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Effect of Aclidinium/Formoterol on Nighttime Lung Function and Morning Symptoms in Chronic Obstructive Pulmonary Disease

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ClinicalTrials.gov Identifier: NCT02429765
Recruitment Status : Recruiting
First Posted : April 29, 2015
Last Update Posted : January 12, 2018
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Dr. Denis O'Donnell, Queen's University

Brief Summary:
A number of studies have documented poor sleep quality and troublesome symptoms (breathlessness, cough and sputum production) upon awakening in patients with COPD. However, the investigators know very little about measurements of respiratory mechanics (i.e., lung volumes, respiratory pressures, diaphragm function, etc) during sleep in these patients. The investigators also know little about how modern bronchodilator therapies, or the timing of when they are taken, affect respiratory mechanics during sleep or the severity of early morning respiratory symptoms. COPD is often treated with inhaled bronchodilator medications which are used to open up airways and make it easier for air to get in and out of the lungs. The investigators are studying the effects of a new inhaler that contains two different types of long-acting bronchodilator: formoterol [a long-acting beta2-agonist (LABA)] and aclidinium bromide [a long-acting muscarinic antagonist (LAMA) or anticholinergic]. Initial studies have shown that this combination therapy taken twice daily can improve some lung function measurements and respiratory symptoms in patients with moderate to severe COPD. There are also reports that evening administration of this medication may provide important advantages in patients with dominant nighttime and early morning symptoms. It is thought that sustained bronchodilation and lung deflation during the night may improve respiratory mechanics, diaphragmatic function, pulmonary gas exchange, sleep quality, and reduce severity of morning symptoms. This study will be the first to explore the effects of a nighttime dose of aclidinium/formoterol combination therapy on detailed measurements of respiratory mechanics and early morning symptoms in COPD. This study will also give us a better understanding of the mechanisms of early morning respiratory symptoms and their improvement with bronchodilators.

Condition or disease Intervention/treatment Phase
COPD Drug: ACL/FOR Drug: Placebo Phase 4

Detailed Description:

STUDY DESIGN: This will be a randomized, placebo-controlled crossover study where patients will receive an evening dose of either aclidinium/formoterol (ACL/FOR) or placebo after steady-state conditions on twice-daily ACL/FOR have been established. Patients will continue to take the same dosage of inhaled corticosteroid (ICS) as they did prior to study entry. Subjects will complete 4 visits as part of the study, with a fifth follow-up visit if required to ensure return to pre-study health status. After an initial screening visit (Visit 1) to confirm eligibility and a 1-week run-in period on stable triple therapy [long-acting beta2-agonist/inhaled corticosteroid (LABA/ICS) + long-acting muscarinic antagonist (LAMA)], subjects will complete baseline testing (Visit 2) which includes: full pulmonary function tests, sleep/symptom questionnaires, and polysomnography which will include periodic measurements of overnight spirometry (sitting and supine). Subjects will then receive 2-week treatment with twice-daily ACL/FOR and continue on the same ICS as during the baseline run-in. Once stability on treatment with ACL/FOR and ICS is established, there will be two overnight treatment visits (Visits 3 and 4), conducted 3-7 days apart to allow for return to normal sleep status between. For these visits, the evening dose of ACL/FOR versus placebo will be randomized to treatment order. Treatment visits will be similar to visit 2 but will include overnight measurements of respiratory mechanics (diaphragm electromyography and respiratory pressures). Short-acting bronchodilators will be withheld for at least 8 hours prior to visits.

SAMPLE SIZE: This is an exploratory physiological study with the primary outcome being an improvement in morning pre-dose trough inspiratory capacity (IC) by 200 ml. A sample size of 20 will provide at least 80% to detect this treatment difference based on a standard deviation (SD) of approximately 0.2 L for a response difference in trough IC (vanNoord, 2006), a two-tailed test and a p<0.05. The investigators anticipate that all patients will not consent to instrumentation; however, the investigators are hoping for n=12 with respiratory mechanical measurements. Due to the complexity of the study and its measurements, an interim analysis will be conducted after 10 subjects have been completed.


