Airway Smooth Muscle and Asthma Severity

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT00779870
• Collaborator: Asthma UK (Other), Royal Brompton & Harefield NHS Foundation Trust (Other)
• Enrollment: 18
• Location: 1
• Actual Duration (Months): 47
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Our hypothesis is that the severity of asthma is determined by the way in which airway smooth muscle cells grow and release inflammatory mediators. Our main objective is to establish how the properties of the airway smooth muscle cell varies with asthma severity. Environmental agents, such as cigarette smoke, and inflammation can give rise to oxidative stress - this is a process whereby harmful chemicals called free radicals are formed in the body and damage tissues. The damage caused can be limited/prevented by protective, or anti-oxidant mediators. We will also look at molecules involved in oxidative stress which may affect the way in which the airway smooth muscle grows and produces inflammatory mediators.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Other: bronchoscopy

Detailed Description

Aims and Objectives The objective of this study is to examine whether the severity of asthma is related to (and possibly caused by) ASM dysfunction. Severe asthmatics have been shown to have more ASM in bronchial biopsies than non-severe asthmatics16. Because ASM cells can be obtained from bronchial biopsies obtained via bronchoscopy, we will examine endobronchial biopsies from mild, moderate and severe asthmatics, and healthy non-asthmatic subjects to compare features of remodelling (severe asthmatic subjects will have been assessed through the Difficult Asthma Protocol at the Royal Brompton Hospital24). In particular, we will focus on ASM mass, proliferation and changes in expression of different contractile proteins (α-actin and myosin) and chemokines, and will assess in vitro the response of ASM cells to stimulation by TGF-β and IL-1β. We will also examine the effect of dexamethasone on chemokine release and induced proliferation in vitro. We will also study enzymes and anti-oxidants involved in oxidative stress, such as Nox4, MnSOD and catalase, to look at their role in regulating ASM cell proliferation and chemokine synthesis. We want to see if there is an oxidant-anti oxidant balance in ASM in severe asthma compared to non-severe asthma.

AIM:

1. To establish the difference in ASM phenotype in asthma patients of differing severity of disease in terms of ASM mass, proliferation, migration and chemokine release.

Study design There will be 3 study visits. In the first two visits, the subjects will undergo spirometry with reversibility testing, a methacholine challenge test (to assess degree of bronchial hyper-responsiveness), skin prick tests and IgE levels (to assess atopic status), measurement of exhaled nitric oxide (as a non-invasive marker of inflammation), and the asthmatic subjects will complete an Asthma Control Questionnaire and an Asthma Quality of Life Questionnaire. The third visit will be on the day admission for the bronchoscopy.

Study protocol:

Visit 1 - screening visit

• Explain purpose of study- address any queries/concerns

• History and examination

• Skin prick tests

• Blood test for full blood count, clotting profile and IgE

• Measurement of exhaled nitric oxide (eNO)

• Spirometry pre and post β agonist

• Completion of Asthma Control Questionnaire and

• Completion of Asthma Quality of Life Questionnaire

Visit 2 - Methacholine challenge test

Visit 3 - Day admission for fibreoptic bronchoscopy

Study Design

• Study Type: Observational
• Actual Enrollment: 18 participants
• Observational Model: Cohort
• Time Perspective: Cross-Sectional
• Official Title: Evaluating the Role of Oxidant/Anti-oxidant Balance and the Relationship of Asthma Severity on Airway Smooth Muscle Proliferation, Migration and Cytokine Release.
• Actual Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
1 healthy volunteers	Other: bronchoscopy; bronchoscopy under local anaesthetic and sedation to obtain endobronchial biopsies
2 mild asthmatics	Other: bronchoscopy; bronchoscopy under local anaesthetic and sedation to obtain endobronchial biopsies
3 moderately-severe asthmatics	Other: bronchoscopy; bronchoscopy under local anaesthetic and sedation to obtain endobronchial biopsies
4 severe asthmatics	Other: bronchoscopy; bronchoscopy under local anaesthetic and sedation to obtain endobronchial biopsies

Outcome Measures

Primary Outcome Measures

1. Difference in ASM Mass Between Groups [at time of bronchoscopy, an average of 1 hour]

2. Difference in ASM Proliferation, Migration and Cytokine Release Between Groups [at time of bronchoscopy, an average of 1 hour]

3. Difference in Intracellular Oxidative Stress Mechanisms From ASM Between Groups [at time of bronchoscopy, an average of 1 hour]

   Expression of Nrf2 protein

Secondary Outcome Measures

1. Correlation Between ASM Mass and Airway Hyper-responsiveness (PC20) [at the time of bronchoscopy, an average of 1 hour]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria - Asthma Age 18-60 Physician diagnosis of asthma Intermittent/mild, moderate and severe asthma as per GINA guidelines [1]

For the severe asthma subjects, they will also have the following:

Major characteristics (at least one of the following criteria)

• Treatment with continuous or near continuous (>50% of year) oral corticosteroids

• Requirement for treatment with high dose inhaled corticosteroids (ICS) Minor characteristics (at least 2 out of the following)

1. Requirement for daily treatment with a controller medication in addition to ICS e.g. LABA, theophylline, leukotriene antagonist

