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The Effect of STIOLTO™ RESPIMAT® on Fatigue in Chronic Obstructive Pulmonary Disease

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ClinicalTrials.gov Identifier: NCT02845752
Recruitment Status : Recruiting
First Posted : July 27, 2016
Last Update Posted : August 21, 2017
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
richard casaburi, phd, md, Los Angeles Biomedical Research Institute

Brief Summary:
The purpose of this study is to determine whether exercise can be prolonged in COPD can by the inhaled bronchodilator Stiolto Respimat. The study will identify whether any endurance benefit is due to reduction in fatigue that originates within the skeletal muscles and/or from effects on neural activation of the skeletal muscles.

Condition or disease Intervention/treatment Phase
Chronic Obstructive Pulmonary Disease Drug: Stiolto Respimat Drug: Placebo Respimat Phase 4

Detailed Description:
Patients with chronic obstructive pulmonary disease (COPD) have reduced exercise tolerance. One mechanism for this is thought to be due to dynamic hyperinflation during exercise (an increase in the end-expiratory lung volume) that contributes to the sensation of breathlessness. Whether this also contributes to inhibiting motor recruitment, and reduces the available power output (termed performance fatigue; PF), is not well understood. Preliminary data suggests that many COPD patients, unlike healthy subjects, stop exercise with a 'skeletal muscle power reserve' i.e. the ability to acutely increase muscle power output. This suggests that they are limited in the exercise task by mechanisms other than acute intramuscular limitations to power production (termed muscle fatigue; MF). Exercise tolerance is increased by treatment with the fixed-dose combination bronchodilator, STIOLTO™ RESPIMAT®. We hypothesize that increased exercise tolerance with STIOLTO™ RESPIMAT® (reduced performance fatigue; PF) will be mediated by a combination of: 1) reduced inhibition of muscle activation (termed activation fatigue; AF) allowing patients to drive their leg muscles harder, and thus; 2) increased muscle fatigue (MF).

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: A Randomized, Crossover, Placebo Controlled, Double-blind Trial of the Effect of STIOLTO™ RESPIMAT® on Central and Peripheral Components of Fatigue During Exercise in Chronic Obstructive Pulmonary Disease
Actual Study Start Date : March 1, 2017
Estimated Primary Completion Date : July 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Stiolto Respimat
Two actuations of Stiolto Respimat inhaler, taken once daily for 7 days. After a washout period of 14 days, participants will then receive matching Placebo for 7 days.
Drug: Stiolto Respimat
Oral inhalation spray
Other Name: Tiotropium Bromide and Olodaterol

Drug: Placebo Respimat
Oral inhalation spray

Placebo Comparator: Placebo Respimat
Two actuations of Placebo Respimat inhaler, taken once daily for 7 days. After a washout period of 14 days, participants will then receive matching Placebo for 7 days.
Drug: Stiolto Respimat
Oral inhalation spray
Other Name: Tiotropium Bromide and Olodaterol

Drug: Placebo Respimat
Oral inhalation spray




Primary Outcome Measures :
  1. Change from period baseline in the reduction in peak isokinetic power (performance fatigue, PF) during constant work rate exercise (CWR) [ Time Frame: Baseline and day 7 of each treatment period ]

Secondary Outcome Measures :
  1. Change from period baseline in the pre/post exercise-induced decline in peak isokinetic muscle activity (activation fatigue, AF) during CWR [ Time Frame: Baseline and day 7 of each treatment period ]
  2. Change from period baseline in the pre/post exercise-induced decline in peak isokineitc power normalized to the measured muscle activity (muscle fatigue, MF) during CWR [ Time Frame: Baseline and day 7 of each treatment period ]
  3. Change from period baseline in the exercise-isotime oxygen uptake during CWR [ Time Frame: Baseline and day 7 of each treatment period ]
  4. Change from period baseline in the exercise-isotime ventilation during CWR [ Time Frame: Baseline and day 7 of each treatment period ]
  5. Change from period baseline in the exercise-isotime inspiratory capacity during CWR [ Time Frame: Baseline and day 7 of each treatment period ]
  6. Change from period baseline in the forced expiratory volume in 1 second [ Time Frame: Baseline and day 7 of each treatment period ]
  7. Change from period baseline in the exercise-isotime perceived exertion for dyspnea and leg discomfort (Borg CR10) during CWR [ Time Frame: Baseline and day 7 of each treatment period ]
  8. Change from period baseline in the exercise-isotime in muscle oxygen saturation during CWR [ Time Frame: Baseline and day 7 of each treatment period ]
  9. Change from period baseline in the exercise-isotime in frontal lobe oxygen saturation during CWR [ Time Frame: Baseline and day 7 of each treatment period ]
  10. Change from period baseline in the exercise-isotime in pulse oximeter oxygen saturation during CWR [ Time Frame: Baseline and day 7 of each treatment period ]


