To Evaluate the Efficacy, Safety, and Tolerability of Dronabinol Oral Solution for Agitation in Patients With Alzheimer's Disease

This is a randomised, double-blind, placebo-controlled study conducted in patients with a diagnosis of AD. The study consists of a screening period of up to 28 days (4 weeks), a 2-week titration period, during which the dose of dronabinol is gradually increased to the target maintenance dose. This is followed by a 10-week maintenance period (Weeks 3 through 12), where the target dose is maintained.

Following the 10-week maintenance period, eligible participants who complete the double-blind treatment period may enter a 6-month (24-week) open-label extension (OLE) to assess long-term safety and tolerability of dronabinol oral solution. Participants originally randomised to active treatment will continue receiving their established dose (2.5 mg, 5 mg, or 9.0 mg/day) without interruption. Participants originally randomised to placebo will undergo a 2-week titration period (Weeks 13 to 14) following the same dose escalation schedule as the main study to reach their target maintenance dose. All participants will receive open label dronabinol during the OLE period (Weeks 15 to 38). A final safety follow-up assessment will be conducted at Week 42 (4 weeks after the last dose of study medication). Standard of care medication will be maintained throughout this study for all participants as per the inclusion/exclusion criteria.

Titration/Transition Schedule:

Week 1/35: The starting dose will be 2.5 mg dronabinol once a day (QD) Week 2/14: Dronabinol dose will be increased to 2.5 mg twice a day (BID) for a total daily dose of 5 mg/day. Optional up-titration (Week 3/15 onwards, if tolerated) to 4.5 mg BID (total daily dose 9.0 mg/day).

Note: maximum dose in this study is 4.5 mg BID.

Dose escalation should occur only when a participant demonstrates BOTH:

Optimal safety profile:

Participant has completed ≥7 consecutive days at 5 mg/day without any clinically significant AE or group of AEs that singularly or in aggregate suggests to the Investigator or Sponsor that the study intervention is poorly tolerated and further treatment per protocol may not be safe (i.e., Grade 3 or above clinically significant AE deemed related to study intervention occurring in at least 2 study participants).

Suboptimal efficacy profile: Minimal or inadequate therapeutic response, defined by specific quantitative thresholds on validated agitation scales

Inclusion criteria

• 1. Participant or legal representative is willing and capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form and is willing and able to return for all study visits and comply with all protocol requirements and procedures.
• 2. Adult males and females, 50 to 90 years of age (inclusive) at screening.
• 3. Participants must have a diagnosis of dementia due to AD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and a diagnosis of probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA).
• 4. Presence of Agit-AD as defined by the provisional criteria from the International Psychogeriatric Association (IPA). The definition requires the presence of cognitive impairment, evidence of emotional distress, one of three observable types of behaviour (excessive motor activity, verbal aggression, physical aggression), requires that the behaviour cause excess disability, and notes that the behaviours cannot be solely attributable to another disorder such as psychiatric illness, medical illness, or effects of substance use.
• 5. Clinically significant severity of agitation defined by NPI-C Agitation or NPI-C Aggression >4.
• 6. Mini Mental Status Examination (MMSE) score of 8-20 (inclusive).
• 7. Cohen-Mansfield Agitation Inventory (CMAI) total score ≥60 at both Screening and Baseline visits, with at least one item in the aggressive behaviour domain (Factor 1) scored >3 (occurring ≥ once or twice per week). Alternatively, meet Factor 1 positivity criterion: one or more aggressive behaviours occurring several times per week, OR two or more occurring once or twice per week, OR three or more occurring less than once per week.
• 8. If a participant is receiving AD-specific treatment, they must have been on a stable dose for >3 months prior to first dose of study drug.
• 9. Participant must have at least 1 study partner (e.g., spouse or caregiver in close contact) to support participant in all scheduled study visits and procedures.
• 10. Participants who do not live in assisted living facilities are eligible to participate and must be capable of returning for study visits.
• 11. Adequate vision and hearing (with corrective devices if needed) to complete study assessments, as judged by the investigator. Participants must be able to:

• Read and understand consent documents and questionnaires
• Hear and respond to verbal instructions for cognitive testing
• Participate in clinical interviews
• 12. Has adequate hematologic and organ function, as indicated by the following laboratory values, prior to Cycle 1 Day 1:

