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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01525615
First received: February 1, 2012
Last updated: August 12, 2015
Last verified: August 2015
  Purpose
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.

Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Device: Respimat inhaler
Drug: tiotropium+olodaterol (low dose)
Drug: tiotropium + olodaterol (high dose)
Drug: placebo to tiotropium+olodaterol
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
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)]

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 12 Weeks [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Adjusted Mean Endurance Time During Endurance Shuttle Walk Test (ESWT) After 12 Weeks [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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.

  • Adjusted Mean Inspiratory Capacity at Pre-exercise After 12 Weeks [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    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.

  • Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) on Day 1 [ Time Frame: 1 day ] [ Designated as safety issue: No ]
    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.

  • Adjusted Mean Endurance Time During Constant Work Rate Cycle Ergometry (CWRCE) After 6 Weeks Treatment [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    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.

  • Adjusted Mean Inspiratory Capacity at Pre-exercise After 1 Day [ Time Frame: 1 day ] [ Designated as safety issue: No ]
    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.

  • Adjusted Mean Inspiratory Capacity at Pre-exercise After 6 Weeks [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    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.

  • Adjusted Mean Slope of the Intensity of Breathing Discomfort on Day 1 [ Time Frame: 1 day ] [ Designated as safety issue: No ]

    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.


  • Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 6 [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

    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.


  • Adjusted Mean Slope of the Intensity of Breathing Discomfort After Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    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.


  • Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) on Day 1 [ Time Frame: 1 day ] [ Designated as safety issue: No ]
    Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed on day 1

  • Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 6 Weeks [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed after 6 weeks of treatment

  • Adjusted Mean 1-hour, Post-dose Forced Expiratory Volume in One Second (FEV1) After 12 Weeks [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Secondary endpoint was adjusted mean 1-hour, post-dose Forced Expiratory Volume in one second (FEV1) observed after 12 weeks of treatment


Enrollment: 404
Study Start Date: February 2012
Study Completion Date: September 2013
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Drug: tiotropium + olodaterol (high dose)
5 µg tiotropium + 5 µg olodaterol
Device: Respimat inhaler
Respimat inhaler
Placebo Comparator: placebo
once daily 2 puffs, solution for inhalation Respimat
Device: Respimat inhaler
Respimat inhaler
Drug: placebo to tiotropium+olodaterol
comparator

  Eligibility

Ages Eligible for Study:   40 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01525615

  Show 60 Study Locations
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01525615     History of Changes
Other Study ID Numbers: 1237.15  2011-004253-11 
Study First Received: February 1, 2012
Results First Received: June 19, 2015
Last Updated: August 12, 2015
Health Authority: Argentina: Admin Nacional de Medicamentos, Alimentos Tecnologia Medica
Canada: Health Canada
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Hungary: National Institute of Pharmacy
Italy: Ethics Committee
Spain: Spanish Agency of Medicines
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration

Additional relevant MeSH terms:
Chronic Disease
Lung Diseases
Pulmonary Disease, Chronic Obstructive
Disease Attributes
Lung Diseases, Obstructive
Pathologic Processes
Respiratory Tract Diseases
Tiotropium
Anti-Asthmatic Agents
Autonomic Agents
Bronchodilator Agents
Cholinergic Agents
Cholinergic Antagonists
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Parasympatholytics
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Respiratory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 03, 2016