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Ages Eligible for Study:   45 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following criteria: (a) Patients must be in a stable state of their disease with no exacerbation within the previous 4 weeks; and (b) At visit 1 spirometric must demonstrate a post-bronchodilator FEV1 <50% of predicted normal and a post-bronchodilator FEV1/FVC <70%.
  • At visit 1, patients will demonstrate appreciable reversibility, defined as a 12% increase in FEV1 in response to albuterol administration.
  • Baseline dyspnea index focal score ≤ 9.
  • Male or female patients, between 45 and 90 years (inclusive) of age.
  • Patients must be current or ex-smokers with a smoking history of more than 10 pack-years
  • Patients must be able to perform technically acceptable pulmonary function tests must be able to complete multiple symptom-limited cycle ergometry tests.
  • Patients must be able to inhale medication in a competent manner from the inhalers used in the study.

Exclusion Criteria:

  • 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.
  • Patients with a documented history of asthma. For patients with allergic rhinitis or atopy, medical records will be required to verify that the patient does not have asthma.
  • Patients with any of the following conditions:

    1. A history of myocardial infarction within 1 year of screening visit.
    2. Unstable or life-threatening cardiac arrhythmia.
    3. Hospitalized for heart failure within the past year.
    4. Known active tuberculosis.
    5. A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last two years (patients with treated basal cell carcinoma are allowed).
    6. A history of life-threatening pulmonary obstruction within the past two years.
    7. A history of cystic fibrosis.
    8. Clinically evident bronchiectasis.
    9. A history of significant alcohol or drug abuse within the past two years.
    10. Any contraindications for exercise testing as outlined below (see contraindications to exercise).
    11. Patients who have undergone thoracotomy with pulmonary resection.
  • 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.
  • 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.
  • Patients who desaturate to SpO2 <85% on screening incremental exercise testing.
  • 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.
  • Patients who have a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnea, such as arthritis in the leg, angina pectoris or claudication or morbid obesity.
  • Patients with a constant power cycle ergometry endurance time less than 4 or greater than 10 minutes after work rate adjustment procedures (described below).
  • Patients who have taken an investigational drug within one month or six half-lives (whichever is greater) prior to screening visit (Visit 1).
  • Pregnant or nursing women.
  • Women of childbearing who have the potential not to be using a highly effective method of birth control. Female patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years.
  • Patients who are currently participating in another interventional study.
  • Patients who are unable to comply with pulmonary medication restrictions prior to randomization.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02845752


Contacts
Contact: Harry Rossiter, PhD (310) 22-8200 hrossiter@ucla.edu

Locations
United States, California
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Recruiting
Torrance, California, United States, 90502
Contact: Harry B Rossiter, PhD    310-222-8200      
Sponsors and Collaborators
Los Angeles Biomedical Research Institute
Boehringer Ingelheim
Investigators
Principal Investigator: Richard Casaburi, PhD, MD LABioMed at Harbor-UCLA Medical Center
Principal Investigator: Harry Rossiter, PhD LABioMed at Harbor-UCLA Medical Center

Responsible Party: richard casaburi, phd, md, Professor, Los Angeles Biomedical Research Institute
ClinicalTrials.gov Identifier: NCT02845752     History of Changes
Other Study ID Numbers: 1237.55
21394-01 ( Other Identifier: Los Angeles Biomedical Research Institute )
First Posted: July 27, 2016    Key Record Dates
Last Update Posted: August 21, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Fatigue
Respiratory Tract Diseases
Signs and Symptoms
Tiotropium Bromide
Olodaterol
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic beta-1 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents