A Study Testing the Safety and Effects of Single Doses of S1-221 in Healthy Volunteers

This is a first-in-human, Phase 1, randomised, double-blind study to evaluate safety, tolerability, PK, and PD following the oral administration of single ascending doses (SAD) of S1-221 to fasted and fed healthy participants.

Due to known sex differences in CBD metabolism, every effort will be made to enrol an equal number of biological females and males in each cohort (ideally no fewer than 30% females in each cohort). Individuals will only be permitted to participate in 1 study part.

Up to 10 cohorts of 8-10 participants each will be enrolled into this study. The study will consist of 3 parts. Part A will be a SAD evaluation in up to 8 cohorts. Eligible participants will be randomised in a ratio of 3:1 to receive a single oral dose of S1-221 or placebo on Day 1. Within each cohort, a sentinel group of 2 participants, randomised 1:1 to S1-221 or placebo, will be dosed at least 24 hours prior to the remaining participants in the cohort. The minimum 24-hour safety data for these sentinels will be reviewed by the Investigator, and if the dosing is deemed to be safe and well tolerated, the remaining participants in the cohort will be dosed. Study drug will be administered in a fasted state. The study duration for each fasted cohort participant will be approximately 35 days.

Parts B and C will proceed at the discretion of the Sponsor, and after review of 4 or more cohorts from Part A. Doses evaluated in Part B and C will not exceed those evaluated in Part A.

Part B will be a crossover evaluation, with and without food. Participants in Part B will be administered S1 221 or placebo once on Day 1 under fasted conditions and once on Day 15 under fed conditions. The 2 periods will be separated by a washout period of at least 14 days. A sentinel group of 2 participants, randomised 1:1 to S1-221 or placebo, will be dosed at least 24 hours prior to the remaining participants in the cohort. The minimum 24-hour safety data for these sentinels will be reviewed by the Investigator, and if the dosing is deemed to be safe and well tolerated, the remaining participants in the cohort will be dosed.

Participants in the Food Effect Cohort will be screened and administered a single oral dose of S1-221 or placebo under fasted conditions on Day 1. Participants will be discharged on Day 3 and return for an outpatient follow-up visit on Day 4 and Day 7 (+/- 2 days).

Following a washout period of at least 14 days after administration of the first dose, participants will be re-admitted 1 day prior to the second (fed) administration of study drug. On Day 15, participants will receive the same dose as in Period 1, this time following consumption of a standardised, FDA-compliant high-fat, high-calorie meal.

The study duration for each Food Effect Cohort participant will be approximately 49 days.

Part C will be a crossover evaluation of S1-221 compared to THC alone. Participants in the Part C cohort will be randomised 1:1 to treatment sequence (S1-221/THC or THC/S1-221) and administered the first treatment assignment on Day 1 and the alternative assigned drug on Day 15. The 2 periods will be separated by a washout period of at least 14 days. Both doses will be administered in a fasted state and no sentinel dosing will be performed in Part C.

The study duration for each Active Comparator Cohort participant will be approximately 49 days.

Inclusion criteria

• Provision of signed and dated participant informed consent form (PICF) and willing and able to follow all study procedures and requirements for the duration of the study.
• Healthy adult males and females aged 18 to 65 years, inclusive, at Screening.
• Body mass index (BMI) of 18 to 32.0 kg/m2, inclusive, and body weight ≥50.0 kg, at Screening.
• Considered healthy, as determined by no clinically significant findings from medical history or physical examination at Screening and Day -1, in the opinion of the Investigator.
• Vital signs after 5 minutes resting in supine position within the following ranges (assessment may be repeated once per schedule time point, at the discretion of the Investigator, to obtain a clinically reliable result):

• Systolic blood pressure: 90 to 140 mmHg inclusive;
• Diastolic blood pressure: 40 to 90 mmHg inclusive;
• Heart rate: 40 to 100 bpm inclusive.
• Standard 12-lead ECG with parameters (average of triplicate readings) after 10 minutes in supine position within the following ranges (assessment may be repeated once per schedule time point, at the discretion of the Investigator, to obtain a clinically reliable result):

