A Pharmacokinetic Study to Compare CBD-NE to Epidyolex in Healthy Adult Volunteers Under Both Fed and Fasted Conditions

A Randomized, Open-Label, 4-Way Crossover, Pharmacokinetic Study to Compare CBD-NE to Epidyolex in Healthy Adult Volunteers Under Both Fed and Fasted Conditions

Cannabidiol (CBD), derived from the Cannabis sativa plant, is being investigated for its potential health benefit without the psychoactive properties and adverse reactions that arise from the use of delta-9-tetrahydrocannabinol (Δ9-THC). Few studies have characterized the pharmacokinetic (PK) effects and safety of oral CBD administration. Epidiolex (Epidyolex), an oil form of CBD, is the only marketed monotherapy approved by the United States Food and Drug Administration (FDA) and Health Canada. Delivery of a CBD in a powder/capsule form may provide a more efficient method for consumers.

The goal of this study is to characterize the PK profile of the test product, CBD-NE (a capsule formulation) compared to Epidyolex under both fasted and fed conditions. Each participant will receive a dose of each product under both fed and fasted conditions in a crossover design.

CBD and Δ9-THC are the most abundant extracts from the Cannabis sativa plant. Δ9-THC is typically associated with psychotropic effects due to its affinity for cannabinoid receptor types 1 and 2. CBD possesses a low affinity and lack of function at these receptors; therefore there is an interest in its potential health benefit without the psychoactive properties and adverse reactions that arise from Δ9-THC use. Only few studies have characterized the PK effects and the safety of oral CBD administration. As CBD is a lipophilic molecule, consuming CBD with a lipid formulation may increase its exposure. Additionally, CBD is known to have poor bioavailability when taken orally because it is rapidly metabolized by the liver to 7-hydroxycannabidiol (7-OH-CBD) and then to cannbidiol-7-oic acid (7-COOH-CBD), which may reduce the potency of CBD. Formulation strategies for orally consumed CBD products are being investigated to by-pass one or both of these limitations and improve the bioavailability of CBD. Epidyolex, a purified form of CBD, is delivered in a solution of sesame oil which aids absorption. Epidyolex, marketed and sold in the US and Canada as Epidiolex, is currently the only marketed CBD monotherapy with US FDA and Health Canada approval and is approved for treatment of certain types of epilepsy. However, administration of CBD in oil form is not ideal for consumers as it is not always convenient or precise. Delivery of CBD in a powder/capsule form may provide a more efficient method of CBD consumption.

The test product will be CBD-NE, a novel formulation of CBD in a powder form. This product will be investigated in healthy adults as its PK profile is not yet characterized in humans. This study is designed to be a randomized, crossover, comparator control trial to evaluate the PK profile and safety of CBD-NE compared to Epidyolex in healthy adults under both fed and fasted conditions.

Two study products, CBD-NE and Epidyolex, will be administered under both fed and fasted conditions. Participants will be randomized in a 1:1:1:1 ratio to one of 4 treatment sequences. There will be a total of 4 treatment periods consisting of 2 consecutive days, and one washout period. Each dose will be followed by a minimum 14-day, maximum of 28-day washout period, with the last dose followed by a follow-up phone call which will occur within the timeframe of the longest washout period over the study. For the fed state, participants will consume a high-fat, high-calorie breakfast within the 30 minutes prior to dosing.

Pharmacokinetic blood sampling will occur pre-dose and at 0.25 h, 0.5 h, 0.75 h, 1.0 h, 1.5 h, 2.0 h, 3.0 h, 4.0 h, 5.0 h, 6.0 h, 8.0 h, 12.0 h and 24.0 h post-dose.

Blood samples collected will be used to assess the PK profiles of CBD-NE and Epidyolex. PK parameters measured will include maximum concentration in plasma (Cmax), time to reach maximum concentration (Tmax), elimination half-life (T1/2), area under the plasma concentration-time curve over 24 hours (AUC0-24), area under the plasma concentration-time curve from zero to infinity (AUCinf) and AUC0-24/AUCinf for CBD, 7-OH-CBD and 7-COOH-CBD. Safety endpoints will be assessed throughout the study and will include reports of adverse events, 12-lead ECG, vital signs, safety laboratory assessments, and abbreviated physical exam.