2. Asthma symptoms requiring SABA on a daily or near daily basis

3. Persistent airways obstruction (FEV1 <80% predicted, diurnal PEF variation >20%)

4. One or more emergency care visits for asthma per year

5. 3 or more steroid "bursts" per year

6. Prompt deterioration with ≤ 25% reduction in oral or ICS

7. Near fatal asthma event in the past

Reference [1] GINA - The Global Initiative for Asthma. www.ginasthma.com

Exclusion criteria - Asthma Intubation for asthma within 6 months of entry into this study Current smokers, or less than 3 years since quitting smoking (< 5 pack/years) Less than 4 weeks from an exacerbation On steroid-sparing agent or immunosuppressant such as azathioprine, methotrexate and ciclosporin Concomitant anti-IgE therapy On anti-platelet or anti-coagulant drugs Low platelet count Pregnancy or breast-feeding Previous bronchoscopy within three months of this study

Healthy volunteer subjects:

We are aiming for 5 atopic and 5 non-atopic healthy volunteers.

Inclusion criteria:

Age 18 - 60 Non smokers (or less than 5 pack/yrs if ex-smokers) Normal lung function

Exclusion criteria:

History of asthma or allergic rhinitis Any chronic illness Current smokers, or less than 3 years since quitting smoking (< 5 pack/years) PC20 less than 16mg/ml On anti-platelet or anti-coagulant drugs Low platelet count Pregnancy or breast-feeding Previous bronchoscopy within three months of this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Royal Brompton Hospital	London		United Kingdom	Sw3 6NP

Sponsors and Collaborators

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

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Fan Chung, Professor, Imperial College London
• ClinicalTrials.gov Identifier: NCT00779870
• Other Study ID Numbers: 08/H0708/2
• First Posted: Oct 24, 2008
• Last Update Posted: Oct 31, 2019
• Last Verified: Oct 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 Fan Chung, Professor, Imperial College London: asthma severity; airway smooth muscle; oxidative stress
• Additional relevant MeSH terms: Asthma

Study Results

Participant Flow

Pre-assignment Detail	Results of the low number of participants the mild and moderate asthma patients were combined to Non severe group

Arm/Group Title	Healthy	Non-severe Asthma	Severe Asthma
Arm/Group Description	Healthy Participant	Patients with mild and moderate asthma	Patients with severe asthma
Period Title: Overall Study
STARTED	5	6	7
COMPLETED	5	6	7
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Healthy	Non-severe Asthma	Severe Asthma	Total
Arm/Group Description	Healthy Participant	Patients with mild and moderate asthma	Patients with severe asthma	Total of all reporting groups
Overall Participants	5	6	7	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.67 (6.3)	38.17 (8.5)	36.67 (4.12)	36.5 (6.3)
Sex: Female, Male (Count of Participants)
Female	1 20%	1 16.7%	2 28.6%	4 22.2%
Male	2 40%	5 83.3%	4 57.1%	11 61.1%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United Kingdom	5 100%	6 100%	7 100%	18 100%

Outcome Measures

1. Primary Outcome

Title	Difference in ASM Mass Between Groups
Time Frame	at time of bronchoscopy, an average of 1 hour

Outcome Measure Data

Analysis Population Description

No data collected

Arm/Group Title	Healthy	Non-severe Asthma	Severe Asthma
Arm/Group Description	Healthy Participant	Patients with mild and moderate asthma	Patients with severe asthma
Measure Participants	0	0	0

2. Primary Outcome

Title	Difference in ASM Proliferation, Migration and Cytokine Release Between Groups
Time Frame	at time of bronchoscopy, an average of 1 hour

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Healthy	Non-severe Asthma	Severe Asthma
Arm/Group Description	Healthy Participant	Patients with mild and moderate asthma	Patients with severe asthma
Measure Participants	0	0	0

3. Primary Outcome

Title	Difference in Intracellular Oxidative Stress Mechanisms From ASM Between Groups
Description	Expression of Nrf2 protein
Time Frame	at time of bronchoscopy, an average of 1 hour

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy	Non-severe Asthma	Severe Asthma
Arm/Group Description	Healthy Participant	Patients with mild and moderate asthma	Patients with severe asthma
Measure Participants	5	6	7
Mean (Full Range) [relative expression unit]	2	3	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy, Non-severe Asthma
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy, Severe Asthma
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Correlation Between ASM Mass and Airway Hyper-responsiveness (PC20)
Time Frame	at the time of bronchoscopy, an average of 1 hour

Outcome Measure Data

Analysis Population Description

No data collected

Arm/Group Title	Healthy	Non-severe Asthma	Severe Asthma
Arm/Group Description	Healthy Participant	Patients with mild and moderate asthma	Patients with severe asthma
Measure Participants	0	0	0

Adverse Events

Time Frame	2 years
Arm/Group Title	Healthy		Non-severe Asthma		Severe Asthma
Arm/Group Description	Healthy Participant		Patients with mild and moderate asthma		Patients with severe asthma
All Cause Mortality
	Healthy		Non-severe Asthma		Severe Asthma
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/6 (0%)		0/7 (0%)
Serious Adverse Events
	Healthy		Non-severe Asthma		Severe Asthma
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/6 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Healthy		Non-severe Asthma		Severe Asthma
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/6 (0%)		0/7 (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.