• QRS <120 msec;
• QT <500 msec;
• QTc ≤450 msec (both genders);
• PR interval ≥120 to ≤220 msec.
• Screening and Day -1 (and Day 14 for Parts B and C) safety laboratory test values within normal ranges. Out of normal range values may be accepted by the Investigator if not considered clinically significant, with the exception of the following:

• ALT or AST >1.5 x upper limit of normal (ULN);
• Total, indirect, or direct bilirubin >1.5 x ULN. Participants with Gilbert's syndrome with indirect bilirubin outside of the normal range will not be excluded from the study;
• Abnormal kidney function, as assessed by estimated glomerular filtration rate (eGFR) calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI);
• Creatinine >1.2 x ULN;
• Haemoglobin <100.0 g/L in females or <115 g/L in males; or white blood cells <3.5 x 109/L or >11.5 x 109/L;
• HbA1c ≥6.5% (participant must be non-diabetic). In Parts B and C, any laboratory abnormalities noted prior to the crossover repeat dosing will be discussed with the medical monitor and Sponsor to determine whether repeat dosing may proceed as planned.
• Negative tests for HBsAg, HBcAb, anti-HCV, and HIV antibodies at Screening.
• Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and Day -1 (and Day 14 for Parts B and C).

Note: Definition of child-bearing potential is fertile and following menarche until becoming post-menopausal, unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause and follicle-stimulating hormone (FSH) documented in the post- menopausal range (≥40 IU/L).

• WOCBP must agree to the use adequate contraception from Screening through 60 days following the last dose of study drug. Additionally, they should avoid egg/ova donation throughout the study and for 60 days after the last dose of the study drug.
• Male participants must agree to use adequate contraception from Screening through 95 days following the last dose of study drug. Male participants with female partners that are surgically sterile or post-menopausal (defined as being amenorrhoeic for at least 12 months without an alternative medical cause) may also be included and will not be required to use above-described methods of contraception. Male partners with potentially post-menopausal females who are under the age of 55 years must use condoms unless their partner's postmenopausal status has been confirmed by FSH level >40mIU/mL. Male participants who have undergone vasectomy and have had testing to confirm azoospermia 90 days after procedure may also be included. The use of condom by male participant will be required if vasectomy is the chosen highly effective method of contraception. Male participants must also agree not to donate sperm throughout the study and for 95 days following the last dose of study drug.
• Non-smoker, ex-smoker, or smoker willing to refrain from use of tobacco/nicotine-containing products, e.g., cigarettes, vaporizers, cigars, pipe tobacco, smokeless tobacco, nicotine gum, lozenges, patches, on more than 5 occasions within 1 month prior to the Screening visit and for the duration of the study. Note: a cotinine level or other observations that, in the opinion of the Investigator, suggest heavy use of tobacco will be exclusionary.
• Willing to refrain from consumption of alcohol as follows:

• Part A: for at least 48 hours prior to Screening and Day -1, then from Day 1 through End of Study (EOS).
• Parts B and C: for at least 48 hours prior to Screening, Day -1, and Day 14, and from Day -1 through Day 7 visit, and from Day 14 through EOS (consumption of alcohol is permitted from Day 8 through Day 13).
• Willing to withhold cannabinoids (including CBD and THC) and cannabis (including hemp) products for 60 days prior to administration of the first dose of study drug and throughout the study.
• Willing to refrain from consumption of food or beverages containing xanthine derivatives or xanthine-related compounds (e.g., coffee, black/green tea, chocolate) or energy drinks from 48 hours prior to each clinic admission and each follow-up visit.
• Willing to defer blood donations to a blood service for minimum of 30 days following the last dose of study drug.
• Willing to comply with the study-specified diet while confined in the CRU. Participants in Part B (Food Effect Cohort) must agree to complete consumption of a standardised high-fat, high-calorie breakfast during the fed period on Day 15.
• Willing to not operate a motor vehicle or heavy machinery for 7 days following administration of study drug.
• In the opinion of the Investigator, is willing and able to comply with and understand study requirements and be available for the required study visits.

