Genetic Susceptibility to Ozone in Mild Asthmatic Volunteers
| Status: | Completed |
|---|---|
| Conditions: | Asthma, Other Indications |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases, Other |
| Healthy: | No |
| Age Range: | 18 - 50 |
| Updated: | 10/15/2017 |
| Start Date: | January 2006 |
| End Date: | November 2015 |
Glutathione S Transferase M1 (GSTM1) Genotype Associated Susceptibility to Airway Response to Ozone in Mild Asthmatic Volunteers.
Recent reports have shown that people with asthma who have a particular gene, known as the
GSTM1 null gene, are more susceptible to the effect of air pollutants. The purpose of this
research study is to learn if volunteers who have asthma and have a GSTM1 null gene have
increased response (change in lung function and increase in lung cells collected from sputum)
compared to volunteers with asthma who have the GSTM1 sufficient gene when challenged with
0.4 ppm ozone during intermittent exercise. The principal purpose of this study is to
identify hyper-responsive, responsive and non-responsive groups of human subjects with mild
asthma based on their airway neutrophilic response to ozone exposure, and to perform analyses
on DNA from airway cells to explore possible differences in genetic profiles between the
three groups. An additional pilot aim is to compare expression of a small number of specific
genes of interest in a subset of ozone-responsive and ozone-non-responsive subjects with mild
asthma.
GSTM1 null gene, are more susceptible to the effect of air pollutants. The purpose of this
research study is to learn if volunteers who have asthma and have a GSTM1 null gene have
increased response (change in lung function and increase in lung cells collected from sputum)
compared to volunteers with asthma who have the GSTM1 sufficient gene when challenged with
0.4 ppm ozone during intermittent exercise. The principal purpose of this study is to
identify hyper-responsive, responsive and non-responsive groups of human subjects with mild
asthma based on their airway neutrophilic response to ozone exposure, and to perform analyses
on DNA from airway cells to explore possible differences in genetic profiles between the
three groups. An additional pilot aim is to compare expression of a small number of specific
genes of interest in a subset of ozone-responsive and ozone-non-responsive subjects with mild
asthma.
Fifty volunteers with mild asthma will be recruited to undergo ozone challenge in the
controlled exposure facility of the US EPA Human Studies Division (104 Mason Farm Road,
Chapel Hill, NC) with 0.4ppm for 2 hours with moderate exercise alternating with rest.
Endpoints will include genetic analysis for the GSTM1 genotype, sputum and spirometry changes
pre and post exposure, and blood endpoints pre and post exposure.
TRAINING DAY: (at least 3 days prior to the ozone challenge) Eligible subjects will report to
the research lab for a 3 hour training session.
- All female volunteers will undergo a urine pregnancy test.
- After informed consent is obtained, Measurement of orally exhaled nitric oxide will be
obtained
- Subjects will perform spirometry.
- Subjects will exercise on a treadmill to determine the workload for the actual exposure.
- Finally the subject will undergo sputum induction following pretreatment with albuterol.
The sputum will be assessed for quality to determine continued eligibility. If a subject has
provided an acceptable sputum sample within the prior 6 months this may be used as inclusion
criteria rather than repeating the induction at this point. After subjects have demonstrated
production of an adequate sputum sample, they will be scheduled for the ozone exposure visit.
24 HOURS PRIOR to the exposure day (Day 1): Subjects will be asked to refrain from smoking as
well as drinking alcohol for 24 hours prior to Day 1 until after completion of Day 3.
- Subjects will have vital signs and oxygen saturation checked, including the symptom
questionnaire.
- They will also undergo a physical examination of the ears, nose, throat and chest (lung
sounds).
- Female volunteers will undergo urine pregnancy testing.
- Measurement of orally exhaled nitric oxide will be obtained.
- Spirometry testing will be performed.
- Subjects will have a sputum induction preceded by administration of 2 puffs of
albuterol.
EXPOSURE DAY (at least 3 days after the training day):
- Subjects will be asked to arrive at the study site at approximately 8 AM and will
undergo assessment of vital signs (temperature, pulse, respiratory rate, blood
pressure), oxygen saturation, and symptom score assessment.
- A telemetry unit will be placed for cardiac monitoring during the exposure.
- Measurement of orally exhaled nitric oxide will be obtained prior to exposure and 4
hours after the end of the exposure
- Spirometry testing to rule out acute illness prior to the exposure.
