Bioavailability, Bioequivalence and Tolerability of IHL-42X Compared to the Reference Drugs

This is a 4‐period crossover bioequivalence and bioavailability clinical trial designedto assess the pharmacokinetics and safety and tolerability of IHL‐42X compared to thereference listed drugs Marinol (reference listed drug for dronabinol) and Taroacetazolamide (reference listed drug for acetazolamide). The study will look to enrol atleast 116 participants. Participants will be enrolled into one of four treatment groups,each group consisting of approximately 29 participants, which will receive all fourtreatments in different orders, as defined by period 1, period 2, period 3 and period 4.The trial will recruit healthy participants if they satisfy all the following criteria: 1. Ages ≥18 to ≤65 at the time of screening 2. BMI ≥18.0 to ≤32.0 3. Physically well, in the opinion of the investigator, with no clinically significantpsychiatric, cardiac, hepatic, renal, endocrine, gastrointestinal, bleeding,thyroid, cholesterol, or hypertension disorders 4. If male, willing to use an approved method of contraception from 30 days prior todosing, throughout the study, and 90 days after last dose. 5. If female of non‐childbearing potential, must be postmenopausal with establishedserum FSH levels >30IU/L (determined during screening or have undergone one of thesterilization procedures, as noted in the protocol, at least 6 months prior to VisitDay 1 If females of childbearing potential, must not be currently pregnant,lactating, or planning to be pregnant and are willing to use an approved method ofcontraception, as noted in the protocol, from 30 days prior to dosing, throughoutthe study, and 30 days after last dose. Partner has had a vasectomy at least 6months prior to first dose Of non‐childbearing potential (postmenopausal orsurgically sterile by any method for at least 3 months prior to check‐in) AbstinenceSame sex relationship 6. Voluntarily consent to participate in the study and complete all study requiredtasks, as instructed by the protocol, including the completion of questionnaires.Participants will be excluded from participating in the study if there is evidence of anyof the following at screening, or prior to dosing at the timepoints in the Schedule ofEvents: 1. History of cardiac disease or arrythmias 2. History of significant psychiatric illness (defined as hospitalisation or history ofpharmacological prescription for psychiatric conditions), suicidal ideation, orsuicidal attempts 3. Current use of illicit drugs or as defined by a positive urine drug test atscreening or baseline 4. History of alcohol abuse or excessive alcohol intake according to the Australianguidelines (more than 10 standard drinks per week/4 standard drinks per day onaverage) or alcohol consumption (by self‐declaration) defined as > 21 alcohol unitsper week (where 1 unit = 284 mL of beer, 25 mL of 40% spirit, or a 125 mL glass ofwine). 5. Any cannabis use within 30 days of screening 6. Known hypersensitivity and/or intolerance to any cannabis products with previous use 7. Known hypersensitivity and/or intolerance to sesame oil (dronabinol is formulated insesame oil) 8. Known hypersensitivity and/or intolerance to acetazolamide 9. Has taken any vitamins, herbal remedies, supplements or cannabidiol products within7 days of each check‐in 10. GAD‐7 score of ≥15, MDI score ≥31 OR 3 core symptoms and 5 accompanying symptoms,C‐SSRS score ≥4 OR reported suicidal behaviour within the past 3 months 11. Any dietary requirements incompatible with study breakfast; must be able to eathigh‐ fat, high‐calorie diet (including meat, dairy products) (As described in FDAguidance for BA and BE studies (See Appendix 6 in protocol)) 12. Hepatic or renal impairment or disease, as defined as AST/ALT >1.5 x ULN, eGFR <60at screening and check‐in. 13. History of gastrointestinal disorders or previous surgeries which may impactabsorption, distribution, metabolism and/or excretion of the IP (such ascholecystitis, cholecystectomy) 14. Female participants who are pregnant, lactating or planning to become pregnant 15. Inability to adhere to the protocol and study restrictions during the study period 16. Participation in another clinical trial of an investigational drug within 30 days or5 half‐ lives of the investigational drug (whichever is longer) prior to first studydrug administration. 17. Any other reason in the opinion of the investigatorDuring the 28‐day screening period, participants will provide information on theirdemographics, medical history, height, weight and BMI. A physical exam, vital signs and12‐lead ECG will be conducted. Blood and urine tests will be performed to ensure thereare no clinically significant outcomes that would exclude the participants from enrollingin the study, and urine will be tested for pregnancy and for the presence of illicitdrugs. Questionnaires to review mental health status of the participants will also beconducted. These will include the General Anxiety Disorder ‐7 (GAD‐7), Major DepressionIndex (MDI) and the Columbia Suicide Severity Rating Scale (C‐SSRS).Once the participant is deemed eligible to be enrolled in the study, the baseline visitwill be performed and the participant will be randomised into one of the four groups andwill receive each of the four treatments in the order, as described below:Participants randomised to Group 1 will receive treatments in the following order:Group 1 ‐ A, B, C DParticipants randomised to Group 2 will receive treatments in the following order:Group 2 ‐ B, D, C, AParticipants randomised to Group 3 will receive treatments in the following order:Group 3 ‐ C, A, D, BParticipants randomised to Group 4 will receive treatments in the following order:Group 4 ‐ D, C, B, A,where; Treatment Group A = dronabinol 5 mg, fasted; Treatment Group B = acetazolamide 250mg, fasted; Treatment Group C = IHL‐42X (5 mg dronabinol, 250 mg acetazolamide), fasted;Treatment Group D = IHL‐42X (5 mg dronabinol, 250 mg acetazolamide), fed.The participant will stay in the clinic for each of the treatment periods. Assessmentsinclude vital signs, 12‐lead ECG, urine and blood sampling and testing will be repeated.Depending on the randomisation group, the participant will receive one dose of thetreatment. Blood draws for pharmacokinetics will be conducted and the participantmonitored for adverse events.For treatment groups A, B and C, the participant will fast for 10 hours prior toreceiving the dose of either dronabinol, acetazolamide or IHL‐42X. For treatment group D,the participant will be required to consume a high fat/high calorie diet 30 minutes priorto receiving the dose of IHL‐42X.Blood samples will be taken for pharmacokinetics analysis throughout the study, atspecific timepoints, including on prior to dosing. These samples will be assessed for THCand acetazolamide, as well as the metabolites of THC.Participants will be discharged from the clinic on day 3 of each period, at least 48hours post dose, and will return to the clinic after a minimum of 7 days, to allow forwashout, from the dose date to begin the next treatment period.The last dose timepoint assessments at 48 hours post final dose for period 4 will serveas the end of study visit.