A Study to Determine the Effect of Tiotropium + Olodaterol Fixed Dose Combination on Exercise Endurance Time During Constant Work Rate Cycle Ergometry Test in COPD

A Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Determine the Effect of 12 Weeks Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (2.5/5 µg and 5/5 µg) Delivered by the Respimat® Inhaler, on Exercise Endurance Time During Constant Work Rate Cycle Ergometry in Patients With Chronic Obstructive Pulmonary Disease (COPD)[Torracto (TM)]

The primary objective of this study is to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5/5 µg; 5/5 µg) with placebo on exercise tolerance after 12 weeks of treatment in patients with COPD.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Device: Respimat inhaler; Drug: tiotropium+olodaterol (low dose); Drug: tiotropium + olodaterol (high dose); Drug: placebo to tiotropium+olodaterol

• Study Type: Interventional
• Enrollment (Actual): 404
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Autonoma de Buenos Aires, Argentina
    • 1237.15.54502 Boehringer Ingelheim Investigational Site
  • Mendonza, Argentina
    • 1237.15.54501 Boehringer Ingelheim Investigational Site
  • Provincia de Buenos Aires, Argentina
    • 1237.15.54503 Boehringer Ingelheim Investigational Site
• Canada
  • Ontario
    • Hamilotn, Ontario, Canada
      • 1237.15.11501 Boehringer Ingelheim Investigational Site
    • Hamilton, Ontario, Canada
      • 1237.15.11503 Boehringer Ingelheim Investigational Site
    • Kingston, Ontario, Canada
      • 1237.15.11504 Boehringer Ingelheim Investigational Site
  • Quebec
    • Montreal, Quebec, Canada
      • 1237.15.11505 Boehringer Ingelheim Investigational Site
    • Ste-Foy, Quebec, Canada
      • 1237.15.11502 Boehringer Ingelheim Investigational Site
• Finland
  • Helsinki, Finland
    • 1237.15.35851 Boehringer Ingelheim Investigational Site
  • Turku, Finland
    • 1237.15.35853 Boehringer Ingelheim Investigational Site
  • Vaasa, Finland
    • 1237.15.35852 Boehringer Ingelheim Investigational Site
• France
  • Nîmes cedex 9, France
    • 1237.15.33502 Boehringer Ingelheim Investigational Site
  • Pessac, France
    • 1237.15.33504 Boehringer Ingelheim Investigational Site
  • Strasbourg Cedex, France
    • 1237.15.33501 Boehringer Ingelheim Investigational Site
• Germany
  • Aschaffenburg, Germany
    • 1237.15.49507 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1237.15.49502 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1237.15.49504 Boehringer Ingelheim Investigational Site
  • Großhansdorf, Germany
    • 1237.15.49501 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1237.15.49509 Boehringer Ingelheim Investigational Site
  • Hannover, Germany
    • 1237.15.49505 Boehringer Ingelheim Investigational Site
  • Koblenz, Germany
    • 1237.15.49508 Boehringer Ingelheim Investigational Site
  • Wiesloch, Germany
    • 1237.15.49506 Boehringer Ingelheim Investigational Site
• Hungary
  • Budapest, Hungary
    • 1237.15.36504 Boehringer Ingelheim Investigational Site
  • Deszk, Hungary
    • 1237.15.36501 Boehringer Ingelheim Investigational Site
  • Nyiregyhaza, Hungary
    • 1237.15.36503 Boehringer Ingelheim Investigational Site
  • Pecs, Hungary
    • 1237.15.36502 Boehringer Ingelheim Investigational Site
• Italy
  • Ferrara, Italy
    • 1237.15.39512 Boehringer Ingelheim Investigational Site
  • Parma, Italy
    • 1237.15.39504 Boehringer Ingelheim Investigational Site
  • Pavia, Italy
    • 1237.15.39503 Boehringer Ingelheim Investigational Site
  • Pisa, Italy
    • 1237.15.39501 Boehringer Ingelheim Investigational Site
  • Pisa, Italy
    • 1237.15.39509 Boehringer Ingelheim Investigational Site
  • Roma, Italy
    • 1237.15.39511 Boehringer Ingelheim Investigational Site
  • Sesto San Giovanni (MI), Italy
    • 1237.15.39508 Boehringer Ingelheim Investigational Site
  • Trieste, Italy
    • 1237.15.39506 Boehringer Ingelheim Investigational Site
• Spain
  • Alicante, Spain
    • 1237.15.34506 Boehringer Ingelheim Investigational Site
  • Barakaldo (Bilbao), Spain
    • 1237.15.34501 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 1237.15.34507 Boehringer Ingelheim Investigational Site
  • Malaga, Spain
    • 1237.15.34009 Boehringer Ingelheim Investigational Site
  • Santander, Spain
    • 1237.15.34001 Boehringer Ingelheim Investigational Site
• United Kingdom
  • Leicester, United Kingdom
    • 1237.15.44152 Boehringer Ingelheim Investigational Site
  • Liverpool, United Kingdom
    • 1237.15.44154 Boehringer Ingelheim Investigational Site
  • London, United Kingdom
    • 1237.15.44153 Boehringer Ingelheim Investigational Site
  • Manchester, United Kingdom
    • 1237.15.44151 Boehringer Ingelheim Investigational Site
  • Norwich, United Kingdom
    • 1237.15.44155 Boehringer Ingelheim Investigational Site
  • Plymouth, United Kingdom
    • 1237.15.44158 Boehringer Ingelheim Investigational Site
• United States
  • California
    • Torrance, California, United States
      • 1237.15.01503 Boehringer Ingelheim Investigational Site
  • Connecticut
    • Hartford, Connecticut, United States
      • 1237.15.01512 Boehringer Ingelheim Investigational Site
  • Illinois
    • Springfield, Illinois, United States
      • 1237.15.01506 Boehringer Ingelheim Investigational Site
  • Iowa
    • Iowa City, Iowa, United States
      • 1237.15.01507 Boehringer Ingelheim Investigational Site
  • Michigan
    • Livonia, Michigan, United States
      • 1237.15.01504 Boehringer Ingelheim Investigational Site
  • Missouri
    • St. Charles, Missouri, United States
      • 1237.15.01511 Boehringer Ingelheim Investigational Site
  • New Hampshire
    • Lebanon, New Hampshire, United States
      • 1237.15.01509 Boehringer Ingelheim Investigational Site
  • North Carolina
    • Charlotte, North Carolina, United States
      • 1237.15.01513 Boehringer Ingelheim Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • 1237.15.01514 Boehringer Ingelheim Investigational Site
    • Pittsburgh, Pennsylvania, United States
      • 1237.15.01516 Boehringer Ingelheim Investigational Site
  • South Carolina
    • Easley, South Carolina, United States
      • 1237.15.01508 Boehringer Ingelheim Investigational Site
    • Greenville, South Carolina, United States
      • 1237.15.01501 Boehringer Ingelheim Investigational Site
    • Spartanburg, South Carolina, United States
      • 1237.15.01505 Boehringer Ingelheim Investigational Site
    • Union, South Carolina, United States
      • 1237.15.01502 Boehringer Ingelheim Investigational Site
  • Virginia
    • Richmond, Virginia, United States
      • 1237.15.01510 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions.

2. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria:

   Patients must have relatively stable airway obstruction with, at visit 1:

   a post-bronchodilator 30% <= FEV1 <80% of predicted normal (ECSC) and a post-bronchodilator FEV1/FVC <70% at Visit 1

3. Male or female patients, between 40 and 75 years (inclusive) of age on day of signing informed consent.
4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years Patients who have never smoked cigarettes must be excluded.
5. Patients must be able to perform technically acceptable pulmonary function tests (spirometry), must be able to complete multiple symptom-limited cycle ergometry tests (and for a subset also shuttle walk tests), 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 inhaler (MDI).

Exclusion criteria:

1. Patients with a significant disease other than COPD
2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an SGOT > x2 ULN, SGPT > x2 ULN, bilirubin > x2 ULN or creatinine > x2 ULN will be excluded regardless of clinical condition
3. Patients with a history of asthma
4. A diagnosis of thyrotoxicosis
5. A diagnosis of paroxysmal tachycardia (>100 beats per minute)
6. A history of myocardial infarction within 1 year of screening visit (Visit 1)
7. Unstable or life-threatening cardiac arrhythmia
8. Hospitalized for heart failure within the past year
9. Known active tuberculosis
10. A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years
11. A history of life-threatening pulmonary obstruction and patients with chronic respiratory failure
12. A history of cystic fibrosis
13. Clinically evident bronchiectasis
14. A history of significant alcohol or drug abuse
15. Any contraindications for exercise testing
16. Patients who have undergone thoracotomy with pulmonary resection
17. Patients being treated with any oral ß-adrenergics
18. Patients being treated with 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
19. 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
20. 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
21. Patients who have a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnoea or morbid obesity
22. Patients with an endurance time >=25 minutes during the training (Visit 2) or baseline (Visit 3) constant work rate cycle ergometry
23. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit (Visit 1)
24. Patients with known hypersensitivity to ß-adrenergic drugs, anticholinergic drugs, BAC, EDTA or any other component of the RESPIMAT inhalation solution delivery system
25. Pregnant or nursing women

