Exacerbations in Severe Asthma Patients: Mechanisms and Biomarkers

Not Applicable

Completed

• Conditions: Asthma
• Interventions: Diagnostic Test: FEV1

• Registration Number: NCT02660853
• Lead Sponsor: Imperial College London

Brief Summary

The purpose of this study is to investigate exacerbations in severe asthma with regard to symptoms, lung function, aetiology and biomarkers.

Detailed Description

Patients will be recruited from the Severe Asthma Clinics at Royal Brompton Hospital. At the first visit the investigators will enrol and characterise patients. This will involve asking patients to keep a diary record of PEFR(Peak Expiratory Flow Rate), spirometry, symptom scores, use of beta-agonist reliever and other treatments for 2 weeks. Bloods tests will be taken for markers of systemic inflammation. Markers of oxidative stress will be measured in blood, exhaled breath condensate (EBC) and urine: malondialdehyde (MDA) and 8-isoprostanes. Nitric oxide (NO) levels in exhaled breath will be measured measured twice daily for 2 weeks using a portable hand-held NO meter. If spontaneous sputum is not available, sputum will be induced using ultrasonic nebulization of isotonic saline. Profile of inflammatory cells, cytokines in supernatants, bacteriological culture and microbiome analysis will be measured in the sputum. Patients will be observed over 12 months during which time the number of exacerbations will be recorded on basis of objective measures with evaluation of ACQ (Asthma Control Questionnaire), daily morning and evening PEF (Peak Expiratory Flow). At the earliest onset of exacerbation, the patient will be requested to contact the Asthma Research Unit. Patients will then be asked to attend the laboratory where similar tests to the first visit will be performed. For other exacerbations not studied, the patient will be asked to keep a detailed diary record of symptoms with severity scoring and spirometric and PEF measurements (Exacerbation Diary) over a period of 2 weeks after onset of exacerbation.

As patients with severe asthma are usually very well experienced in what the symptoms of exacerbations are, they will therefore be asked to recognise their own exacerbations. Each patient has their own way of recognising an exacerbation and the investigators will discuss this with each patient and try and establish whether an earlier warning signal is possible. Patients will be asked to record their symptoms and lung function as soon as they feel the onset of an exacerbation, since exacerbations are recognised by the patient as events that are 'clinically identified by being outside the patient's usual range of day-to-day variation'. The patient will receive or administer treatments for the exacerbation as usual without interference from the Research Team except for starting any antibiotic therapies, which will be started (if prescribed) as soon as the visit studies have been completed. Those who have been hospitalized will not be studied, and only those who can attend the Clinical Research Unit will be studied.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2015-06
• Study First Submitted: 2015-11-02
• Study First Submitted QC: 2016-01-20
• Study First Posted: 2016-01-21
• Primary Completion: 2017-06
• Study Completion: 2017-06
• Results First Submitted: 2019-09-13
• Results First Submitted QC: 2019-10-08
• Results First Posted: 2019-10-31
• Status Verified: 2019-11
• Last Update Submitted: 2019-11-22
• Last Update Posted: 2019-12-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

• All patients must be able to give informed consent. The definition of severe asthma will be on the basis of

  • Uncontrolled asthma: three or more of the following features present in any week in the previous 4 weeks:

    • Daytime symptoms more than twice per week
    • Any limitation of activities
    • Nocturnal symptoms once or more per week
    • Need for reliever treatment more than twice per week
    • Pre bronchodilator FEV1 <80% predicted or personal best OR

  • Frequent severe exacerbations (≥2 per year) OR

  • Require prescription of daily or alternate day oral corticosteroids (OCS) to achieve asthma control despite the prescription of high dose inhaled corticosteroids (>1000mcg fluticasone propionate daily or equivalent) or maintenance oral corticosteroids plus a long acting beta agonist or one other controller medication (for example anti-cholinergics, leukotriene receptor antagonists or theophylline).

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Exclusion Criteria

• • Current smoker, or Ex-smoker with a >10 year pack history or having smoked within the past 6 months

  • Significant alternative diagnoses that may mimic or complicate asthma, in particular dysfunctional breathing, panic attacks, and overt psychosocial problems (if these are thought to be the major problem rather than in addition to severe asthma)
  • Significant other primary pulmonary disorders in particular pulmonary embolism, pulmonary hypertension, interstitial lung disease and lung cancer
  • Subjects with emphysema and bronchiectasis should only be excluded if this is thought to be the major pulmonary disorder rather than in addition to severe asthma
  • Diagnosis or current investigation of occupational asthma
  • Any subjects currently participating, or having participated within 3 months of the first dose in a study using a new molecular entity, or the first dose in any other study investigating drugs.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Severe Asthma	FEV1	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines

Primary Outcome Measures

Name	Time	Method
Percent Predicted FEV1	Baseline Visit, 12 months	From date of screening visit until date of first asthma exacerbation visit Percent predicted Forced Expiratory Volume in First Second

Secondary Outcome Measures

Name	Time	Method
Exhaled Nitric Oxide	Baseline Visit, 12 months
Sputum Analysis	From baseline visit and 12 months	Eosinophils as percentage of total count
Sputum Microbiome	Baseline Visit, 12 months
Exhaled Hydrogen Sulphide	Baseline Visit, 12 months
Markers of Oxidative Stress in Urine	Baseline Visit, 12 months	8-isoprostanes
Corticosteroid Insensitivity in Peripheral Blood Mononuclear Cells	Baseline Visit, 12 months
Exhaled Breath Condensate	Baseline Visit, 12 months	pH and free Iron
PCR for Respiratory Viruses	Baseline Visit, 12 months	nasopharyngeal swabs

Trial Locations

Locations (1)

Biomedical research Unit, Royal Brompton Hospital, Sydney Street; 🇬🇧 London, United Kingdom