Exacerbations in Severe Asthma Patients: Mechanisms and Biomarkers

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT02660853
• Collaborator: Royal Brompton & Harefield NHS Foundation Trust (Other)
• Enrollment: 25
• Location: 1
• Arm: 1
• Duration (Months): 24
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Asthma	Diagnostic Test: FEV1	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Exacerbations in Severe Asthma Patients: Mechanisms and Biomarkers
• Study Start Date: Jun 1, 2015
• Actual Primary Completion Date: Jun 1, 2017
• Actual Study Completion Date: Jun 1, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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

1. Exhaled Breath Condensate [Baseline Visit, 12 months]

   pH and free Iron

2. Markers of Oxidative Stress in Urine [Baseline Visit, 12 months]

   malondialdehyde (MDA)

3. Markers of Oxidative Stress in Urine [Baseline Visit, 12 months]

   8-isoprostanes

4. Sputum Analysis [From baseline visit and 12 months]

   Eosinophils as percentage of total count

5. PCR for Respiratory Viruses [Baseline Visit, 12 months]

   nasopharyngeal swabs

6. Sputum Microbiome [Baseline Visit, 12 months]

7. Corticosteroid Insensitivity in Peripheral Blood Mononuclear Cells [Baseline Visit, 12 months]

8. Exhaled Nitric Oxide [Baseline Visit, 12 months]

9. Exhaled Hydrogen Sulphide [Baseline Visit, 12 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Biomedical research Unit, Royal Brompton Hospital, Sydney Street	London		United Kingdom	SW3 6NP

Sponsors and Collaborators

• Imperial College London
• Royal Brompton & Harefield NHS Foundation Trust

Investigators

• Principal Investigator: Kian F Chung, MBBS MD FRCP, Imperial College London

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Jun 21, 2013

More Information

Publications

None provided.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT02660853
• Other Study ID Numbers: 13/LO/1198
• First Posted: Jan 21, 2016
• Last Update Posted: Dec 3, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Imperial College London: Exacerbations
• Additional relevant MeSH terms: Asthma

Study Results

Participant Flow

Arm/Group Title	Severe Asthma
Arm/Group Description	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines, Observational study
Period Title: Overall Study
STARTED	25
COMPLETED	25
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Severe Asthma
Arm/Group Description	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines
Overall Participants	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.9 (11.5)
Sex: Female, Male (Count of Participants)
Female	17 68%
Male	8 32%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United Kingdom	25 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Severe Asthma
Arm/Group Description	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines
Measure Participants	25
baseline	58.6 (20.4)
During exacerbation	56.3 (22.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Asthma
	Comments	Baseline versus during exacerbation.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.745
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Exhaled Breath Condensate
Description	pH and free Iron
Time Frame	Baseline Visit, 12 months

Outcome Measure Data

Analysis Population Description

No data collected

Arm/Group Title	Severe Asthma
Arm/Group Description	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines
Measure Participants	0

3. Secondary Outcome

Title	Markers of Oxidative Stress in Urine
Description	malondialdehyde (MDA)
Time Frame	Baseline Visit, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Markers of Oxidative Stress in Urine
Description	8-isoprostanes
Time Frame	Baseline Visit, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Sputum Analysis
Description	Eosinophils as percentage of total count
Time Frame	From baseline visit and 12 months

Outcome Measure Data

Analysis Population Description

Severe asthma at baseline

Arm/Group Title	Severe Asthma
Arm/Group Description	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines
Measure Participants	25
Baseline	10.9 (30.6)
At exacerbation	4.47 (9.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Asthma
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.326
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	PCR for Respiratory Viruses
Description	nasopharyngeal swabs
Time Frame	Baseline Visit, 12 months

Outcome Measure Data

Analysis Population Description

No data collected

Arm/Group Title	Severe Asthma
Arm/Group Description	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines
Measure Participants	0

7. Secondary Outcome

Title	Sputum Microbiome
Time Frame	Baseline Visit, 12 months

Outcome Measure Data

Analysis Population Description

No data collected

Arm/Group Title	Severe Asthma
Arm/Group Description	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines
Measure Participants	0

8. Secondary Outcome

Title	Corticosteroid Insensitivity in Peripheral Blood Mononuclear Cells
Time Frame	Baseline Visit, 12 months

Outcome Measure Data

Analysis Population Description

No data collected

Arm/Group Title	Severe Asthma
Arm/Group Description	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines
Measure Participants	0

9. Secondary Outcome

Title	Exhaled Nitric Oxide
Time Frame	Baseline Visit, 12 months

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Severe Asthma
Arm/Group Description	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines
Measure Participants	0

10. Secondary Outcome

Title	Exhaled Hydrogen Sulphide
Time Frame	Baseline Visit, 12 months

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Severe Asthma
Arm/Group Description	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines
Measure Participants	0

Adverse Events

Time Frame	12 months
Arm/Group Title	Severe Asthma
Arm/Group Description	Patients under Steps 4/5 of Asthma Treatment - SIGN (Scottish Intercollegiate Guidelines Network) / BTS (British Thoracic Society) Guidelines
All Cause Mortality
	Severe Asthma
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Serious Adverse Events
	Severe Asthma
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Other (Not Including Serious) Adverse Events
	Severe Asthma
	Affected / at Risk (%)	# Events
Total	0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.