- They will also undergo a physical examination of the ears, nose, throat and chest.
- Exposure sessions: The 0.4 ppm ozone exposure will be conducted in an ozone exposure
chamber. Each subject will be exposed to 0.4 ppm ozone for 2 hours. During exposures,
subjects will perform four 15 minute bouts of moderate exercise (minute ventilation or
VE = 30 40 L/min) on a treadmill, each separated by 15 minutes of seated rest. Minute
ventilation is measured for 2 to 3 minutes after about 4 minutes of exercise during the
first exercise period, and again at about 12 minutes of exercise. It is then measured at
about 12 minutes into each exercise period. Two subjects may be exposed simultaneously,
in which case the exercise/rest periods will be alternated.
- Immediately post exposure and 4 hours after completion of exposure, subjects will have
an assessment of vital signs, oxygen saturation, symptom score assessment and undergo
spirometry evaluation.
- Venipuncture: 20 ml of blood will be collected for a CBC/ differential, assessment of
blood monocyte phagocytic function and cell surface markers just prior to the exposure
and 4 hours after the end of exposure. A portion of the sample will be used for
genotyping.
- Induced sputum will be collected 6 hours after initiation of exposure after subjects
have been premedicated with albuterol. The subjects will be observed at the study site
until sputum induction is complete. Subjects will not be discharged home following the
post-exposure sputum induction until FEV1 is within 90% of baseline values and vital
signs are normal. Subjects not meeting safety criteria at the end of the exposure day
will be admitted to the GCRC for overnight observation.
24 HOURS POST EXPOSURE (Day 3): The following morning, approximately 24 hours after
exposure, the volunteer subject will be assessed directly at the study site. The subject
will undergo spirometry, vital sign monitoring and symptom scoring.
STUDY DISCONTINUATION VISIT (5-10 days after exposure): The volunteer subject will again be
assessed directly at the study site. The subject will undergo spirometry, vital sign
monitoring and symptom scoring.
controlled exposure facility of the US EPA Human Studies Division (104 Mason Farm Road,
Chapel Hill, NC) with 0.4ppm for 2 hours with moderate exercise alternating with rest.
Endpoints will include genetic analysis for the GSTM1 genotype, sputum and spirometry changes
pre and post exposure, and blood endpoints pre and post exposure.
TRAINING DAY: (at least 3 days prior to the ozone challenge) Eligible subjects will report to
the research lab for a 3 hour training session.
- All female volunteers will undergo a urine pregnancy test.
- After informed consent is obtained, Measurement of orally exhaled nitric oxide will be
obtained
- Subjects will perform spirometry.
- Subjects will exercise on a treadmill to determine the workload for the actual exposure.
- Finally the subject will undergo sputum induction following pretreatment with albuterol.
The sputum will be assessed for quality to determine continued eligibility. If a subject has
provided an acceptable sputum sample within the prior 6 months this may be used as inclusion
criteria rather than repeating the induction at this point. After subjects have demonstrated
production of an adequate sputum sample, they will be scheduled for the ozone exposure visit.
24 HOURS PRIOR to the exposure day (Day 1): Subjects will be asked to refrain from smoking as
well as drinking alcohol for 24 hours prior to Day 1 until after completion of Day 3.
- Subjects will have vital signs and oxygen saturation checked, including the symptom
questionnaire.
- They will also undergo a physical examination of the ears, nose, throat and chest (lung
sounds).
- Female volunteers will undergo urine pregnancy testing.
- Measurement of orally exhaled nitric oxide will be obtained.
- Spirometry testing will be performed.
- Subjects will have a sputum induction preceded by administration of 2 puffs of
albuterol.
EXPOSURE DAY (at least 3 days after the training day):
- Subjects will be asked to arrive at the study site at approximately 8 AM and will
undergo assessment of vital signs (temperature, pulse, respiratory rate, blood
pressure), oxygen saturation, and symptom score assessment.
- A telemetry unit will be placed for cardiac monitoring during the exposure.
- Measurement of orally exhaled nitric oxide will be obtained prior to exposure and 4
hours after the end of the exposure
- Spirometry testing to rule out acute illness prior to the exposure.
- They will also undergo a physical examination of the ears, nose, throat and chest.
