Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01492517 |
| Other study ID # |
E10-025CS |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
December 13, 2011 |
| Last updated |
January 15, 2016 |
| Start date |
May 2010 |
| Est. completion date |
May 2015 |
Study information
| Verified date |
February 2015 |
| Source |
Environmental Protection Agency (EPA) |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Federal Government |
| Study type |
Interventional
|
Clinical Trial Summary
Purpose: The purpose of this protocol is to compare the genetic and epigenetic effects
between diesel exhaust and ozone exposure in healthy individuals and in mild/moderate
asthmatics.
Participants: The investigators will recruit up to 30 mild to moderate asthmatics and up to
50 healthy adults to participate in this study.
Procedures (methods): Subjects will be exposed to clean air, to 300 µg/m3 of diesel exhaust
for 2 hours and to 0.3 ppm of ozone for 2 hours with intermittent exercise in a controlled
environment chamber. Primary endpoints will include spirometry and lung cell changes
post-exposure. Secondary endpoints will include analysis of blood clotting/coagulation
factors, Holter monitoring of cardiac parameters, analysis of soluble factors present in
plasma and bronchial lavage and analysis of intracellular factors present in lung tissue
obtained from a brush biopsy.
Description:
This study will compare the epigenetic responses of healthy adults and adults with mild
asthma to diesel exhaust and ozone exposures. Up to fifty subjects will be recruited into
the healthy adult group and up to thirty subjects into the mild to moderate asthmatic group.
Both the normal healthy group and the asthmatic group will be randomly exposed to clean air,
diesel exhaust and ozone with exposures separated by a minimum of two weeks followed by a
bronchoscopy procedure 18-24 h post-exposure. Additionally, the healthy group will
participate in a second arm of the study in which they will be randomly exposed to clean air
and ozone only separated by a minimum of 2 weeks followed by a bronchoscopy procedure 1 h
post-exposure. Responses of primary interest will include: 1) genetic and epigenetic changes
2) FEV1 as measured by spirometry, and 3) lung inflammation and cell changes as evaluated by
bronchoalveolar lavage. The performance of these tests and procedures are considered
essential to conducting the study. Exploratory endpoints will include: blood CBC and
differential, fibrinogen and platelets, changes in IL 6 and IL 8 comparing pre-exposure with
post-exposure values. Safety endpoints will include comparison of temperature, telemetry,
respiratory rate, O2 saturation and symptoms scores for pre- and post-exposure, and at 18-24
hours post-exposure. All medical procedures will be performed by study personnel.
Up to an additional 15 healthy subjects will be recruited specifically to be exposed to
ozone generated using the heavy non-radioactive isotope of oxygen (18O). There is no risk to
the subject of inhaling this isotope, which is naturally occurring in small concentrations.
We have previously used 18Ozone in a study approved by the UNC IRB in 1993. The purpose of
these exposures is to measure the amount of 18O label attached to airway epithelial cells
removed during bronchoscopy and thus calculate the dose of ozone these cells received. We
will draw a small blood sample but no other tests will be performed on these subjects other
than routine spirometry to ensure they are not at risk for bronchoscopy.
Physical Examination Day:
Prior to recruitment into the study, subjects will undergo a physical exam. During this
visit, a short review of the subject's history will be performed and vital signs, height and
weight will be assessed (temperature, pulse, respiratory rate, and blood pressure), to
determine whether the individual meets any major exclusion criteria for the study. Up to 50
ml of blood may be collected for a CBC/ differential, chemistry and lipid panels. At this
time the subject may undergo a physical examination for bronchoscopy or may be scheduled for
one at another time.
In order to participate in this study, subjects will be asked to:
- Avoid smoke and fumes for 24 hours before all visits.
- Avoid drinking alcohol 24 hours before all visits.
- Avoid strenuous exercise for 24 hours prior to and after all visits.
- No caffeine for 12 hours prior to all study visits.
- Eat a normal breakfast prior to the exposures where the bronchoscopy is being performed
~24 h post-exposure.
- Not eat or drink anything after midnight the night before the bronchoscopy. This
includes not eating or drinking prior to the exposures in which the bronchoscopy is
being performed 1 h post-exposure.
Training Day
1. Eligible subjects will report to the research lab for an approximate 2-hour training
session.
