Mechanisms of Adverse Effects of Long-Acting Beta-Agonists in Asthma
Mechanisms of Adverse Effects of Long-Acting Beta-Agonists in Asthma
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.
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.
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 > 80% 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