Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT04258852 |
| Other study ID # |
2000023604 |
| Secondary ID |
1K23DA045957-01 |
| Status |
Withdrawn |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
December 30, 2022 |
| Est. completion date |
February 1, 2025 |
Study information
| Verified date |
February 2024 |
| Source |
Yale University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The goal of this proposal is to test the overall hypothesis that e-cigarettes (ECs) provide
efficient nicotine delivery to the brain and arterial blood in non-EC-naïve smokers and
e-cigarette users and that EC liquid characteristics modulate this effect. This study will
test the hypothesis through complementary methods that include [ [18F]NCFHEB (aka
[18F]Flubatine) PET neuroimaging, arterial blood nicotine measurements, and subjective drug
effects assessments.
Description:
C.2 Subject Inclusion and Assessments Overall study design: Non-EC-naïve smokers or
e-cigarette users (n=20) will abstain from tobacco smoking/nicotine products for 5 days prior
to each PET scan. In a randomized order (counterbalanced), after baseline quantification of
receptor availability, subjects will be scanned while using an EC: (1) "JUUL" 5%, a common
commercially available unmodified nicotine salt EC, and (2) JUUL 3%, a lower nicotine
strength product. A third optional scan where subjects smoke a cigarette may be conducted but
is not required. During scanning, subjects will undergo arterial blood nicotine level
measurements following EC use and measures of nicotine withdrawal, craving, and drug effects
will be measured. 5-7 days of smoking abstinence will be required prior to each PET scan to
ensure no residual nicotine occupies receptors. Subjects will go back to smoking as usual
after first scan for 2-3 weeks prior to subsequent smoking abstinence/PET scanning. Subjects
will be provided with smoking cessation resources upon request.
C.2.b Subjects: Twenty non-EC-naïve tobacco dependent smokers or e-cigarette users will be
recruited for the study. All research subjects will be recruited under guidelines of the Yale
University Institutional Review Board (Human Investigation Committee). Smokers will be
recruited from the community via IRB-approved advertising. After completing informed consent,
subjects will have a psychiatric, physical and neurological examination, laboratory tests and
an electrocardiogram (EKG) (see C.2.c Clinical Assessments below). This is considered the
screening phase. Subjects will be excluded for major medical, neurological or psychiatric
illness, abnormal laboratory tests, or contraindication to PET or MR imaging. A urine drug
screen and pregnancy test are performed at screening and prior to each imaging session and
participants are excluded for a positive test. Detailed inclusion/exclusion criteria can be
found in Protection of Human Subjects section. All women will be required to have a negative
urine pregnancy test and all subjects are required to have a negative urine drug toxicology
test prior to radiotracer administration.
C.2.c Clinical Assessments: A standardized battery will be administered to all subjects at
intake including Health Questionnaire, the SCID, assessments of demographics, measures of
tobacco use, alcohol and drug use, family history of smoking, mood (PROMIS short forms for
depression, anxiety, and anger), Center for Epidemiologic Studies Depression Scale), anxiety
(State Trait Anxiety Inventory), impulsivity (Brief - Barratt Impulsivity Scale, smoking
dependence (PROMIS nicotine dependence scale), smoking craving (Tiffany QSU) and withdrawal
(Minnesota Nicotine Withdrawal Scale). Mood and smoking assessments will be repeated on each
scan day before and after challenge. Product liking, craving and the Drug Effects
Questionnaire (DEQ) will be assessed on a subjective scale (0-100, low-high) immediately
following product use. The DEQ will measure acute effects consisting of seven items: drug
strength, high, feeling stimulated, good effects, bad effects, wanting more drugs, and drug
liking.
Baseline and after each PET scan/e-cig challenge:
- Health Questionnaire
- PROMIS Dyspnea Severity Item Pool
- PROMIS Dyspnea Characteristics
- PROMIS Fatigue Short Form
- Functional Assessment of Chronic Illness Therapy (FACIT) Cough item
- The health questionnaire titled 'assessment of health problems' (and provided as an
attachment via a comment in IRES) will be added to the protocol and will be completed at
intake and before each exposure. Note that potential subjects with chronic symptoms that
would interfere with monitoring of vaping complications, will not be enrolled.