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: Treatment
Official Title: Effect of Aclidinium Bromide/Formoterol on Nighttime Lung Function, Respiratory Mechanics and Early Morning Symptoms in Chronic Obstructive Pulmonary Disease (COPD)
Study Start Date : October 2015
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: ACL/FOR
The evening dose of twice-daily dual bronchodilator medication will consist of aclidinium/formoterol 400/12mcg . After 2-weeks of treatment with twice-daily aclidinium/formoterol 400/12mcg, subjects will be randomized to receive an evening dose consisting of active drug or placebo.
Drug: ACL/FOR
Other Name: aclidinium/formoterol, Duaklir

Placebo Comparator: Placebo
The evening dose of twice-daily dual bronchodilator medication will consist of a placebo inhaler. After 2-weeks of treatment with twice-daily aclidinium/formoterol 400/12mcg, subjects will be randomized to receive an evening dose consisting of active drug or placebo.
Drug: Placebo



Primary Outcome Measures :
  1. Morning trough inspiratory capacity (IC) as measured by a spirometer [ Time Frame: 10 hours after the evening dose of randomized study drug ]
    Early morning IC (~6:00am) will be measured to assess improvements in lung hyperinflation in response to the evening dose (~8:00pm) of a twice-daily bronchodilator vs. placebo.


Secondary Outcome Measures :
  1. Early Morning Symptoms of COPD Instrument (EMSCI) [ Time Frame: Upon awakening in the morning: 10 hours after the evening dose of randomized study drug ]
  2. Distribution of sleep stages obtained during polysomnography [ Time Frame: Participants will be followed for the duration of the night after the evening dose of randomized study medication: between bedtime at 10pm and upon waking or 5:45am, whichever is sooner ]
  3. Changes in the forced expired volume in 1 second (FEV1) as measured by a spirometer [ Time Frame: Measurements will be collected at 2-hr intervals after the evening dose of randomized study medication (i.e., 2, 4, 6, 8 and 10 hrs post-dose) ]
  4. Changes in IC as measured by a spirometer [ Time Frame: Measurements will be collected at 2-hr intervals after the evening dose of randomized study medication (i.e., 2, 4, 6, 8 and 10 hrs post-dose) ]
  5. Morning trough functional residual capacity (FRC) as measured by body plethysmography [ Time Frame: 10 hours after the evening dose of randomized study drug ]
    For assessment of lung hyperinflation

  6. Diaphragm electromyography (EMGdi) [ Time Frame: Measurements will be collected at 2-hr intervals after the evening dose of randomized study medication (i.e., 2, 4, 6, 8 and 10 hrs post-dose) ]
    A combined electrode-balloon esophageal/gastric catheter will be inserted nasally to measure EMGdi and respiratory pressures (esophageal and gastric pressures)

  7. Transdiaphragmatic pressure (Pdi) [ Time Frame: Measurements will be collected at 2-hr intervals after the evening dose of randomized study medication (i.e., 2, 4, 6, 8 and 10 hrs post-dose) ]
    A combined electrode-balloon esophageal/gastric catheter will be inserted nasally to measure EMGdi and respiratory pressures (esophageal and gastric pressures). Transdiaphragmatic pressure is calculated as the difference between esophageal pressure and gastric pressure.



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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Moderate to severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) 30-79%predicted);
  • Resting functional residual capacity (FRC) >120% predicted;
  • Clinically stable and on stable triple therapy with an ICS/LABA and tiotropium;
  • Symptomatic: Baseline Dyspnea Index ≤8 and answer "in the morning" when asked about what time of day their COPD symptoms are worst.

Exclusion Criteria:

  • A diagnosis of sleep disordered breathing;
  • Nocturnal oxygen therapy.

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): NCT02429765


Contacts
Contact: Nicolle Domnik, Ph.D. (613) 549-6666 ext 4033 n.j.domnik@queensu.ca

Locations
Canada, Ontario
Respiratory Investigation Unit, Kingston General Hospital Recruiting
Kingston, Ontario, Canada, K7L 2V7
Principal Investigator: Denis E O'Donnell, MD, FRCPC         
Sponsors and Collaborators
Queen's University
AstraZeneca
Investigators
Principal Investigator: Denis E O'Donnell, MD, FRCPC Queen's University & Kingston General Hospital

Responsible Party: Dr. Denis O'Donnell, Principal Investigator, Queen's University
ClinicalTrials.gov Identifier: NCT02429765     History of Changes
Other Study ID Numbers: DMED-1744-14
First Posted: April 29, 2015    Key Record Dates
Last Update Posted: January 12, 2018
Last Verified: January 2018

Additional relevant MeSH terms:
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Formoterol Fumarate
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action