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

Pulmonary Disease, Chronic Obstructive Clinical Trial

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)]

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01525615
• Other study ID #: 1237.15
• Secondary ID: 2011-004253-11
• Status: Completed
• Phase: Phase 3
• First received: February 1, 2012
• Last updated: August 12, 2015
• Start date: February 2012
• Est. completion date: September 2013

Study information

• Verified date: August 2015
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Admin Nacional de Medicamentos, Alimentos Tecnologia MedicaCanada: Health CanadaFinland: Finnish Medicines AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesHungary: National Institute of PharmacyItaly: Ethics CommitteeSpain: Spanish Agency of MedicinesUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 404
• Est. completion date: September 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Pulmonary Disease, Chronic Obstructive

Intervention

Device:
• Respimat inhaler
Respimat inhaler

Drug:
• tiotropium+olodaterol (low dose)
2.5 µg tiotropium + 5 µg olodaterol
• tiotropium + olodaterol (high dose)
5 µg tiotropium + 5 µg olodaterol

Device:
• Respimat inhaler
Respimat inhaler
• Respimat inhaler
Respimat inhaler

Drug:
• placebo to tiotropium+olodaterol
comparator

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Canada,  Finland,  France,  Germany,  Hungary,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No

External Links

•   Link