Positive findings of a change in symptom or single severe symptom would trigger clinical
referral to a treating physician or the emergency room.
C.2.d Contingency Management: All smokers/e-cigarette users will be helped to remain
abstinent for 5- 7 days prior to each PET scan with highly successful contingency management
techniques that have been used extensively in the laboratory before. Subjects will return to
smoking use as usual after the first PET scan and repeat smoking abstinence prior to the next
PET scan. This technique has been successful in the past to study nicotine occupancy of
receptors after multiple challenges by recruiting smokers who are non-treatment seeking.
Subjects will be met daily over the course of abstinence provide support and obtain CO and
urine cotinine levels to ensure smoking abstinence. Subjects who are not able to abstain from
tobacco smoking (2 consecutive days without a decrease in urine cotinine levels or a sudden
increase in urine cotinine or CO levels) will be withdrawn from the study.
C.2.e - MRI/cognitive testing Subjects will be asked to go to the MRRC at The Anlyan Center
for Medical Research & Education (TAC, 300 Cedar Street) to have an MRI (Magnetic Resonance
Imaging) scan of their brain. The purpose of the MRI is to help us identify the different
regions of their brain on the PET scans.
The MRI scan is a routine way to get pictures of the inside of the body. Subjects will be
asked if they are carrying any metallic objects before they move toward the MRI system. These
objects will be held for them in a locked cabinet in the MRI Center to avoid having these
objects fly toward the magnet when they approach it. They will also be asked to walk through
a metal detector. They will be asked to lie still in the MRI scanner for about 30 minutes.
The scanner looks like a deep tunnel. They will be inside the tunnel from head to knees. They
will not be able to see out of it, but they will be able to hear us and be heard if they wish
to say anything. They will hear a drumming noise when the camera is taking pictures of their
brain. If they feel uncomfortable during the scan, the scan will be ended at any time they
wish. However, if they cannot complete the MRI scan, they will not be able to participate in
any more of these studies.
Two sessions of testing of their memory, attention, and concentration may take place. This
will take approximately 1hr total. They will be given a break between these sessions. This
may take place on the same day as the MRI scan, or on another day prior to PET scans if that
works better with their and staff schedule.
During this visit, they may play a computer game called the Face Game. The goal of the Face
Game is to win as much money as possible. They may earn money by quickly and correctly
pressing one of two keys on the keyboard, each time they see a face on the screen. They will
press one key if they think that the mouth on the face is long, and the other if they think
it is short.
Cold Pressor Task Subjects may also be asked to participate in the cold pressor task during
the study to test the body's physiological response to cold water. They will be asked to
immerse your hand in a bucket of ice cold water maintained at 0-4°C. They will be told to
raise their other hand when they begin to feel pain and to remove their hand from the water
when they can no longer tolerate the pain. While their hand is immersed in water, they will
also be asked to rate their pain on a scale from 0-100 and their heart rate and blood
pressure will be monitored.
Impulsivity Subjects may be asked to play a game in which they will use a computer mouse to
click a balloon pump that inflates a balloon on the screen. The objective of the task is to
get the largest amount of the money possible while avoiding balloon explosions. This
assessment tests their impulsivity. They may be asked to play this game on the day of their
PET scan too.
C.3. PET Imaging Procedures PET procedures will be conducted at the Yale University PET
Center. Female subjects will be given a urine pregnancy test prior to the initiation of any
imaging procedures. If the test is positive, the scans will be canceled. Subjects will
receive a minimum of 2 and maximum of 3 PET scans. The 3rd scan is optional.
PET scans: Prior to the PET scans, a T1-weighted MRI will be acquired for all subjects on a
3.0 Tesla Siemens Trio camera to rule out any brain abnormalities and for anatomical
reference in the image analysis.
