AsthmaPhase 4MAELABANCT04503460
Mechanisms of Adverse Effects of Long-Acting Beta-Agonists in Asthma
A Phase 4 study testing Salmeterol Xinafoate and Salmeterol Fluticasone in people with Asthma, run by Imperial College London at 1 site in United Kingdom.
Trial summary
This study aims to elucidate the pathophysiological mechanisms underlying the adverse effects associated with the use of long-acting beta-agonists (LABAs) in asthma. Participants with mild asthma will be enrolled into a single-arm, unblinded trial in which they receive 2 weeks of salmeterol xinafoate monotherapy… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Asthma
- What is being tested?
- Salmeterol Xinafoate and Salmeterol Fluticasone
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 23 Jul 2021to 30 Sep 2024
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age > 18 years
- A doctor's diagnosis of asthma (mild in severity)
- No current regular asthma treatment or regular asthma treatment in the preceding 6 weeks; only a history of using short-acting bronchodilator inhalers on demand is allowed
- Pre-bronchodilator FEV1 value > 70% of the predicted value
Who cannot join
- History or evidence of chronic respiratory disease other than asthma
- History or evidence of other disease, blood test results outside the normal reference range or medication use that would impair the ability of participants to safely undertake the study or the ability of researchers to interpret the study results; this includes, but is not limited to, the use of anticoagulants (e.g. warfarin), adenosine diphosphate (ADP) receptor inhibitors (e.g. clopidogrel), antiretroviral therapy (due to the potential for interaction with fluticasone), certain antifungal agents (due to the potential for interaction with fluticasone) and beta-blockers
- Current use or use in the last 6 weeks of systemic or nasal topical steroids, inhaled corticosteroids or systemic immunosuppressants
- Platelet count < 150 x 109/L or international normalised ratio (INR) > 1.5
- History of smoking > 5 pack years, current smoker or history of smoking in the last 4 weeks
- Current vaping or history of vaping in the last 4 weeks
Show all 17Show fewer
- Current illicit drug use/abuse
- Abnormal chest x-ray appearance
- Signs or symptoms of upper respiratory tract infection or lower respiratory tract infection in the preceding 6 weeks
- Cardiac conduction abnormalities on electrocardiogram (ECG)
- Current pregnancy or planning to become pregnant during the study period
- Breastfeeding during the study period
- Inability to provide informed consent to participate in the study
- Current involvement in any other clinical research studies involving medicinal products or devices; or involvement in clinical research studies involving medicinal products within the last 30 days or within 5 half-lives of the medicinal product (whichever is longer)
- Inability to speak English or inability to understand verbal or written English
- Inability to attend hospital for all scheduled study visits
- Hypersensitivity to any of the investigational medicinal products (IMPs) or their excipients
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site, 1 recruiting
- Recruiting
St Mary's Hospital, Imperial College Healthcare NHS Trust
London, W2 1NY
Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci, +44 20 7594 3764, s.johnston@imperial.ac.uk
Pil Joo Kim, BSc RGN, +44 7900883689, piljoo.kim@nhs.net
About this study
This study aims to elucidate the pathophysiological mechanisms underlying the adverse effects associated with the use of long-acting beta-agonists (LABAs) in asthma. Participants with mild asthma will be enrolled into a single-arm, unblinded trial in which they receive 2 weeks of salmeterol xinafoate monotherapy, followed by a 2-week washout period, followed by 2 weeks of salmeterol xinafoate / fluticasone propionate combination therapy. The induction of asthma disease-relevant pro-inflammatory mediators in the airways will be measured at each stage and correlated with relevant clinical parameters.
Read the detailed description
The use of long-acting beta-agonists (LABAs) alone to treat asthma has been associated with increased mortality rates. Between 2012 and 2013, 3% of patients who died from asthma in the UK were found to be on LABA monotherapy, despite guidelines recommending that LABAs must always be administered with inhaled corticosteroids (ICS). Monotherapy with the LABA salmeterol has been linked to a significant increase in asthma-related mortality rates when used without ICS. When salmeterol is used with ICS, it is not associated with an increased risk of serious asthma-related events and is associated with fewer exacerbations than when using ICS alone. The purpose of this study is to understand the mechanisms underlying why LABA use on its own causes worse outcomes in asthma patients. If the mechanisms can be successfully understood, this could provide further compelling evidence to optimise safe of these medicines in airway disease.
