + Olodaterol on Breathlessness in COPD Patients

Study Overview
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Brief Summary
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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.

Official Title
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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]

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Tiotropium
* Drug: Olodaterol
* Drug: Tiotropium


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tiotropium + Olodaterol<br>Patients will receive tiotropium 5mcg + olodaterol 5mcg in a fixed dose combination once daily. | Drug: Tiotropium<br>* fixed dose combination once daily<br>Drug: Olodaterol<br>* fixed dose combination once daily<br>|
| Active Comparator: Tiotropium<br> | Drug: Tiotropium<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Intensity of Breathlessness Measured Using the Modified Borg Scale at the End of the 3 Minute (Min) Constant Speed Shuttle Test After 6 Weeks of Treatment. | At 3 min or end of exercise (if 3 min not achieved), patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). The modified Borg scale is 10-point subjective scoring system, in which a patient rates effort of exertion while performing a particular activity. The scale is 0 to 10, the higher the score, the greater the perceived difficulty. Measure type is actually Adjusted Mean Change from Baseline. | Baseline and week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured Prior to Exercise | Inspiratory Capacity (IC) is a standard measurement for the assessment of lung function. IC measurements were performed prior to the 3min Constant Speed Shuttle Test (CSST) (at rest). Measure type is actually Adjusted Mean Change from Baseline. | Baseline and week 6 | 
| Change From Baseline After 6 Weeks of Treatment for Inspiratory Capacity Measured at the End of Exercise | Inspiratory Capacity (IC) is a standard measurement for the assessment of lung function. IC measurements were performed at the end of the 3min Constant Speed Shuttle Test (CSST). Measure type is actually Adjusted Mean Change from Baseline. | Baseline and week 6 | 
| Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Expiratory Volume | Forced Expiratory Volume in 1st second (FEV1) is a standard measurement for the assessment of lung function. The best of 3 efforts was defined as the highest FEV1, each obtained on any of 3 manoeuvres meeting the American Thoracic Society (ATS) criteria (to a maximum of 5 attempts). Measure type is actually Adjusted Mean Change from Baseline. | Baseline and week 6 | 
| Change From Baseline After 6 Weeks of Treatment for 1 Hour Post-dose Forced Vital Capacity | Forced Vital Capacity (FVC) is a standard measurement for the assessment of lung function. The best of 3 efforts was defined as the highest FVC, each obtained on any of 3 manoeuvres meeting the American Thoracic Society (ATS) criteria (to a maximum of 5 attempts). Measure type is actually Adjusted Mean Change from Baseline. | Baseline and week 6 | 
| Change From Baseline After 6 Weeks of Treatment for Intensity of Breathlessness (MBS-S) at 1, 2 and 2.5 Minute (Min) During the 3 Min Constant Speed Shuttle Test | At 1, 2 and 2.5 min during exercise, patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). At 3 min or end of exercise (if 3 min not achieved), patients were asked to estimate the intensity of breathing discomfort that they were experiencing by matching their subjective estimate to descriptive phrases that best described the intensity of each sensation using the Modified Borg Scale (MBS-S). The modified Borg scale is 10-point subjective scoring system, in which a patient rates effort of exertion while performing a particular activity. The scale is 0 to 10, the higher the score, the greater the perceived difficulty. Measure type is actually Adjusted Mean Change from Baseline. | Baseline and week 6 | 
| Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Individualized (CRQ-SAI) Dyspnoea Domain Score | CRQ-SAI refers to the CRQ-Self-administered individualized format as it contains a dyspnea domain that is individualized to each patient. This version was derived from the original CRQ tool & therefore, is scored on 7-point Likert-type scale (1: maximum impairment to 7: no impairment) for each 4 domains covering: dyspnea, fatigue, emotional function & mastery. Dyspnea items may be selected from list of 26 suggested items or written in by the patients. The patients are asked to select up to 5 activities associated with breathlessness that they perform frequently and are most important to them. The scores for each question of each domain were added together and divided by the number of questions answered in each domain. The higher scores indicate better health-related quality of life in the respective domain. Measure type is actually Adjusted Mean Change from Baseline. | Baseline and week 6 | 
| Change From Baseline After 6 Weeks of Treatment for Chronic Respiratory Questionnaire - Self Administered Standardized (CRQ-SAS) Dyspnoea Domain Score | CRQ-SAS was questionnaire to assess patients' perception of COPD and measures the impact of COPD on their life. This version was derived from the original CRQ tool & therefore, is scored on 7-point Likert-type scale (1: maximum impairment to 7: no impairment) for each 4 domains covering: dyspnea, fatigue, emotional function & mastery. The CRQ-SAS refers to the CRQ-Self-administered standardized format & contains 20 questions. The first part of the questionnaire contains 5 standardized dyspnea questions and the patients must indicate how much shortness of breath they have experienced while performing each of these 5 activities. The scores for each question of each domain were added together and divided by the number of questions answered in each domain. The higher scores indicate better health-related quality of life in the respective domain. Measure type is actually Adjusted Mean Change from Baseline. | Baseline and week 6 |