Inclusion Criteria:

1. Healthy male or female participants who are 19 to 55 years of age (inclusive).
2. Have a body mass index (BMI) range of 18.0 - 29.9 kg/m2 (inclusive) and body weight ≥ 50 kg.
3. In good general health as deemed by the investigator.
4. Naïve to oral or inhaled cannabis or hemp, or light user of oral or inhaled cannabis or hemp products (not more than 2 times per month on average) who have used cannabis for recreational (non-therapeutic) purposes without severe side effects.
5. Non-smoker (including nicotine vaping) and have not used any nicotine products (e.g., patches, gums, etc.) for >3 months prior to the first PK blood draw (Visit 2). Note: A non-smoker is defined as someone who does not habitually/regularly use products containing nicotine.
6. Have suitable veins for repeated venipuncture.
7. Have systolic blood pressure within 90 to 139 mmHg (inclusive) and diastolic blood pressure within 60 to 89 mmHg (inclusive) at screening and Visit 2.
8. Able to consume oil formulation, and swallow pills or capsules whole, and without chewing.
9. Agree to follow the restrictions on concomitant treatments listed in the protocol.
10. Agree to follow the restrictions on lifestyle listed in the protocol.
11. Agree to adhere to the contraception requirements for this study.
12. Able to consume the entire high-fat, high-calorie breakfast provided within 30 minutes at the site during Visits 2 and 4.
13. Agree to fast overnight, i.e., no food or liquids (except for water, permitted up to 1 h prior to dosing) for a minimum 10 h prior to starting the high-fat, high-calorie breakfast on Visits 2 and 4 or prior to dosing on Visits 6 and 8.
14. Have maintained consistent dietary habits (including supplement intake) and lifestyle for the last 3 months prior to screening.
15. Willing and able to agree to the requirements and restrictions of this study, be willing to voluntarily consent, and carry out all study related procedures.

Exclusion Criteria:

1. Participants who are lactating, pregnant, or planning to become pregnant during the study as confirmed by a positive pregnancy test during study visits or not willing to perform a pregnancy test.
2. Male participants that are planning to conceive during the study.
3. Have a known sensitivity, intolerability, or allergy to any of the study products or their excipients, or any of the items that could be included in the standardized meals/snacks.
4. Current COVID-19 infection at the time of screening or Visit 2, or currently have the post COVID-19 condition as defined by the World Health Organization (WHO) (i.e., individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by alternative diagnosis).
5. Presence of any clinically significant or abnormal results from laboratory tests at screening (Visit 1) and/or vital sign assessments at Visits 1 or 2 as judged by the investigator and or/designee.
6. Demonstrates a positive screen for Hepatitis B Surface Antigen (HBsAg), Hepatitis C (HCV), or Human Immune Deficiency Virus (HIV) at screening.
7. Demonstrates a positive urine drug screen, positive cotinine test or positive breath alcohol test at screening or Visit 2.
8. Have abnormal 12-lead electrocardiogram (ECG) results at screening or Visit 2 as determined at the discretion of the investigator.
9. Evidence of hepatic or renal dysfunction as evidenced by alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) or gamma-glutamyl transferase (GGT) being ≥ 2 times the upper limit of normal or serum creatinine value ≥ 176.84 µmol/L at screening.
10. Have thyroid disease, Type I or Type II diabetes.
11. Have a history of blood clotting disorders.
12. Have a history of heart disease/cardiovascular disease, renal or hepatic impairment/ disease, bipolar disorder, immune disorders and/or immunocompromised [(e.g., HIV/acquired immunodeficiency syndrome (AIDS)].
13. Have a history of cancer (except localized skin cancer without metastases or in situ cervical cancer) within 5 years prior to the screening visit.
14. Have an abnormality or obstruction of the gastrointestinal tract precluding swallowing (e.g., dysphagia) and digestion (e.g., known intestinal malabsorption, celiac disease, inflammatory bowel disease, chronic pancreatitis, steatorrhea).
15. Have medical condition(s) known to interfere with absorption, distribution, metabolism or excretion of the study product (e.g., Crohn's disease, short bowel, acute or chronic pancreatitis or pancreatic insufficiency).
16. Major surgery with general anesthesia in the 3 months prior to screening or planned major surgery during the study.
17. Reports a significant blood loss or blood donation totaling between 101 mL to 449 mL of blood within 30 days prior to the first PK visit (Visit 2) or a blood donation of more than 450 mL within 56 days prior to Visit 2.
18. Reports donating plasma (e.g., plasmapheresis) within 15 days prior to Visit 2.
19. History of alcohol or substance abuse in the 12 months prior to screening (including having been hospitalized for such in an in-patient or out-patient intervention program).
20. Currently consumes, on average, more than 2 standard alcoholic beverages a day or has any habit of alcohol use that, to the opinion of the investigator, may be of a concern for the study. A standard alcoholic beverage is defined as 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of liquor.
21. Receipt or use of test product(s) in another research study within 28 days prior to Visit 2 or longer if the previous test product is deemed by the investigator to have lasting effects that might influence the eligibility criteria or outcomes of current study.
22. Any other medical condition/situation or use of medications/supplements/therapies that, in the opinion of the investigator, may adversely affect the participant's ability to complete the study or its measures or pose a significant risk to the participant.