The primary objective of this study will be: to determine whether LABA monotherapy with salmeterol for 2 weeks in asthmatic patients induces disease-relevant mediators (as identified through ex vivo studies) in the airways in vivo; and to determine whether LABA/ICS combination therapy with salmeterol xinafoate/fluticasone propionate for 2 weeks in the same asthmatic patients will abolish the induction of disease-relevant mediators in the airways in vivo. If it can be shown that the levels of these inflammatory mediators increase in the airways of asthmatic patients when they are on salmeterol xinafoate monotherapy, and that this effect is decreased when asthmatic patients are on salmeterol xinafoate /fluticasone propionate combination therapy, this will provide evidence for a mechanism underlying the adverse effects of salmeterol in asthmatic patients.
Secondary objectives will be to determine the impact of LABA monotherapy with salmeterol xinafoate for 2 weeks and LABA/ICS therapy with salmeterol xinafoate/fluticasone propionate for 2 weeks on the following parameters in asthmatic patients: lung function (assessed by spirometry); airway inflammation (assessed by measuring fractional exhaled nitric oxide); airway hyperresponsiveness (assessed by histamine challenge testing); asthma symptom control (assessed by the Asthma Control Questionnaire-6); and serum brain-derived neurotrophic factor (BDNF) concentration and platelet BDNF concentration.
- Conditions
- Asthma
- Being tested
- Salmeterol Xinafoate, Salmeterol Fluticasone
- Keywords
- Asthma, Salmeterol, Fluticasone
- Medical subject headings
- Asthma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Salmeterol XinafoateDrug
All participants will receive inhaled salmeterol xinafoate 50 μg twice in the morning and twice in the evening for 2 weeks; this will be followed by a 2-week washout period during which time no beta-agonists will be administered. Participants will be asked to use 'as required' ipratropium bromide during this period when needed in place of short-acting beta agonists.
Salmeterol FluticasoneDrug
Following the 2-week washout period, all participants will receive inhaled salmeterol xinafoate 50 μg combined with fluticasone propionate 250 μg twice in the morning and twice in the evening for 2 weeks. Participants will be asked to use 'as required' ipratropium bromide during this period when needed in place of short-acting beta agonists.
| Study group | Role | What they receive |
|---|---|---|
| Single treatment arm | Experimental | All participants who are deemed eligible for inclusion in the study following screening will be enrolled into a single experimental arm which will comprise the following sequential stages:
1. Baseline sampling; participants only use 'as required' ipratropium bromide when needed (1 week)
2. Salmeterol xinafoate monotherapy 50 μg twice in the morning and twice in the evening + 'as required' ipratropium bromide when needed (2 weeks)
3. Washout period; participants only use 'as required' ipratropium bromide when needed (2 weeks)
4. Salmeterol xinafoate 50 μg / fluticasone propionate 250 μg combination therapy twice in the morning and twice in the evening + 'as required' ipratropium bromide when needed (2 weeks) Receives: Drug: Salmeterol Xinafoate; Drug: Salmeterol Fluticasone |
What is being measured
The primary outcome is the main question the study is designed to answer.
1. Pro-inflammatory mediator protein expression following salmeterol monotherapy
Change from baseline in the level of disease-relevant pro-inflammatory mediator IL-6 in Bronchoalveolar Lavage (BAL) fluid following 2 weeks of salmeterol monotherapy.
Measured: [Time Frame: Change between Day 1 (baseline bronchoscopy) and Day 15 (post-salmeterol monotherapy bronchoscopy)]
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Aug 2020
- Study start23 Jul 2021
- Primary completion30 Sep 2024 (estimated)
- Study completion30 Sep 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AsthmaStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- 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
- Basic science
- Allocation
- Not applicable
- Intervention model
- Sequential
- Model description
- All participants will receive salmeterol xinafoate monotherapy for 2 weeks, followed by a washout period for 2 weeks, followed by salmeterol xinafoate/fluticasone propionate combination therapy for 2 weeks.
