COPDPhase 4NCT02429765
Effect of Aclidinium/Formoterol on Nighttime Lung Function and Morning Symptoms in Chronic Obstructive Pulmonary Disease
A Phase 4 study testing ACL/FOR in people with COPD, run by Queen's University at 1 site in Canada.
Trial 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… Read more about this study
- Who is it for?
- Ages 40 years and older
- Conditions the study is for
- COPD
- What is being tested?
- ACL/FOR
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteCanada
- Study dates
- Oct 2015to Aug 2018
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- A diagnosis of sleep disordered breathing;
- Nocturnal oxygen therapy.
Trial locations and contacts
1 site in 1 country.
Canada1 site
Respiratory Investigation Unit, Kingston General Hospital
Kingston, Ontario, K7L 2V7
About this study
Official title: Effect of Aclidinium Bromide/Formoterol on Nighttime Lung Function, Respiratory Mechanics and Early Morning Symptoms in Chronic Obstructive Pulmonary Disease (COPD)
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.
Read the 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.
- Conditions
- COPD
- Being tested
- ACL/FOR, Placebo
- Medical subject headings
- Pulmonary Disease, Chronic Obstructive
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ACL/FORDrug
Also called aclidinium/formoterol, Duaklir
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| ACL/FOR | Active comparator | 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. Receives: Drug: ACL/FOR |
| Placebo | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Morning trough inspiratory capacity (IC) as measured by a spirometer
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.
Measured: 10 hours after the evening dose of randomized study drug
Secondary outcomes (7)
Early Morning Symptoms of COPD Instrument (EMSCI)
Measured: Upon awakening in the morning: 10 hours after the evening dose of randomized study drug
Distribution of sleep stages obtained during polysomnography
Measured: 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
Changes in the forced expired volume in 1 second (FEV1) as measured by a spirometer
Measured: 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)
Changes in IC as measured by a spirometer
Measured: 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)
Morning trough functional residual capacity (FRC) as measured by body plethysmography
For assessment of lung hyperinflation
Measured: 10 hours after the evening dose of randomized study drug
Diaphragm electromyography (EMGdi)
A combined electrode-balloon esophageal/gastric catheter will be inserted nasally to measure EMGdi and respiratory pressures (esophageal and gastric pressures)
Measured: 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)
Transdiaphragmatic pressure (Pdi)
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.
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Apr 2015 (estimated)
- Study startOct 2015
- Primary completionAug 2018
- Study completionAug 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for COPDStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Queen's University
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Principal investigator, Dr. Denis O'Donnell, Queen's University
- Investigators
- Denis E O'Donnell, MD, FRCPC, Principal investigator, Queen's University & Kingston General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02429765
- Sponsor's protocol ID
- DMED-1744-14
- Status last verified
- Jul 2019
- First submitted
- 7 Nov 2014
- Last updated
- 12 Jul 2019
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Domnik NJ, Phillips DB, James MD, Ayoo GA, Taylor SM, Scheeren RE, Di Luch AT, Milne KM, Vincent SG, Elbehairy AF, Crinion SJ, Driver HS, Neder JA, O'Donnell DE. Compensatory responses to increased mechanical abnormalities in COPD during sleep. Eur J Appl Physiol. 2022 Mar;122(3):663-676. doi: 10.1007/s00421-021-04869-0. Epub 2022 Jan 16.
PubMed 35034195Domnik NJ, James MD, Scheeren RE, Ayoo GA, Taylor SM, Di Luch AT, Milne KM, Vincent SG, Phillips DB, Elbehairy AF, Crinion SJ, Driver HS, Neder JA, O'Donnell DE. Deterioration of Nighttime Respiratory Mechanics in COPD: Impact of Bronchodilator Therapy. Chest. 2021 Jan;159(1):116-127. doi: 10.1016/j.chest.2020.06.033. Epub 2020 Jun 27.
PubMed 32603714
Study at a glance
From the registry record, last updated by the sponsor on 12 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Aclidinium Bromide/Formoterol on Nighttime Lung Function, Respiratory Mechanics and Early Morning Symptoms in Chronic Obstructive Pulmonary Disease (COPD)
- ClinicalTrials.gov ID
- NCT02429765
- Acronym / sponsor ID
- DMED-1744-14
- Conditions
- COPD
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Queen's UniversityUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- Oct 2015
- Primary completion
- Aug 2018 (actual)
- Study completion
- Aug 2018 (actual)
- First posted
- 29 Apr 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ACL/FOR | Active comparator | Drug: ACL/FORThe 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. |
| Placebo | Placebo comparator | Drug: PlaceboThe 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. |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (2 listed)
- A diagnosis of sleep disordered breathing;
- Nocturnal oxygen therapy.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ACL/FORAlso: aclidinium/formoterol, Duaklir | Drug | ACL/FOR |
| Placebo | Drug | Placebo |
Primary outcome
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.
7 secondary outcomes
Early Morning Symptoms of COPD Instrument (EMSCI)
Time frame: Upon awakening in the morning: 10 hours after the evening dose of randomized study drug
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
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)
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)
Morning trough functional residual capacity (FRC) as measured by body plethysmography
Time frame: 10 hours after the evening dose of randomized study drug
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)
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)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Jul 2019.
- Derived from this study: PubMed 35034195Domnik NJ, Phillips DB, James MD, Ayoo GA, Taylor SM, Scheeren RE, Di Luch AT, Milne KM, Vincent SG, Elbehairy AF, Crinion SJ, Driver HS, Neder JA, O'Donnell DE. Compensatory responses to increased mechanical abnormalities in COPD during sleep. Eur J Appl Physiol. 2022 Mar;122(3):663-676. doi: 10.1007/s00421-021-04869-0. Epub 2022 Jan 16.
- Derived from this study: PubMed 32603714Domnik NJ, James MD, Scheeren RE, Ayoo GA, Taylor SM, Di Luch AT, Milne KM, Vincent SG, Phillips DB, Elbehairy AF, Crinion SJ, Driver HS, Neder JA, O'Donnell DE. Deterioration of Nighttime Respiratory Mechanics in COPD: Impact of Bronchodilator Therapy. Chest. 2021 Jan;159(1):116-127. doi: 10.1016/j.chest.2020.06.033. Epub 2020 Jun 27.
Related trials for COPD
Active, not recruiting
Symptoms and Functions in Patients With COPD and Chronic Bronchitis Switching From CIG to THS
COPD, Smoking
Not yet recruitingPhase 2/3
An Open-Label Extension Study to Evaluate Inhaled Treprostinil SMI in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD)
Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease
Not yet recruiting
The Aim of the Study is to Decipher the Alterations in Signalling Pathways of Skeletal Muscle Stem Cells (Satellite Cells (SCs)) in Individuals With COPD, as Well as to Examine the Effect of Exercise Training on SCs.
COPD (Chronic Obstructive Pulmonary Disease), Sarcopenia in Elderly
Not yet recruitingPhase 2
Study of Treprostinil Administered Via Soft Mist Inhaler (SMI) in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD)
Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease
Active, not recruitingPhase 1
A Study for GSK3862995B in Healthy Participants and Participants With Chronic Obstructive Pulmonary Disease
Pulmonary Disease, Chronic Obstructive
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Denis E O'Donnell, MD, FRCPC principal investigator
Queen's University & Kingston General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing ACL/FOR in people with COPD, run by Queen's University at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Morning trough inspiratory capacity (IC) as measured by a spirometer (time frame: 10 hours after the evening dose of randomized study drug). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02429765, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jul 2019.