2. Informed consent will be obtained.
3. Assessment of vital signs (temperature, pulse, respiratory rate, and blood pressure),
oxygen saturation
4. Pregnancy tests will be administered to any women who may have child-bearing potential.
5. Subjects will be trained on the cycle ergometer and the work load to elicit a minute
ventilation normalized for body surface of 25L/m2/BSA will be determined. In most
subjects this will be about 50 L/minute (IE. VO2 of approximately 2.0 L/m). A cycle
ergometer work setting of 75 to 100 watts will usually achieve such a physiological
response
6. Subjects will perform spirometry.
7. Subjects will be shown chamber where exposures will take place. Study Arm 1 -
Bronchoscopy ~24 h Post-Exposure (Healthy & Asthmatic Subjects)
Exposure Day 1
The subjects will be exposed to ozone, diesel exhaust and clean air on three separate
occasions, with the exposures separated by a minimum of two weeks (these will be 2-visit
exposure sessions). Subjects receiving 18Ozone, will only be exposed to ozone.
1. Subjects will be asked to arrive at the study site no sooner than 8 AM and will undergo
assessment of vital signs (temperature, pulse, respiratory rate, and blood pressure),
oxygen saturation, and symptom score assessment.
2. Pregnancy tests will be administered to any women who may have child-bearing potential.
3. A telemetry unit will be attached for cardiac monitoring.
4. Subject will be fitted with a Holter monitor and the subject will be asked to recline
in a quiet dark place for 30 minutes. After approximately 20 minutes a time marker will
be activated so that heart rate variability frequency readings can be taken over the
next 10 minutes. The subject will wear the Holter monitor for the next 24 hrs. Subjects
exposed to 18Ozone will not be fitted with a Holter.
5. Venipuncture: Up to 80 ml of blood will be collected for a CBC/ differential, and may
be used for assessment of coagulation function and markers, phagocytic function,
inflammation, and cell surface markers. A portion of the sample may be used for RNA
isolation for microarray analysis and for DNA isolation for genotyping purposes.
Pre-exposure blood will not be taken from subjects being exposed to 18Ozone
6. Baseline Spirometry
7. Exposure sessions: Exposure to ozone, diesel exhaust or clean air will be conducted in
an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject
will be exposed up to 0.3ppm ozone, diesel exhaust (up to 300 ug/m3) or clean air for 2
hours. Subjects will begin exercising on an exercise bike. Each exercise session will
consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a
15 minute rest period. Minute ventilation may be measured during each exercise period.
Continuous heart rate and rhythm, and oxygen saturation, will be monitored using
telemetry and pulse oximetry respectively. Blood pressure may be monitored
intermittently. Subjects will be asked to refrain but not prohibited from using inhaled
bronchodilator during exposures; if medication use is necessary subjects will be
instructed to maintain consistent medication use across the two exposures. The subjects
will be able to end their exposure and exit the chamber at any time. Indications for
terminating the exposure include significant respiratory distress or dyspnea, chest or
angina-like pain, significant cardiac arrhythmias, pallor, ataxia, or a greater than 5
point drop in saturated oxygen (or a drop to lower than 89%). They will be monitored
continuously by trained personnel and a physician is on call whenever a subject is
undergoing a procedure at the facility. A detailed description of the physical
facilities in the Human Studies Division of the U.S. EPA Health Effects Research
Laboratory located on the UNC-CH campus have been published as U.S. Government
Publication EPA-600/1-78-064, and is on file in the office of the UNC Committee on the
Protection of the Rights of Human Subjects. The medical station of the Human Studies
Division includes a fully-equipped medical examination room, a cardiac/respiratory
emergency cart, a subject recovery room, a nurse's station, a waiting room and
conference rooms. The facility is staffed by qualified RNs, and an on-site physician is
available to respond to a medical emergency in a timely manner. The exposure atmosphere
will be at approximately 40 + 10% RH and approximately 22 + 2 oC. The DE will be
generated from a diesel generator used to power a load bank that is located outside the
Human Studies Facility, and subsequently introduced into the exposure chamber after
different dilutions with clean HEPA and charcoal filtered and humidified air to give a
chamber concentration of up to 300 μg/m3. The monitoring analyzer registers a
concentration in real time. Exposures will be terminated at values ≥ 400 µg/m3 during
runs in which the exposure targets 300 µg/m3 DE. This safety limit will prevent an
inhalational exposure greater than 1080 µg, which assumes that the subject will inhale
2.7 m3 during the 120 min exposure. Levels of carbon monoxide (CO), and oxides of
nitrogen (NOx; mainly NO, and some NO2), will be kept under 10 ppm CO, 15 ppm NO, and
2.5 ppm NO2 or the exposure will be terminated. [The OSHA 8 hr time-weighted average
(TWA) for these substances are: CO=50 ppm; NO=25 ppm; NO2=5 ppm; Diesel fuel used for
the study will be purchased as a commercial ultra low sulfur fuel. Subjects will enter
the exposure chamber (about 6 ft x 6 ft x 8 ft ). Particle mass will be measured in
real time. Particle size distribution may not be determined during each subject
exposure but at regular intervals (e.g., monthly) to show that the size distribution
does not change radically. Filter samples will also be analyzed for chemical
composition of particles. Ozone exposures will be conducted in a (6 ft x 6 ft x 8 ft)
stainless steel chamber with a continuous supply of exposure medium. Ozone will be
monitored continuously. Immediately post exposure, subjects will again undergo
spirometry, Holter monitor frequency reading, symptom scoring and assessment of vital
signs.
8. Then, up to 80 ml of blood will be collected for a CBC/ differential, assessment of
coagulation function, blood leukocyte phagocytic function, cytokines, cell surface
markers and RNA isolation for microarray analysis. Subjects exposed to 18Ozone will
have only 20 mls of blood removed for analysis of 18O tag present on blood cells and
have post exposure Spirometry measurements.
9. Subjects exposed to 18Ozone will have bronchoscopy performed about 1 hr post-exposure.
Exposure to 18Ozone and undergoing a bronchoscopy approximately one hour later should
not increase the risk to the subjects. We have completed two earlier studies in which
subjects underwent bronchoscopy following exposure to concentrations of ozone higher
than used in this study, and encountered no problems. Others have also published
studies in which subjects were exposed to ozone followed by bronchoscopy one hour later
10. Subjects will then be assessed and discharged by the nursing staff.
Exposure Day 2 (approximately 24 hours after exposure) Subjects being exposed to 18O will
not be returning for a Day 2
The subject will arrive at the U.S. EPA HSF for:
1. Vital sign monitoring.
2. Symptom scoring.
3. Venipuncture: up to 80 ml of blood will be collected for a CBC/ differential,
coagulation function, assessment of blood monocyte phagocytic function, inflammation,
and cell surface markers, and RNA isolation for microarray analysis.
4. Holter monitor frequency reading and removal
5. Spirometry
6. Bronchoscopy. Subjects will have undergone a physical examination including assessment
for suitability for transnasal fiberoptic bronchoscopy at the Human Studies Facility by
a board certified or board eligible pulmonologist.
Prior to the procedure, subjects will perform spirometry (as above); bronchoscopy will not
be performed if lung function does not meet the recommended performance level (NIH
guidelines; FEV1≥ 60 % predicted). Prior to bronchoscopy, a small tube (IV) will be placed
in a vein for potential use in administering fluids. Subjects will receive inhaled albuterol
prior to the bronchoscopy at the discretion of the pulmonary physician performing the
procedure. Bronchoscopy with bronchoalveolar lavage and brush biopsy will be performed by a
licensed physician who is Board certified or board eligible in pulmonary medicine and is
experienced in fiberoptic bronchoscopy. The physician will be assisted by at least one R.N
experienced in bronchoscopy. The subjects will be monitored closely throughout the procedure
in the following manner: 1) Chest electrodes for continuous electrocardiogram, 2) Pulse
oximetry of arterial blood, and 3) blood pressure monitoring using an electronic
sphygmomanometer. Subjects may be premedicated with IV atropine (0.6 mg) to prevent
bradycardia and hypotension that could result from vagal stimulation provoked by passing the
bronchoscope through the subject's larynx and to minimize the amount of airways secretions.
Nasal oxygen will be administered during the procedure. No sedatives and/or narcotics are
administered at any time during bronchoscopy. We have found that premedication with
sedatives (midazolam) or with opiates (demerol) is not required for research bronchoscopy
subjects. Avoidance of these drugs reduces procedure risk and markedly shortens
post-procedure recovery time. Neosynephrine will be used to decongest nasal passages,
followed by gargling with a lidocaine solution for a few seconds to anesthetize the throat.
