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

NCT04503460 | Unknown Phase 4 DMC

• 2 other identifiers: 19SM51012019-003036-23
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Asthma

Keywords

Asthma; Salmeterol; Fluticasone

Outcome Measures

Primary Outcomes (1)

• 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.

  [Time Frame: Change between Day 1 (baseline bronchoscopy) and Day 15 (post-salmeterol monotherapy bronchoscopy)]

Other Outcomes (7)

• 1. Pro-inflammatory mediator gene expression following salmeterol monotherapy

  [Time Frame: Change between Day 1 (baseline bronchoscopy) and Day 15 (post-salmeterol monotherapy bronchoscopy)]

• 2. Pro-inflammatory mediator protein expression following salmeterol/fluticasone combination therapy

  [Time Frame: Change between Day 29 (post-salmeterol washout bronchoscopy) and Day 43 (post salmeterol/fluticasone combination therapy bronchoscopy)]

• 3. Pro-inflammatory mediator gene expression following salmeterol/fluticasone combination therapy

  [Time Frame: Change between Day 29 (post-salmeterol washout bronchoscopy) and Day 43 (post salmeterol/fluticasone combination therapy bronchoscopy)]

Study Arms (1)

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)

Drug: Salmeterol Xinafoate; Drug: Salmeterol Fluticasone

Interventions

Salmeterol Xinafoate 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.

Single treatment arm

Salmeterol Fluticasone 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.

Single treatment arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Imperial College London: lead
• European Research Council: collaborator

Study Sites (1)

St Mary's Hospital, Imperial College Healthcare NHS Trust

London, W2 1NY, United Kingdom

RECRUITING

MeSH Terms

Conditions

Asthma

Interventions

Salmeterol Xinafoate; Fluticasone-Salmeterol Drug Combination

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Albuterol; Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Phenethylamines; Ethylamines; Fluticasone; Androstadienes; Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci

  Imperial College London

  STUDY CHAIR

Central Study Contacts

Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci

CONTACT

+44 20 7594 3764; s.johnston@imperial.ac.uk

Eva Fiorenzo, BMBS

CONTACT

+44 20 7594 3751; e.fiorenzo@imperial.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 1, 2019
• First Posted: August 7, 2020
• Study Start: July 23, 2021
• Primary Completion: September 30, 2024
• Study Completion: September 30, 2024
• Last Updated: April 25, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will share

Locations

GB (1)