Exclusion criteria

• Female participant who is pregnant or breastfeeding, or planning to become pregnant or breastfeed during study participation.
• Evidence of clinically significant abnormalities or disease, including, but not limited to, the following:

• Any pulmonary, cardiovascular, neurologic, gastrointestinal, hepatic, renal, endocrine or other disease, at the discretion of the Investigator including, but not limited to, history of epilepsy.
• Any history of gastrointestinal condition, including surgeries, or use of any medications (including glucagon-like peptide-1 [GLP-1] agonists) which may affect absorption or gastric motility after oral administration.
• Has a lifetime history or current diagnosis of a significant psychiatric disorder including, but not limited to, schizophrenia spectrum or other psychotic disorders, major depressive disorder, or generalized anxiety disorder per Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5), and/or has first-degree relative with a history of psychosis or schizophrenia.
• Meets DSM-5 criteria for lifetime or current substance use disorder for any psychoactive substances other than nicotine or caffeine.
• Has a history of, or active, suicidal ideation as identified by positive response to questions 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening, or has any prior history of suicidal behaviour, as evidenced by medical history of suicide attempt or a "Yes" response to the following suicidal behaviour questions on the C-SSRS: actual attempt, interrupted attempt, or aborted attempt.
• History or ECG evidence of myocardial ischemia or infarct, 2nd or 3rd degree AV block, bundle branch block, with the exception of incomplete right bundle branch block in the absence of clinical heart disease, or multiple or multifocal premature ventricular contractions.
• History of fainting or syncope that, in the Investigator's opinion, would interfere with study conduct or compliance.
• Any other laboratory, vital sign, ECG abnormality, or clinical history or finding that, in the Investigator's opinion, is likely to unfavourably alter the risk-benefit of study participation, confound study results, or interfere with study conduct or compliance.
• Positive urine drug test or alcohol breath test at Screening or Day -1 (and Day 14 for the Parts B and C), unless there is an explanation deemed acceptable by the Investigator and/or the participant tests negative upon re-test. Note: one re-test for drug screen is permitted per scheduled time point. No retest is permitted for alcohol breath test.
• History of clinically significant allergy, hypersensitivity, or adverse reaction to cannabis or any cannabinoid, including dysphoria, or to any excipient in the investigational product (e.g., sesame allergy) at the discretion of the Investigator.
• Donation or loss of greater than 1 unit (450 mL) of blood within the 4 weeks prior to Screening.
• Has received any prescription medication within 14 days or 5 half-lives (whichever is longer) of Day -1 and throughout the study (exceptions: contraceptives are permitted). Prescriptions of known inhibitors or inducers of hepatic drug metabolism (e.g., rifampin, carbamazepine, phenytoin, barbiturates [e.g., phenobarbital and butalbital], dexamethasone, antidepressants [e.g., fluoxetine, paroxetine], proton pump inhibitors, ketoconazole itraconazole and clarithromycin) will be prohibited.
• Has received any non-prescription medication within 5 days of Day -1 and throughout the study (exception: occasional [PRN] paracetamol [up to 2 g/day] or ibuprofen [up to 1.2 g/day] use may be permitted, at Investigator discretion).
• Use of vitamins, natural and herbal remedies including St. John's wort, supplements (including kratom), or vaccines in the 14 days prior to Day -1 and throughout the study.
• Use of any investigational drug within 30 days or <5 half-lives, whichever is longer, prior to administration of first dose of study drug and throughout the study.
• Consumption of grapefruit, starfruit, pomegranate, pomelo, pineapple, or Seville orange, products in the 7 days prior to Day -1 until completion of the EOS visit.
• Regular alcohol consumption in excess of 14 units per week or 2 standard drinks in a single day. One standard drink is defined as containing 10 grams of pure alcohol, e.g., 285 mL normal-strength beer (4.9% alcohol), 100 mL of non-fortified wine (13% alcohol), or 30 mL of spirits (40% alcohol).
• Behaviour suggestive of unreliability or inability to comply with study requirements per discretion of the Investigator.
• Identified as a site employee of the Investigator or study centre, with direct involvement in the proposed study or other studies under the direction of that Investigator or study centre, as well as family members (i.e., immediate, husband, wife or de facto and their children, adopted or natural) of the site employees or the Investigator.