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Mechanisms of Adverse Effects of Long-Acting Beta-Agonists in Asthma (MAELABA)

Primary Purpose

Asthma

Status
Recruiting
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Salmeterol Xinafoate
Salmeterol Fluticasone
Sponsored by
Imperial College London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Asthma focused on measuring Asthma, Salmeterol, Fluticasone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • St Mary's Hospital, Imperial College Healthcare NHS TrustRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single treatment arm

Arm Description

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: Baseline sampling; participants only use 'as required' ipratropium bromide when needed (1 week) Salmeterol xinafoate monotherapy 50 μg twice in the morning and twice in the evening + 'as required' ipratropium bromide when needed (2 weeks) Washout period; participants only use 'as required' ipratropium bromide when needed (2 weeks) 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)

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Full Information

First Posted
July 1, 2019
Last Updated
April 21, 2023
Sponsor
Imperial College London
Collaborators
European Research Council
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1. Study Identification

Unique Protocol Identification Number
NCT04503460
Brief Title
Mechanisms of Adverse Effects of Long-Acting Beta-Agonists in Asthma
Acronym
MAELABA
Official Title
Mechanisms of Adverse Effects of Long-Acting Beta-Agonists in Asthma
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 23, 2021 (Actual)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
September 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Imperial College London
Collaborators
European Research Council

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asthma
Keywords
Asthma, Salmeterol, Fluticasone

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Sequential Assignment
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)
Allocation
N/A
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Single treatment arm
Arm Type
Experimental
Arm Description
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: Baseline sampling; participants only use 'as required' ipratropium bromide when needed (1 week) Salmeterol xinafoate monotherapy 50 μg twice in the morning and twice in the evening + 'as required' ipratropium bromide when needed (2 weeks) Washout period; participants only use 'as required' ipratropium bromide when needed (2 weeks) 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)
Intervention Type
Drug
Intervention Name(s)
Salmeterol Xinafoate
Intervention Description
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
Intervention Name(s)
Salmeterol Fluticasone
Intervention Description
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.
Primary Outcome Measure Information:
Title
1. Pro-inflammatory mediator protein expression following salmeterol monotherapy
Description
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
[Time Frame: Change between Day 1 (baseline bronchoscopy) and Day 15 (post-salmeterol monotherapy bronchoscopy)]
Other Pre-specified Outcome Measures:
Title
1. Pro-inflammatory mediator gene expression following salmeterol monotherapy
Description
Change from baseline in the levels of gene expression of disease-relevant pro-inflammatory mediators in BAL fluid following 2 weeks of salmeterol monotherapy.
Time Frame
[Time Frame: Change between Day 1 (baseline bronchoscopy) and Day 15 (post-salmeterol monotherapy bronchoscopy)]
Title
2. Pro-inflammatory mediator protein expression following salmeterol/fluticasone combination therapy
Description
Change from baseline in protein levels of disease-relevant pro-inflammatory mediators in BAL fluid following 2 weeks of salmeterol/fluticasone combination therapy
Time Frame
[Time Frame: Change between Day 29 (post-salmeterol washout bronchoscopy) and Day 43 (post salmeterol/fluticasone combination therapy bronchoscopy)]
Title
3. Pro-inflammatory mediator gene expression following salmeterol/fluticasone combination therapy
Description
Change from baseline in the levels of gene expression of disease-relevant pro-inflammatory mediators in BAL fluid following 2 weeks of salmeterol/fluticasone combination therapy
Time Frame
[Time Frame: Change between Day 29 (post-salmeterol washout bronchoscopy) and Day 43 (post salmeterol/fluticasone combination therapy bronchoscopy)]
Title
4. Lung function (spirometry)
Description
Change in lung function, measured by spirometry, between baseline and following 2 weeks of salmeterol monotherapy; and between post-salmeterol washout baseline and following 2 weeks salmeterol/fluticasone combination therapy
Time Frame
[Time Frame: Over 7 weeks]
Title
5. Fractional exhaled nitric oxide
Description
Change in fractional exhaled nitric oxide between baseline and following 2 weeks of salmeterol monotherapy; and between post-salmeterol washout baseline and following 2 weeks salmeterol/fluticasone combination therapy
Time Frame
[Time Frame: Over 7 weeks]
Title
6. Airway hyperresponsiveness (histamine challenge)
Description
Change in airway hyperresponsiveness, measured by histamine challenge, between baseline and following 2 weeks of salmeterol monotherapy; and between post-salmeterol washout baseline and following 2 weeks salmeterol/fluticasone combination therapy
Time Frame
[Time Frame: Over 7 weeks]
Title
7. Asthma symptom control (Asthma Control Questionnaire 6 / ACQ-6 score)
Description
Change in asthma symptom control, measured by ACQ-6 scoring, between baseline and following 2 weeks of salmeterol monotherapy; and between post-salmeterol washout baseline and following 2 weeks salmeterol/fluticasone combination therapy. ACQ-6 is a validated tool for assessing patients' perceived degree of severity and symptom control of their asthma. The questionnaire comprises of 6 multiple choice questions, each with 7 possible choices (only one selectable) carrying scores between 0 and 6 - total added ACQ-6 score ranges between 0 and 36, with a score of 36 representing the highest possible symptom burden measured by this questionnaire.
Time Frame
[Time Frame: Over 7 weeks]

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci
Phone
+44 20 7594 3764
Email
s.johnston@imperial.ac.uk
First Name & Middle Initial & Last Name or Official Title & Degree
Eva Fiorenzo, BMBS
Phone
+44 20 7594 3751
Email
e.fiorenzo@imperial.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci
Organizational Affiliation
Imperial College London
Official's Role
Study Chair
Facility Information:
Facility Name
St Mary's Hospital, Imperial College Healthcare NHS Trust
City
London
ZIP/Postal Code
W2 1NY
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci
Phone
+44 20 7594 3764
Email
s.johnston@imperial.ac.uk
First Name & Middle Initial & Last Name & Degree
Pil Joo Kim, BSc RGN
Phone
+44 7900883689
Email
piljoo.kim@nhs.net
First Name & Middle Initial & Last Name & Degree
Sebastian L Johnston, MBBS PhD FRCP FRSB FMedSci
First Name & Middle Initial & Last Name & Degree
Aran Singanayagam, MBChB PhD MRCP
First Name & Middle Initial & Last Name & Degree
Patrick Mallia, MD PhD FRCP
First Name & Middle Initial & Last Name & Degree
Onn Min Kon, MD FRCP

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
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.

Learn more about this trial

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

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