PET scans are acquired as subjects lie supine on the scanner bed. Venous catheters will be
used for intravenous administration of the radiotracer, and possibly for additional venous
blood sampling. A radial artery catheter will be inserted by an experienced physician before
the PET scan to draw arterial blood samples for metabolite analysis and for determination of
the fraction of plasma radioactivity unbound to protein.
Infusion of the radiotracer takes 210 minutes (3.5 hours). Subjects will be scanned for 2
hours (starting 90 minutes after initiation of radiotracer infusion).
[18F]NCFHEB will be synthesized and administered on PET scan days as a bolus plus constant
infusion with a Kbol of 360 minutes over 3.5 hours. PET data will be acquired on the MCT. A
6-min transmission scan will be acquired at the beginning or end of each PET scan to correct
for attenuation. Arterial blood samples will be taken to obtain a metabolite-corrected
[18F]NCFHEB input function. Baseline receptor availability will be measured 90-120mins after
radiotracer infusion. Then, subjects will start a challenge (NIDA EC or JUUL EC,
counterbalanced order) at 125min for 5 minutes in the scanner. Thereafter, post nicotine
scanning will continue until end of 4 hrs of infusion. Vital signs (blood pressure, pulse,
respiration) and ECG's will be obtained before and after radiotracer administration. The same
procedures will follow for the 2nd PET scan.
Use of EC: Subjects will receive 2 different scans and will puff one of two EC products (in
random order, counterbalanced): "JUUL" 5% (50 mg/ml), a common commercially available
unmodified nicotine salt EC, and (2) JUUL 3% (30 mg/ml), a lower nicotine strength product.
Only tobacco flavor will be used. A training session to familiarize smokers with the EC
product used in the study will be conducted at an appointment prior to the PET scans.
Subjects will be advised to take longer and slower puffs from the EC (at least 3-4 seconds)
as compared with puffing a cigarette. During each scan, subjects will be instructed to puff
on the EC for up to 5 minutes. All users will be directly observed during EC use to ensure
they do not have any problems operating the device. If available, a mouthpiece to measure
puff topography may be used as previously described.
Use of Regular Cigarette: A third PET scan using a regular cigarette may be offered for
cigarette smokers but is not required for study completion.
Blood Samples: On PET scan days, arterial blood samples will be collected prior to
radiotracer administration and at multiple time points (t = 0, 0.3, 1, 3, 5, 10, 20, 30, 60,
90 minutes post challenge) after EC/cigarette use to determine nicotine concentrations in the
blood, which will be assayed using liquid chromatography tandem-mass spectrometry with
deuterated internal standards.47 These data will be used to calculate pharmacokinetic
patterns of nicotine delivery under each condition (Cmax, Tmax, and AUC for nicotine).
Image Analysis and Outcome Measure: List-mode PET data will be reconstructed with OSEM with
built-in corrections for attenuation, normalization, scatter, randoms, deadtime and subject
motion.53,54 Following image reconstruction, a summed image will be registered to the
subject's MRI. Regions of interest (ROIs) will be anatomically defined using a template
[Anatomical Automatic Labeling (AAL)] coregistered to the subject's MRI image. ROIs used for
calculation of receptor occupancy will be: cerebellum, frontal, parietal, temporal, and
occipital cortices, caudate, putamen, hippocampus, and amygdala. These regions are chosen
because they were previously examined in β2*-nAChR studies, have significant density in the
human brain, and are relevant to the craving and withdrawal properties of nicotine. The
thalamus will not be included because equilibrium is not reached in this region with the
bolus-infusion paradigm. The volume of distribution VT will be estimated using the
equilibrium ratio between total radioactivity concentration in tissue and parent
concentration in arterial plasma. Baseline VT will be estimated from 90-120 min after
infusion start, previously shown to establish good equilibrium in brain Post-ECig VT will be
estimated from 180-210 minutes after infusion start (55-85 minutes post challenge). Prior
preliminary data show that this is a sufficient amount of time for a new steady state to be
achieved. Receptor occupancy and VND will be estimated using the Lassen plot approach.