26. Women of childbearing potential not using a highly effective method of birth control.

    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

27. Patients who have previously been randomized in this study or are currently participating in another study

28. Patients who are unable to comply with pulmonary medication restrictions prior to randomization

    At sites performing the shuttle walk tests, patients with the following criteria will be excluded from the shuttle walk tests:

29. Patients who complete level 12 at the incremental shuttle walk test at visit 1a.
30. Patients with an endurance time >=15 minutes during the training (Visit 2a) or baseline (visit 3a) endurance shuttle walk test.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: tiotropium+olodaterol low dose; once daily 2 puffs, fixed dose combination (FDC) solution for inhalation Respimat	Device: Respimat inhaler; Respimat inhaler; Drug: tiotropium+olodaterol (low dose); 2.5 µg tiotropium + 5 µg olodaterol
Experimental: tiotropium+olodaterol high dose; once daily 2 puffs, FDC solution for inhalation Respimat	Device: Respimat inhaler; Respimat inhaler; Drug: tiotropium + olodaterol (high dose); 5 µg tiotropium + 5 µg olodaterol
Placebo Comparator: placebo; once daily 2 puffs, solution for inhalation Respimat	Device: Respimat inhaler; Respimat inhaler; Drug: placebo to tiotropium+olodaterol; comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 12 Weeks	Primary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment. The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Mean Endurance Time During Endurance Shuttle Walk Test (ESWT) After 12 Weeks	Key secondary endpoint was endurance time during endurance shuttle walk test to symptom limitation at 85% of predicted maximum oxygen consumption (VO2) peak after 12 weeks of treatment. The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean.	12 weeks
Adjusted Mean Inspiratory Capacity at Pre-exercise After 12 Weeks	Secondary endpoint was pre-exercise inspiratory capacity (IC) before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) after 12 weeks of treatment.	12 weeks
Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) on Day 1	Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity on Day 1. Analysis of covariance model on log10 transformation data. Adjusted means are back transformed to report in original units. Standard errors (SEs) are calculated using the delta method.	1 day
Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 6 Weeks Treatment	Secondary endpoint was endurance time during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment.The endurance time in seconds was transformed using log10 scale to correct skewness in endurance time on original scale and then the MMRM model was fitted to the log10-transformed data and the least square means and SEs were obtained. To present the results in a way easier for interpretation, the least square mean from the MMRM fitted to the log10-transformed data were transformed back taking 10 to the power of the least square estimate for the log10 of geometric mean and the corresponding SE was transformed using delta method to get the corresponding SEs of the geometric mean.	6 weeks
Adjusted Mean Inspiratory Capacity at Pre-exercise After 1 Day	Secondary endpoint was pre-exercise inspiratory capacity (IC) during constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) on Day 1.	1 day
Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks	Secondary endpoint was pre-exercise inspiratory capacity (IC) during constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap) after 6 weeks of treatment.	6 weeks
Adjusted Mean Slope of the Intensity of Breathing Discomfort on Day 1	Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 1 day of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates slowing down in decline in breathing, i.e., favorable results.	1 day
Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 6	Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 6 weeks of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results.	6 weeks
Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 12	Secondary endpoint was the slope of the intensity of breathing discomfort during constant work rate cycle ergometry to symptom limitation at 75% of maximal work capacity after 12 weeks of treatment. The intensity of breathing discomfort was rated on the Borg Scale with categories from 0 (nothing at all) to 10 (maximal). The slope of the intensity of breathing discomfort was defined as the Borg scale value of breathing discomfort at the end of exercise minus the Borg scale value of breathing discomfort at pre-exercise divided by the endurance time. A decrease in slope indicates favorable results.	12 weeks
Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) on Day 1	Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed on day 1	1 day
Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 6 Weeks	Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed after 6 weeks of treatment	6 weeks
Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 12 Weeks	Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed after 12 weeks of treatment	12 weeks

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Maltais F, O'Donnell D, Galdiz Iturri JB, Kirsten AM, Singh D, Hamilton A, Tetzlaff K, Zhao Y, Casaburi R. Effect of 12 weeks of once-daily tiotropium/olodaterol on exercise endurance during constant work-rate cycling and endurance shuttle walking in chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2018 Jan-Dec;12:1753465818755091. doi: 10.1177/1753465818755091.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: February 1, 2012
• First Submitted That Met QC Criteria: February 1, 2012
• First Posted (Estimate): February 3, 2012

Study Record Updates

• Last Update Posted (Estimate): August 29, 2016
• Last Update Submitted That Met QC Criteria: July 28, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide; Olodaterol
• Other Study ID Numbers: 1237.15; 2011-004253-11 (EudraCT Number: EudraCT)