- Exposure sessions: The 0.4 ppm ozone exposure will be conducted in an ozone exposure
chamber. Each subject will be exposed to 0.4 ppm ozone for 2 hours. During exposures,
subjects will perform four 15 minute bouts of moderate exercise (minute ventilation or
VE = 30 40 L/min) on a treadmill, each separated by 15 minutes of seated rest. Minute
ventilation is measured for 2 to 3 minutes after about 4 minutes of exercise during the
first exercise period, and again at about 12 minutes of exercise. It is then measured at
about 12 minutes into each exercise period. Two subjects may be exposed simultaneously,
in which case the exercise/rest periods will be alternated.
- Immediately post exposure and 4 hours after completion of exposure, subjects will have
an assessment of vital signs, oxygen saturation, symptom score assessment and undergo
spirometry evaluation.
- Venipuncture: 20 ml of blood will be collected for a CBC/ differential, assessment of
blood monocyte phagocytic function and cell surface markers just prior to the exposure
and 4 hours after the end of exposure. A portion of the sample will be used for
genotyping.
- Induced sputum will be collected 6 hours after initiation of exposure after subjects
have been premedicated with albuterol. The subjects will be observed at the study site
until sputum induction is complete. Subjects will not be discharged home following the
post-exposure sputum induction until FEV1 is within 90% of baseline values and vital
signs are normal. Subjects not meeting safety criteria at the end of the exposure day
will be admitted to the GCRC for overnight observation.
24 HOURS POST EXPOSURE (Day 3): The following morning, approximately 24 hours after
exposure, the volunteer subject will be assessed directly at the study site. The subject
will undergo spirometry, vital sign monitoring and symptom scoring.
STUDY DISCONTINUATION VISIT (5-10 days after exposure): The volunteer subject will again be
assessed directly at the study site. The subject will undergo spirometry, vital sign
monitoring and symptom scoring.
Inclusion Criteria:
- healthy volunteers with mild asthma
- Normal lung function,
- Oxygen saturation of > 94 %
- Normal blood pressure
Exclusion Criteria:
- A history of significant chronic illnesses
- Allergy to any medications which may be used or prescribed in the course of this study
(albuterol, acetaminophen, aspirin or non-steroidal anti-inflammatory agents,
corticosteroids, lactose, polyethylene glycol)
- Positive pregnancy test within 48 hours of the time of challenge
- Subjects currently taking medications which may impact the results of the ozone
challenge, interfere with any other medications potentially used in the study (to
include steroids, beta antagonists, non-steroidal anti-inflammatory agents) or suggest
an ongoing illness (such as antibiotics).
- Mega doses of vitamins and supplements, homeopathic/naturopathic medicines
- Any acute, non-chronic, medical conditions occurring in the prior two weeks. Such
illnesses must be totally resolved symptomatically for 2 weeks and documentation of
normal lung function must be obtained.
- Unspecified illnesses, which in the judgment of the investigator might increase the
risk associated with ozone inhalation challenge, will be a basis for exclusion.
- Physician directed emergency treatment for an asthma exacerbation within the preceding
12 months.
- Use of systemic steroid therapy within the preceding 12 months.
- > 0.5 pack year history of tobacco use
- Use of inhaled steroids, cromolyn or leukotriene inhibitors initiated within the past
month (except for use of cromolyn exclusively prior to exercise). Patients must be on
a stable regimen of therapy.
- Use of daily theophylline within the past month.
- Pregnancy or nursing a baby.
- Nighttime symptoms of cough or wheeze greater than 1x/week at baseline (not during a
clearly recognized viral induced asthma exacerbation) which would be characteristic of
a person of moderate or severe persistent asthma as outlined in the current NHLBI
guidelines for diagnosis and management of asthma.
- Exacerbation of asthma more than 2x/week which would be characteristic of a person
with moderate or severe persistent asthma as outlined in the current NHLBI guidelines
for diagnosis and management of asthma.
- Daily requirement for albuterol due to asthma symptoms (cough, wheeze, chest
tightness) which would be characteristic of a person of moderate or severe persistent
asthma as outlined in the current NHLBI guidelines for diagnosis and management of
asthma. (Not to include prophylactic use of albuterol prior to exercise).
- Dosing level of an inhaled steroid must be consistent with mild episodic asthma as
outlined by the NHLBI NAEPP guidelines. Use of inhaled steroid at doses typically used
for moderate or severe asthma will result in exclusion of that individual from the
protocol.
- Students or staff members who work directly for the PI, Dr David Peden, are excluded
from study participation
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