Effect on Exercise Endurance and Lung Hyperinflation of Tiotropium + Olodaterol in COPD Patients.

A Randomised, Double-blind, 5 Treatment Arms, 4-period, Incomplete Cross-over Study to Determine the Effect of 6 Weeks Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination (FDC) (2.5 / 5 µg; and 5 / 5 µg) (Delivered by the Respimat® Inhaler) Compared With Tiotropium (5 µg), Olodaterol (5 µg ) and Placebo (Delivered by the Respimat® Inhaler) on Lung Hyperinflation and Exercise Endurance Time During Constant Work Rate Cycle Ergometry in Patients With Chronic Obstructive Pulmonary Disease (COPD) [MORACTO TM 2]

The primary objective of this trial is to investigate the effect of 6 weeks treatment with tiotropium + olodaterol fixed dose combination inhalation solution on lung hyperinflation and exercise tolerance in patients with COPD.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: Olodaterol; Device: Respimat; Drug: Placebo; Drug: Tiotropium; Drug: Tiotropium + Olodaterol; Drug: tiotropium + Olodaterol

• Study Type: Interventional
• Enrollment (Actual): 291
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • 1237.14.54402 Boehringer Ingelheim Investigational Site
  • Mendoza, Argentina
    • 1237.14.54401 Boehringer Ingelheim Investigational Site
• Austria
  • Grieskirchen, Austria
    • 1237.14.43402 Boehringer Ingelheim Investigational Site
  • Neumarkt am Wallersee, Austria
    • 1237.14.43401 Boehringer Ingelheim Investigational Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
      • 1237.14.11404 Boehringer Ingelheim Investigational Site
  • Ontario
    • Toronto, Ontario, Canada
      • 1237.14.11403 Boehringer Ingelheim Investigational Site
  • Quebec
    • Montreal, Quebec, Canada
      • 1237.14.11402 Boehringer Ingelheim Investigational Site
    • Ste-Foy, Quebec, Canada
      • 1237.14.11401 Boehringer Ingelheim Investigational Site
• Germany
  • Bamberg, Germany
    • 1237.14.49406 Boehringer Ingelheim Investigational Site
  • Bochum, Germany
    • 1237.14.49404 Boehringer Ingelheim Investigational Site
  • Großhansdorf, Germany
    • 1237.14.49401 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1237.14.49405 Boehringer Ingelheim Investigational Site
  • Hannover, Germany
    • 1237.14.49403 Boehringer Ingelheim Investigational Site
  • Kiel, Germany
    • 1237.14.49402 Boehringer Ingelheim Investigational Site
• Netherlands
  • Heerlen, Netherlands
    • 1237.14.31001 Boehringer Ingelheim Investigational Site
  • Hoofddorp, Netherlands
    • 1237.14.31005 Boehringer Ingelheim Investigational Site
  • Hoorn, Netherlands
    • 1237.14.31004 Boehringer Ingelheim Investigational Site
  • Leeuwarden, Netherlands
    • 1237.14.31006 Medisch Centrum Leeuwarden
  • Leiden, Netherlands
    • 1237.14.31007 Boehringer Ingelheim Investigational Site
• Russian Federation
  • Moscow, Russian Federation
    • 1237.14.70401 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 1237.14.70402 Boehringer Ingelheim Investigational Site
• Sweden
  • Lund, Sweden
    • 1237.14.46001 Boehringer Ingelheim Investigational Site
• United States
  • Arizona
    • Phoenix, Arizona, United States
      • 1237.14.01404 Boehringer Ingelheim Investigational Site
  • Georgia
    • Austell, Georgia, United States
      • 1237.14.01414 Boehringer Ingelheim Investigational Site
  • Maryland
    • Baltimore, Maryland, United States
      • 1237.14.01417 Boehringer Ingelheim Investigational Site
  • Minnesota
    • Rochester, Minnesota, United States
      • 1237.14.01418 Boehringer Ingelheim Investigational Site
  • Missouri
    • St. Charles, Missouri, United States
      • 1237.14.01408 Boehringer Ingelheim Investigational Site
  • North Carolina
    • Charlotte, North Carolina, United States
      • 1237.14.01409 Boehringer Ingelheim Investigational Site
  • South Carolina
    • Greenville, South Carolina, United States
      • 1237.14.01407 Boehringer Ingelheim Investigational Site
    • Spartanburg, South Carolina, United States
      • 1237.14.01403 Boehringer Ingelheim Investigational Site
    • Union, South Carolina, United States
      • 1237.14.01401 Boehringer Ingelheim Investigational Site
  • Texas
    • Dallas, Texas, United States
      • 1237.14.01412 Boehringer Ingelheim Investigational Site
  • Washington
    • Seattle, Washington, United States
      • 1237.14.01410 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 a post-bronchodilator FEV1 <80% of predicted normal and a post-bronchodilator FEV1/FVC <70% at Visit 1.

