Exacerbations in Severe Asthma Patients: Mechanisms and Biomarkers

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

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Diagnostic test: FEV1

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SW3 6NP
    • Biomedical research Unit, Royal Brompton Hospital, Sydney Street

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Severe Asthma; Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines	Diagnostic test: FEV1; Participants have FEV1 test

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Royal Brompton & Harefield NHS Foundation Trust
• Investigators: Principal Investigator: Kian F Chung, MBBS MD FRCP, Imperial College London

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: November 2, 2015
• First Submitted That Met QC Criteria: January 20, 2016
• First Posted (Estimate): January 21, 2016

Study Record Updates

• Last Update Posted (Actual): December 3, 2019
• Last Update Submitted That Met QC Criteria: November 22, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Exacerbations
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma
• Other Study ID Numbers: 13/LO/1198

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No