Mechanisms of Adverse Effects of Long-Acting Beta-Agonists in Asthma

NCT ID: NCT04503460

Last Updated: 2023-04-25

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-07-23
• Study Completion Date: 2024-09-30

Brief 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, 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.

Conditions

Asthma

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Single treatment arm

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)

Group Type: EXPERIMENTAL

Salmeterol Xinafoate

Intervention Type: DRUG

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 Fluticasone

Intervention Type: DRUG

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.

Interventions

Salmeterol Xinafoate

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.

Intervention Type: DRUG

Salmeterol Fluticasone

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.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Research Council

OTHER

Sponsor Role: collaborator

Imperial College London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci

Role: STUDY_CHAIR

Imperial College London

Locations

St Mary's Hospital, Imperial College Healthcare NHS Trust

London, , United Kingdom

Site Status: RECRUITING

Countries

United Kingdom

Central Contacts

Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci

Role: CONTACT

s.johnston@imperial.ac.uk

+44 20 7594 3764

Eva Fiorenzo, BMBS

Role: CONTACT

e.fiorenzo@imperial.ac.uk

+44 20 7594 3751

Facility Contacts

Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci

Role: primary

s.johnston@imperial.ac.uk

+44 20 7594 3764

Pil Joo Kim, BSc RGN

Role: backup

piljoo.kim@nhs.net

+44 7900883689

Other Identifiers

2019-003036-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

19SM5101

Identifier Type: -

Identifier Source: org_study_id