General Experimental Design: This will be a randomized, double-blind, placebo-controlled,
comparison study of Nantheia ATL5 (CBD) vs. placebo on smoking behavior in participants
who have Tobacco Use Disorder (TUD) and have a desire for smoking cessation, conducted at
CRI-Help, Inc., a residential substance use treatment center in N. Hollywood, CA. The
investigators will instruct participants and provide support via text messages from the
National Cancer Institute's Smokefree.gov website. Smokefree.gov offers free messaging
programs that give encouragement, advice, and tips for becoming smoke-free and being
healthier. The NCI website also helps people who smoke create a personalized quit plan
that makes it easier to stay on track, get through hard times, and quit for good.
Creating this plan will be part of baseline procedures.
Randomization to Treatment, Sample Size: Participants will receive CBD at a dose of 800
mg per day or placebo (n = 60/group). The investigators will randomize by sex and age
(18-30, greater than/equal to 31 years) to ensure equal representation across the groups.
The investigators will use an intention-to-treat analysis, including data from all
participants who are randomized (see below for power analysis).
Dosing and Testing Schedule: After screening (Days -7 to 0) and baseline (Day 0)
assessments, the study will comprise a 56-day (8-week) treatment period with follow up
assessments at 1 and 3 months after termination of treatment as part of this trial.
Measurements will be obtained at daily and weekly assessments during the 8-week treatment
period.
Measures Collected: A baseline assessment will include assay of blood plasma cotinine to
indicate heaviness of smoking, and self-reports of smoking-related behaviors on the
following smoking-related questionnaires:
Fagerström Test for Nicotine Dependence (FTND). This 6-item survey (~2 min) is
closely linked to nicotine intake.
Smoking History Questionnaire. Developed in Dr. London's Lab, this 25-item survey
(~5 min) queries age at initiation, longest quit attempt, number of quit attempts,
reasons for quitting, and current smoking behavior (e.g., preferred brand,
cigarettes per day, etc.).
Minnesota Nicotine Withdrawal Scale (MNWS) measures withdrawal symptoms: craving,
irritability, anxiety, difficulty concentrating, restlessness, headache, drowsiness,
and GI disturbances. These symptoms are scored on an ordinal scale [0 (not present)
to 3 (severe)].
General Anxiety Screener (GAD-7). This is a self-administered seven-item
questionnaire that is used to measure or assess the severity of generalized anxiety
disorder (GAD). The GAD-7 takes ~1-2 min to complete.
Patient Health Questoinnaire-9 (PHQ-9). This self-administered nine-item scale
measures the degree of depression. The PHQ-9 only takes ~1-2 min to complete.
Participants will self-report cigarette use and adverse events (AEs) each day using
structured questionnaires. At screening and on days 7, 14, 28 and 56, the investigators
will take vital signs and draw blood for clinical laboratory tests for safety, to assay
cotinine as an index of heaviness of smoking, and to assay cannabinoids (CBD, anandamide,
2-AG); participants will complete the FTND, MNWS, GAD-7, and PHQ-9. At 1- and 3-month
follow up, the investigators will take vital signs, measure CO in breath, and take the
same behavioral/self-report measures as on Days 7, 14, 28 and 56.
Retention: The index of retention will be the number of days a participant remains in the
study.
Assay of CBD, anandamide, 2-AG and cotinine: The investigators will use liquid
chromatography/mass spectrometry-multiple reaction monitoring (LC/MS-MRM) assays.
Internal standards are added after sample extracts are processed and injected onto a
multi-mode column with reversed phase, cation and anion exchange capabilities. After
equilibration and elution, column effluents are passed through an electrospray ion source
attached to a triple quadrupole mass spectrometer, and MRM signals are recorded. Each
compound is quantified by interpolation from response curves using data from internal
standards and increasing concentrations of unlabeled authentic analytes.
Risks and Minimization of Risk
Risks associated with taking CBD include:
Increase in liver alanine aminotransferase enzymes (ALT test)
Increase in blood clotting (International Normalized Ratio, INR).
Given the possibility that individuals with substance use disorders will participate in
the study and may exhibit abnormality in liver function at baseline, liver function tests
will be performed in screening, and individuals with abnormal values will be excluded.
Abuse Potential of CBD: The DEA has classified CBD as a Schedule I drug In the United
States, suggesting that CBD has a high potential for abuse, but the World Health
Organization Expert Committee on Drug Dependence concluded that no abuse potential could
be confirmed based on findings from animal and human research. The type of CBD used here
is derived from hemp and contains less than 0.3% tetrahydrocannabinol (THC; i.e., the
primary psychoactive ingredient in cannabis). CBD used in Nantheia ATL-5 is not
considered a scheduled drug by the DEA.
Note: Careful screening at baseline and ongoing monitoring of plasma levels for potential
emergence of adverse events will be practiced, ensuring minimization of all risks.