The subject will then sniff (snort) a small amount of lidocaine jelly through one nostril to
anesthetize the nose and the back of throat. A Q-tip with lidocaine jelly will be gently
inserted into the nose to ensure that it is completely numb before the bronchoscope is
inserted. Topical lidocaine anesthesia will be administered to the larynx and lower airways
through the bronchoscope for subject comfort and to prevent cough, with a maximum dose of 15
ml of 2% lidocaine solution (360 mg lidocaine) Up to 8 endobronchial brush biopsies will be
obtained from the lower trachea and right and left mainstem bronchi. A cytology brush
(Bronchoscope Cytology Brush; Bard, Tewksbury, MA) is applied to the region under direct
visualization. For a single brushing, six passes, each with a linear excursion of
approximately 2-5 cm, are made with the brush along the endobronchial surface.
Bronchoalveolar lavage will be performed in the right middle lobe using a total volume of up
to 250 cc of sterile 0.9% saline; from one to 5 aliquots of 50 cc each will be injected and
immediately aspirated through the channel in the bronchoscope using a syringe.
Subjects are observed and monitored for a minimum of 1 to 2 hours after the procedure in the
on-site medical station by a registered nurse with physician supervision. At discharge
subjects will be symptom-free. At least 2 physicians, including the responsible
bronchoscopist, will be available (24 hours daily) to subjects who develop any symptoms
after discharge. The subject is discharged by a physician and is provided with the names and
telephone numbers of the bronchoscopist and one other physician. The subject is contacted 24
hours post-bronchoscopy to ask about any untoward effects.
Subjects will return to the U.S. EPA HSF for an additional exposure sessions and post
exposure bronchoscopies (air control, ozone or diesel exhaust) after a minimum time interval
of two weeks.
Study Arm 2 - Bronchoscopy 1 h Post-Exposure (Healthy Subjects ONLY)
Exposure Day 1
The subjects will be exposed to ozone and clean air on two separate occasions, with the
exposures separated by a minimum of two weeks (these will be 1-visit exposure sessions).
1. Subjects will be asked to arrive at the study site no sooner than 8 AM and will undergo
assessment of vital signs (temperature, pulse, respiratory rate, and blood pressure),
and oxygen saturation.
2. Pregnancy tests will be administered to any women who may have child-bearing potential.
3. A telemetry unit will be attached for cardiac monitoring.
4. Baseline Spirometry
5. A saline lock will be placed in the subject's arm in preparation for IV fluids to be
administered post-exposure.
6. Exposure sessions: Exposure to ozone or clean air will be conducted in an exposure
chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be
exposed up to 0.3ppm ozone or clean air for 2 hours. Subjects will begin exercising on
an exercise bike. Each exercise session will consist of a 15 minute exercise interval
at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. Minute ventilation
may be measured during each exercise period. Continuous heart rate and rhythm, and
oxygen saturation, will be monitored using telemetry and pulse oximetry respectively.
Blood pressure may be monitored intermittently. The subjects will be able to end their
exposure and exit the chamber at any time. Indications for terminating the exposure
include significant respiratory distress or dyspnea, chest or angina-like pain,
significant cardiac arrhythmias, pallor, ataxia, or a greater than 5 point drop in
saturated oxygen (or a drop to lower than 89%). They will be monitored continuously by
trained personnel and a physician is on call whenever a subject is undergoing a
procedure at the facility. A detailed description of the physical facilities in the
Human Studies Division of the U.S. EPA Health Effects Research Laboratory located on
the UNC-CH campus have been published as U.S. Government Publication EPA-600/1-78-064,
and is on file in the office of the UNC Committee on the Protection of the Rights of
Human Subjects. The medical station of the Human Studies Division includes a
fully-equipped medical examination room, a cardiac/respiratory emergency cart, a
subject recovery room, a nurse's station, a waiting room and conference rooms. The
facility is staffed by qualified RNs, and an on-site physician is available to respond
to a medical emergency in a timely manner. The exposure atmosphere will be at
approximately 40 + 10% RH and approximately 22 + 2 oC. Ozone exposures will be
conducted in a (6 ft x 6 ft x 8 ft) stainless steel chamber with a continuous supply of
exposure medium. Ozone will be monitored continuously. Immediately post exposure,
subjects will again undergo spirometry and assessment of vital signs.