- Masking
- None (open label)
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Collaborators
- European Research Council
- Responsible party
- Sponsor
- Investigators
- Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci, Study chair, Imperial College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04503460
- Sponsor's protocol ID
- 19SM5101
- Other IDs
- 2019-003036-23, 2019
- Acronym
- MAELABA
- Status last verified
- Apr 2023
- First submitted
- 1 Jul 2019
- Last updated
- 25 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Anonymised study data to be stored in an online repository for potential future sharing with other researchers. Current protocol and other related documents are undergoing amendments in order to include this plan.
Study at a glance
From the registry record, last updated by the sponsor on 25 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanisms of Adverse Effects of Long-Acting Beta-Agonists in Asthma
- ClinicalTrials.gov ID
- NCT04503460
- Acronym / sponsor ID
- MAELABA / 19SM5101
- Conditions
- Asthma
- Keywords
- Asthma, Salmeterol, Fluticasone
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Collaborators
- European Research Council
- Study start
- 23 Jul 2021 (actual)
- Primary completion
- 30 Sep 2024 (estimated)
- Study completion
- 30 Sep 2024 (estimated)
- First posted
- 7 Aug 2020 (actual)
- 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.
This study aims to elucidate the pathophysiological mechanisms underlying the adverse effects associated with the use of long-acting beta-agonists (LABAs) in asthma. Participants with mild asthma will be enrolled into a single-arm, unblinded trial in which they receive 2 weeks of salmeterol xinafoate monotherapy, followed by a 2-week washout period, followed by 2 weeks of salmeterol xinafoate / fluticasone propionate combination therapy. The induction of asthma disease-relevant pro-inflammatory mediators in the airways will be measured at each stage and correlated with relevant clinical parameters.
Detailed description
The use of long-acting beta-agonists (LABAs) alone to treat asthma has been associated with increased mortality rates. Between 2012 and 2013, 3% of patients who died from asthma in the UK were found to be on LABA monotherapy, despite guidelines recommending that LABAs must always be administered with inhaled corticosteroids (ICS). Monotherapy with the LABA salmeterol has been linked to a significant increase in asthma-related mortality rates when used without ICS. When salmeterol is used with ICS, it is not associated with an increased risk of serious asthma-related events and is associated with fewer exacerbations than when using ICS alone. The purpose of this study is to understand the mechanisms underlying why LABA use on its own causes worse outcomes in asthma patients. If the mechanisms can be successfully understood, this could provide further compelling evidence to optimise safe of these medicines in airway disease.
The primary objective of this study will be: to determine whether LABA monotherapy with salmeterol for 2 weeks in asthmatic patients induces disease-relevant mediators (as identified through ex vivo studies) in the airways in vivo; and to determine whether LABA/ICS combination therapy with salmeterol xinafoate/fluticasone propionate for 2 weeks in the same asthmatic patients will abolish the induction of disease-relevant mediators in the airways in vivo. If it can be shown that the levels of these inflammatory mediators increase in the airways of asthmatic patients when they are on salmeterol xinafoate monotherapy, and that this effect is decreased when asthmatic patients are on salmeterol xinafoate /fluticasone propionate combination therapy, this will provide evidence for a mechanism underlying the adverse effects of salmeterol in asthmatic patients.
Secondary objectives will be to determine the impact of LABA monotherapy with salmeterol xinafoate for 2 weeks and LABA/ICS therapy with salmeterol xinafoate/fluticasone propionate for 2 weeks on the following parameters in asthmatic patients: lung function (assessed by spirometry); airway inflammation (assessed by measuring fractional exhaled nitric oxide); airway hyperresponsiveness (assessed by histamine challenge testing); asthma symptom control (assessed by the Asthma Control Questionnaire-6); and serum brain-derived neurotrophic factor (BDNF) concentration and platelet BDNF concentration.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- All participants will receive salmeterol xinafoate monotherapy for 2 weeks, followed by a washout period for 2 weeks, followed by salmeterol xinafoate/fluticasone propionate combination therapy for 2 weeks.
