Clinical trial NCT01525615: 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
Official title: 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)]
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Disease, Chronic Obstructive
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2012-02-03
Enrollment: 404
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 12 Weeks
timeFrame: 12 weeks
Secondary outcomes:
measure: Adjusted Mean Endurance Time During Endurance Shuttle Walk Test (ESWT) After 12 Weeks
timeFrame: 12 weeks
measure: Adjusted Mean Inspiratory Capacity at Pre-exercise After 12 Weeks
timeFrame: 12 weeks
measure: Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) on Day 1
timeFrame: 1 day
measure: Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 6 Weeks Treatment
timeFrame: 6 weeks
measure: Adjusted Mean Inspiratory Capacity at Pre-exercise After 1 Day
timeFrame: 1 day
measure: Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks
timeFrame: 6 weeks
measure: Adjusted Mean Slope of the Intensity of Breathing Discomfort on Day 1
timeFrame: 1 day
measure: Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 6
timeFrame: 6 weeks
measure: Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 12
timeFrame: 12 weeks
measure: Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) on Day 1
timeFrame: 1 day
measure: Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 6 Weeks
timeFrame: 6 weeks
measure: Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 12 Weeks
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Torrance
country: United States
facility: 1237.15.01503 Boehringer Ingelheim Investigational Site
state: California
city: Hartford
country: United States
facility: 1237.15.01512 Boehringer Ingelheim Investigational Site
state: Connecticut
city: Springfield
country: United States
facility: 1237.15.01506 Boehringer Ingelheim Investigational Site
state: Illinois
city: Iowa City
country: United States
facility: 1237.15.01507 Boehringer Ingelheim Investigational Site
state: Iowa
city: Livonia
country: United States
facility: 1237.15.01504 Boehringer Ingelheim Investigational Site
state: Michigan
city: St. Charles
country: United States
facility: 1237.15.01511 Boehringer Ingelheim Investigational Site
state: Missouri
city: Lebanon
country: United States
facility: 1237.15.01509 Boehringer Ingelheim Investigational Site
state: New Hampshire
city: Charlotte
country: United States
facility: 1237.15.01513 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Philadelphia
country: United States
facility: 1237.15.01514 Boehringer Ingelheim Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: 1237.15.01516 Boehringer Ingelheim Investigational Site
state: Pennsylvania
city: Easley
country: United States
facility: 1237.15.01508 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Greenville
country: United States
facility: 1237.15.01501 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Spartanburg
country: United States
facility: 1237.15.01505 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Union
country: United States
facility: 1237.15.01502 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Richmond
country: United States
facility: 1237.15.01510 Boehringer Ingelheim Investigational Site
state: Virginia
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: 1237.15.54502 Boehringer Ingelheim Investigational Site
city: Mendonza
country: Argentina
facility: 1237.15.54501 Boehringer Ingelheim Investigational Site
city: Provincia de Buenos Aires
country: Argentina
facility: 1237.15.54503 Boehringer Ingelheim Investigational Site
city: Hamilotn
country: Canada
facility: 1237.15.11501 Boehringer Ingelheim Investigational Site
state: Ontario
city: Hamilton
country: Canada
facility: 1237.15.11503 Boehringer Ingelheim Investigational Site
state: Ontario
city: Kingston
country: Canada
facility: 1237.15.11504 Boehringer Ingelheim Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: 1237.15.11505 Boehringer Ingelheim Investigational Site
state: Quebec
city: Ste-Foy
country: Canada
facility: 1237.15.11502 Boehringer Ingelheim Investigational Site
state: Quebec
city: Helsinki
country: Finland
facility: 1237.15.35851 Boehringer Ingelheim Investigational Site
city: Turku
country: Finland
facility: 1237.15.35853 Boehringer Ingelheim Investigational Site
city: Vaasa
country: Finland
facility: 1237.15.35852 Boehringer Ingelheim Investigational Site
city: Nîmes cedex 9
country: France
facility: 1237.15.33502 Boehringer Ingelheim Investigational Site
city: Pessac
country: France
facility: 1237.15.33504 Boehringer Ingelheim Investigational Site
city: Strasbourg Cedex
country: France
facility: 1237.15.33501 Boehringer Ingelheim Investigational Site
city: Aschaffenburg
country: Germany
facility: 1237.15.49507 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1237.15.49502 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1237.15.49504 Boehringer Ingelheim Investigational Site
city: Großhansdorf
country: Germany
facility: 1237.15.49501 Boehringer Ingelheim Investigational Site
city: Hamburg
country: Germany
facility: 1237.15.49509 Boehringer Ingelheim Investigational Site
city: Hannover
country: Germany
facility: 1237.15.49505 Boehringer Ingelheim Investigational Site
city: Koblenz
country: Germany
facility: 1237.15.49508 Boehringer Ingelheim Investigational Site
city: Wiesloch
country: Germany
facility: 1237.15.49506 Boehringer Ingelheim Investigational Site
city: Budapest
country: Hungary
facility: 1237.15.36504 Boehringer Ingelheim Investigational Site
city: Deszk
country: Hungary
facility: 1237.15.36501 Boehringer Ingelheim Investigational Site
city: Nyiregyhaza
country: Hungary
facility: 1237.15.36503 Boehringer Ingelheim Investigational Site
city: Pecs
country: Hungary
facility: 1237.15.36502 Boehringer Ingelheim Investigational Site
city: Ferrara
country: Italy
facility: 1237.15.39512 Boehringer Ingelheim Investigational Site
city: Parma
country: Italy
facility: 1237.15.39504 Boehringer Ingelheim Investigational Site
city: Pavia
country: Italy
facility: 1237.15.39503 Boehringer Ingelheim Investigational Site
city: Pisa
country: Italy
facility: 1237.15.39501 Boehringer Ingelheim Investigational Site
city: Pisa
country: Italy
facility: 1237.15.39509 Boehringer Ingelheim Investigational Site
city: Roma
country: Italy
facility: 1237.15.39511 Boehringer Ingelheim Investigational Site
city: Sesto San Giovanni (MI)
country: Italy
facility: 1237.15.39508 Boehringer Ingelheim Investigational Site
city: Trieste
country: Italy
facility: 1237.15.39506 Boehringer Ingelheim Investigational Site
city: Alicante
country: Spain
facility: 1237.15.34506 Boehringer Ingelheim Investigational Site
city: Barakaldo (Bilbao)
country: Spain
facility: 1237.15.34501 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1237.15.34507 Boehringer Ingelheim Investigational Site
city: Malaga
country: Spain
facility: 1237.15.34009 Boehringer Ingelheim Investigational Site
city: Santander
country: Spain
facility: 1237.15.34001 Boehringer Ingelheim Investigational Site
city: Leicester
country: United Kingdom
facility: 1237.15.44152 Boehringer Ingelheim Investigational Site
city: Liverpool
country: United Kingdom
facility: 1237.15.44154 Boehringer Ingelheim Investigational Site
city: London
country: United Kingdom
facility: 1237.15.44153 Boehringer Ingelheim Investigational Site
city: Manchester
country: United Kingdom
facility: 1237.15.44151 Boehringer Ingelheim Investigational Site
city: Norwich
country: United Kingdom
facility: 1237.15.44155 Boehringer Ingelheim Investigational Site
city: Plymouth
country: United Kingdom
facility: 1237.15.44158 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: 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.