7. IV fluids will be administered prior to the bronchoscopy to ensure proper hydration of
the subject
8. Subjects will have bronchoscopy performed about 1 hr post-exposure. Undergoing a
bronchoscopy approximately one hour post-exposure should not increase the risk to the
subjects. We have completed two earlier studies in which subjects underwent
bronchoscopy following exposure to concentrations of ozone higher than used in this
study, and encountered no problems. Others have also published studies in which
subjects were exposed to ozone followed by bronchoscopy one hour later.
Subjects will have undergone a physical examination including assessment for suitability for
transnasal fiberoptic bronchoscopy at the Human Studies Facility by a board certified or
board eligible pulmonologist. Prior to the procedure, subjects will perform spirometry (as
above); bronchoscopy will not be performed if lung function does not meet the recommended
performance level (NIH guidelines; FEV1≥ 60 % predicted). Bronchoscopy with bronchoalveolar
lavage and brush biopsy will be performed by a licensed physician who is Board certified or
board eligible in pulmonary medicine and is experienced in fiberoptic bronchoscopy. The
physician will be assisted by at least one R.N experienced in bronchoscopy. The subjects
will be monitored closely throughout the procedure in the following manner: 1) Chest
electrodes for continuous electrocardiogram, 2) Pulse oximetry of arterial blood, and 3)
blood pressure monitoring using an electronic sphygmomanometer. Subjects may be premedicated
with IV atropine (0.6 mg) to prevent bradycardia and hypotension that could result from
vagal stimulation provoked by passing the bronchoscope through the subject's larynx and to
minimize the amount of airways secretions. Nasal oxygen will be administered during the
procedure. No sedatives and/or narcotics are administered at any time during bronchoscopy.
We have found that premedication with sedatives (midazolam) or with opiates (demerol) is not
required for research bronchoscopy subjects. Avoidance of these drugs reduces procedure risk
and markedly shortens post-procedure recovery time. Neosynephrine will be used to decongest
nasal passages, followed by gargling with a lidocaine solution for a few seconds to
anesthetize the throat. The subject will then sniff (snort) a small amount of lidocaine
jelly through one nostril to anesthetize the nose and the back of throat. A Q-tip with
lidocaine jelly will be gently inserted into the nose to ensure that it is completely numb
before the bronchoscope is inserted. Topical lidocaine anesthesia will be administered to
the larynx and lower airways through the bronchoscope for subject comfort and to prevent
cough, with a maximum dose of 15 ml of 2% lidocaine solution (360 mg lidocaine) Up to 8
endobronchial brush biopsies will be obtained from the lower trachea and right and left
mainstem bronchi. A cytology brush (Bronchoscope Cytology Brush; Bard, Tewksbury, MA) is
applied to the region under direct visualization. For a single brushing, six passes, each
with a linear excursion of approximately 2-5 cm, are made with the brush along the
endobronchial surface. Bronchoalveolar lavage will be performed in the right middle lobe
using a total volume of up to 250 cc of sterile 0.9% saline; from one to 5 aliquots of 50 cc
each will be injected and immediately aspirated through the channel in the bronchoscope
using a syringe.
Subjects are observed and monitored for a minimum of 1 to 2 hours after the procedure in the
on-site medical station by a registered nurse with physician supervision. At discharge
subjects will be symptom-free and able to void urine. At least 2 physicians, including the
responsible bronchoscopist, will be available (24 hours daily) to subjects who develop any
symptoms after discharge. The subject is discharged by a physician and is provided with the
names and telephone numbers of the bronchoscopist and one other physician. The subject is
contacted 24 hours post-bronchoscopy to ask about any untoward effects.
Subjects will return to the U.S. EPA HSF for an additional exposure sessions and post
exposure bronchoscopies (air control or ozone) after a minimum time interval of two weeks.
We anticipate performing several clinical procedures during the course of this study which
include primary, secondary and exploratory endpoints. However, it is possible that not all
procedures will be performed on every subject. If we are unable to perform a procedure,
because of a investigator problem (such as but not limited too building/equipment failures,
weather delays, or staffing issues), then the patient will be compensated for said
procedure(s) and time on that day and may be rescheduled.