| Arm | Type | Receives |
|---|---|---|
| Single treatment arm | Experimental | Drug: Salmeterol Xinafoate, Drug: Salmeterol FluticasoneAll participants who are deemed eligible for inclusion in the study following screening will be enrolled into a single experimental arm which will comprise the following sequential stages: 1. Baseline sampling; participants only use 'as required' ipratropium bromide when needed (1 week) 2. Salmeterol xinafoate monotherapy 50 μg twice in the morning and twice in the evening + 'as required' ipratropium bromide when needed (2 weeks) 3. Washout period; participants only use 'as required' ipratropium bromide when needed (2 weeks) 4. Salmeterol xinafoate 50 μg / fluticasone propionate 250 μg combination therapy twice in the morning and twice in the evening + 'as required' ipratropium bromide when needed (2 weeks) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Age > 18 years
- A doctor's diagnosis of asthma (mild in severity)
- No current regular asthma treatment or regular asthma treatment in the preceding 6 weeks; only a history of using short-acting bronchodilator inhalers on demand is allowed
- Pre-bronchodilator FEV1 value > 70% of the predicted value
Key exclusion criteria (17 listed)
- History or evidence of chronic respiratory disease other than asthma
- History or evidence of other disease, blood test results outside the normal reference range or medication use that would impair the ability of participants to safely undertake the study or the ability of researchers to interpret the study results; this includes, but is not limited to, the use of anticoagulants (e.g. warfarin), adenosine diphosphate (ADP) receptor inhibitors (e.g. clopidogrel), antiretroviral therapy (due to the potential for interaction with fluticasone), certain antifungal agents (due to the potential for interaction with fluticasone) and beta-blockers
- Current use or use in the last 6 weeks of systemic or nasal topical steroids, inhaled corticosteroids or systemic immunosuppressants
- Platelet count < 150 x 109/L or international normalised ratio (INR) > 1.5
- History of smoking > 5 pack years, current smoker or history of smoking in the last 4 weeks
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 |
|---|---|---|
| Salmeterol XinafoateAll participants will receive inhaled salmeterol xinafoate 50 μg twice in the morning and twice in the evening for 2 weeks; this will be followed by a 2-week washout period during which time no beta-agonists will be administered. Participants will be asked to use 'as required' ipratropium bromide during this period when needed in place of short-acting beta agonists. | Drug | Single treatment arm |
| Salmeterol FluticasoneFollowing the 2-week washout period, all participants will receive inhaled salmeterol xinafoate 50 μg combined with fluticasone propionate 250 μg twice in the morning and twice in the evening for 2 weeks. Participants will be asked to use 'as required' ipratropium bromide during this period when needed in place of short-acting beta agonists. | Drug | Single treatment arm |
Primary outcome
1. Pro-inflammatory mediator protein expression following salmeterol monotherapy
Time frame: [Time Frame: Change between Day 1 (baseline bronchoscopy) and Day 15 (post-salmeterol monotherapy bronchoscopy)]
Change from baseline in the level of disease-relevant pro-inflammatory mediator IL-6 in Bronchoalveolar Lavage (BAL) fluid following 2 weeks of salmeterol monotherapy.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Apr 2023.
- Individual participant dataSharing planned: Yes. Anonymised study data to be stored in an online repository for potential future sharing with other researchers. Current protocol and other related documents are undergoing amendments in order to include this plan.
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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.
Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci study chair
Imperial College London
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 Salmeterol Xinafoate and Salmeterol Fluticasone in people with Asthma, run by Imperial College London at 1 site in United Kingdom.
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 17 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: status not confirmed, as of the sponsor's last update on 25 Apr 2023. 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 United Kingdom. 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. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci (+44 20 7594 3764, s.johnston@imperial.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
1. Pro-inflammatory mediator protein expression following salmeterol monotherapy (time frame: [Time Frame: Change between Day 1 (baseline bronchoscopy) and Day 15 (post-salmeterol monotherapy bronchoscopy)]). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 25 Apr 2023.