3. Male or female patients, between 40 and 75 years of age (inclusive) on day of signing informed consent.
4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years.

Exclusion criteria:

1. Patients with a significant disease other than COPD; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patient's ability to participate in the study
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. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma.

   Patients with any of the following conditions:

4. A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists)
5. A diagnosis of paroxysmal tachycardia (>100 beats per minute) (due to the known class side effect profile of ß2-agonists)
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 (patients with treated basal cell carcinoma are allowed)
11. A history of life-threatening pulmonary obstruction
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 (patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1)
17. Patients being treated with any oral ß-adrenergics
18. Patients being treated with oral corticosteroid medication at unstable doses
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 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, such as arthritis in the leg, angina pectoris or claudication or morbid obesity.
22. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit
23. Patients with known hypersensitivity to ß-adrenergics drugs, anticholinergic drugs, BAC, EDTA or any other component of the Respimat® inhalation solution delivery system
24. Pregnant or nursing women
25. Women of childbearing potential not using highly effective methods of birth control.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Olodaterol 5 mcg QD; patient will receive olodaterol 5 mcg once daily	Drug: Olodaterol; Olodaterol 5 mcg once daily; Device: Respimat; Respimat inhaler
Placebo Comparator: Placebo QD; placebo comparator for tiotropium + olodaterol	Device: Respimat; Respimat inhaler; Drug: Placebo; placebo matching tiotropium + olodaterol
Active Comparator: Tiotropium 5 mcg QD; patient will receive tiotropium 5 mcg once daily	Device: Respimat; Respimat inhaler; Drug: Tiotropium; tiotropium
Experimental: Tiotropium + olodaterol low dose QD; patient will receive tiotropium 2.5 mcg + olodaterol 5 mcg in fixed dose combination once daily	Device: Respimat; Respimat inhaler; Drug: Tiotropium + Olodaterol; Tiotropium 2.5 mcg + olodaterol 5 mcg once daily
Experimental: Tiotropium + olodaterol high dose; patient will receive tiotropium 5 mcg + olodaterol 5 mcg in fixed dose combination once daily	Device: Respimat; Respimat inhaler; Drug: tiotropium + Olodaterol; tiotropium 5 mcg + olodaterol 5 mcg once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inspiratory Capacity at Rest Before Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Work Capacity	Inspiratory capacity (IC) at rest before constant work rate cycle ergometry to symptom limitation at 75% maximal work capacity (Wcap). Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1. The presented means are adjusted means from the MMRM (Mixed Effects Model Repeated Measures) model.	6 weeks
Endurance Time During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap	Endurance time during constant work rate cycle ergometry (CWRCE) to symptom limitation at 75% Wcap Wcap was defined as the maximum work rate achieved for at least 30 seconds during the incremental cycle ergometry performed at Visit 1. The presented means are adjusted mean from the MMRM model.	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Slope of the Intensity of Breathing Discomfort (Borg Scale) During Constant Work Rate Cycle Ergometry to Symptom Limitation at 75% Wcap	Slope of the intensity of breathing discomfort (Borg Scale) during CWRCE to symptom limitation at 75% Wcap. The intensity of breathing discomfort was rated using the modified Borg scale with ratings from 0 (nothing at all) to 10 (maximal). Slope is defined as : (intensity of breathing discomfort at the end of exercise minus intensity of breathing discomfort at rest) / endurance time. A decrease in slope indicates improvement. The presented means are adjusted means from MMRM model.	6 weeks
FEV1 (1 Hour Post-dose)	Forced Expiratory Volume in 1 Second (FEV1) (one hour post-dose). The presented means are adjusted means from MMRM model.	6 weeks

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• O'Donnell DE, Casaburi R, Frith P, Kirsten A, De Sousa D, Hamilton A, Xue W, Maltais F. Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD. Eur Respir J. 2017 Apr 19;49(4):1601348. doi: 10.1183/13993003.01348-2016. Print 2017 Apr.

Helpful Links

• Related Info

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: February 13, 2012
• First Submitted That Met QC Criteria: February 15, 2012
• First Posted (Estimate): February 16, 2012

Study Record Updates

• Last Update Posted (Estimate): September 15, 2015
• Last Update Submitted That Met QC Criteria: August 12, 2015
• Last Verified: August 1, 2015

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: 1237.14; 2011-004660-30 (EudraCT Number: EudraCT)