In addition, trial stopping rules were developed with the following criteria applied.
Patient safety dose stopping and discontinuation criteria (no re-challenge):
ALT or AST >3 x ULN and [total bilirubin level (TBL) >2 x ULN or INR >1.5).
ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
Other risks of CBD administration Possible effects on a fetus: There are no long-term
studies in humans on CBD effects on fetal development; however, animal studies suggest
that long-term use is safe, with very low potential for effects on a fetus at doses
associated with human treatment. To minimize this potential risk, pregnancy is an
exclusion criterion, and a participant who becomes pregnant will be withdrawn from the
study.
Risk of ovarian suppression: Animal studies have indicated this possibility. Female
participants will undergo a hormonal battery at screening with ultrasound upon abnormal
findings. Participants with evidence of ovarian suppression will be excluded. Ovarian
function will also be tested during the treatment phase, and any abnormality followed up
with referral for further investigation.
This study will be conducted in a residential treatment facility. Thus, participants will
be closely monitored, dosing will be controlled, and clinical and laboratory assessments
will be done on a regular schedule.
Participant Withdrawal from the Protocol: Participants can be withdrawn for safety (see
stopping criteria above) and noncompliance with medication administration protocols.
Decisions regarding safety will be made by the PI with advice from Co-Investigator
Larissa Mooney, M.D. Participants will also be withdrawn upon leaving inpatient treatment
at CRI-Help. Participants can decide on their own to withdraw from the protocol at any
time without prejudice, and this will not affect their treatment at CRI-Help. All
participants will receive compensation for all of the procedures/assessments completed.
Drug Administration Details
Investigational Product and Mode of Administration: Nantheia ATL5, which is CBD,
extracted from hemp, at a 10% strength (softgel capsules with 100 mg/ml of CBD per
capsule) or matching placebo. The formulation that was selected for this clinical trial
contains CBD and excipients as here:
emulsifying agents: Cremophor EL (Polyoxyl 35 castor oil), Tween 80 (Polysorbate
80), Plurol® Oleique (polyglyceryl-3 dioleate);
cwe o-surfactant: propylene glycol;
oil: Labrosol® (caprylocapryol polyoxyl-8 glycerides), medium chain triglycerides;
antioxidant: BHT (butylated hydroxytoluene).
Nantheia ATL5 Softgel Capsules will be manufactured by Baxco Pharmaceutical Inc.
(California, USA), under cGMP conditions for Ananda Therapeutics. Ananda will supply
Nantheia ATL5 Softgel Capsules and matching placebo for this study. Capsules will be
administered orally as indicated below. Ananda Therapeutics is FDA-approved to supply
this product.
Dosage and Duration of Treatment: This study will evaluate Nantheia ATL5 in participants
given CBD or placebo (1:1). The treatment period will be 56 days (8 weeks). Participants
will be in the study for up to 24 weeks, including follow-up at 1 and 3 months after
completion of the treatment protocol. The CBD/placebo dose will be 800 mg/day. Dose
Justification: A daily dose of 600 mg is being evaluated in our ongoing trial of CBD for
opioid use disorder (ClinicalTrials.gov Identifier: NCT03787628). Doses of CBD as high as
50 mg/kg (i.e., 3500 mg for a 70-kg participant) were well tolerated; and doses between
300 and 1500 mg have been used in humans without serious adverse events. Forty-two
subjects received 200 mg of CBD 4x daily (total 800 mg per day) for 2-4 weeks to treat
schizophrenia without notable side effects. Additionally, a review of 132 reports
including animal and human studies concluded that CBD was well-tolerated in humans, at
doses of up to 1500 mg/day.
Regulatory Considerations: CBD will be administered in this protocol as Nantheia ATL5, a
hemp-derived product that contains < 0.3% tetrahydrocannabinol (THC). Nantheia ATL5 is
not a Schedule 1 controlled substance because Nantheia ATL5 is hemp-derived CBD with a
THC concentration of no more than 0.3%. The investigators have obtained FDA approval for
this project. The investigators will receive oversight and obtain approval from the UCLA
Institutional Review Board.
Receipt and Storage of the Investigational Product (IP). The IP will be delivered by the
manufacturer in bottles containing 28 1-mL softgels each for testing of 800 mg CBD vs.
placebo. Nantheia ATL5 will be stored at room temperature, 59-86°F (15-30°C), in a locked
cabinet in a locked office of a staff member blinded to its identity (CBD or placebo).
Dispensation of the IP: Staff not involved in data entry or any other aspects of the
study will distribute the IP into containers labeled with the subject-ID number and/or
patient initials and doses will be divided for AM or PM. The investigational product (CBD
or placebo) will be taken under staff supervision at the CRI-Help treatment center. A
Residential Technician (RADT) will be responsible for supervising and recording patient's
self-administration of the IP. Unused or missed medication will be collected once weekly
and prepared for return to the manufacturer.