• Absolute Neutrophil Count ≥1500/mm3; or 1.5 x 109/L
• Platelet count ≥100,000/mm3; or 1.0 x 109/L
• Hemoglobin ≥8 g/dL
• Adequate renal function characterized by estimated creatinine clearance ≥50 mL/min Chronic Kidney Disease Epidemiology Collaboration equation (CKDEPI).
• Total bilirubin ≤1.5 x ULN (≤3 x ULN for participants with Gilbert's syndrome).
• AST and ALT ≤3 x ULN.
• 13. Female patients:

a. Must be of non-child-bearing potential i.e., surgical menopause (hysterectomy, bilateral salpingectomy, bilateral oophorectomy) at least 6 weeks before the screening visit or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone [FSH] level consistent with postmenopausal status, per local laboratory guidelines), or b. If of child-bearing potential, must: i. Have a negative pregnancy test at the screening visit and on admission to the study site on Day-1.

ii. Agree not to attempt to become pregnant or donate ova from signing the ICF until at least 30 days after the last dose of study drug.

iii. Agree to use adequate contraception (defined as use of a condom by the male partner combined with use of a highly effective method of contraception [Section 10.4.3]) from one month prior to screening until at least 30 days after the last dose of study drug, if not exclusively in a same-sex relationship or abstinent as a committed lifestyle.

• 14. Male patients:

• Must agree not to donate sperm from signing the ICF until at least 90 days after the last dose of study drug.
• If engaging in sexual intercourse with a female partner who could become pregnant, must agree to use adequate contraception (defined as use of a condom combined with use of a highly effective method of contraception [Section 10.4.3]) from signing the ICF until at least 90 days after the last dose of study drug.
• If engaging in sexual intercourse with a female partner who is not of childbearing potential or a same-sex partner, must agree to use a condom from signing the ICF until at least 5 half-lives of IP after the last dose of study drug.
• 15. Have suitable venous access for blood sampling.
• 16. Willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Exclusion criteria

• 1. Known hypersensitivity to the study drug or any of the study drug ingredients.
• 2. History of anaphylaxis or other significant allergy which, in the opinion of the PI (or delegate), would interfere with the volunteer's ability to participate in the study.
• 3. History or presence of clinically significant, unstable (not well controlled on medications) cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, psychiatric, or neurological disease/disorder, within the past 3 months determined by the PI (or delegate) to be clinically relevant.
• 4. History of recurrent falls (≥2 falls within 6 months prior to Screening) resulting in injury or associated with acute illness, loss of consciousness, or abnormal vital signs, history of fall with fracture within 12 months of Screening.
• 5. History of surgery or hospitalisation within 3 months prior to screening, or surgery planned during the study.
• 6. Any history of malignant disease in the last 5 years (excludes surgically resected skin squamous cell or basal cell carcinoma).
• 7. History of clinically significant CNS event and/or diagnosis in the past 5 years, including but not limited to epilepsy, significant CNS trauma, CNS surgery, neurosyphilis, meningitis, encephalitis or meningoencephalitis.
• 8. Baseline delirium as determined by Confusion Assessment Method (CAM) and Diagnostic and Statistical Manual of Mental Disorders (DSM) - criteria.
• 9. Commencement of medications that affect the CNS within <4 weeks prior to first dose of study drug, including but not limited to cannabinoid, benzodiazepines, anti-depressant, and antipsychotic medications.
• 10. History of major psychiatric disorder(s) in the past 5 years, including but not limited to psychosis and bipolar disorder. Mild psychiatric disorder(s) that is well controlled and stable on medication therapy for >1 year that is not prohibited on this study may be allowed on a case-by-case basis in discussion with study sponsor, if deemed unlikely to put participant at a higher risk of treatment-related toxicity and/or interfere with the integrity of study outcome.
• 11. A history of or positive test results for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the screening visit. A negative HCV RNA result is acceptable for enrolment.
• 12. Medications with significant drug-drug interaction potential:

• Strong CYP3A4 or CYP2C9 inhibitors (e.g., ketoconazole, ritonavir, fluconazole, amiodarone) within 2 weeks of Screening or anticipated need during study
• disulfiram/metronidazole (risk due to alcohol content)
• 13. Positive drugs of abuse test (for a list of drugs tested refer to Section 11.1.8), cotinine test, or alcohol breath test results at screening and prior to dosing on Day 1.
• 14. Regular consumption of more than 10 standard alcoholic drinks/week and/or more than 4 standard alcoholic drinks on any one day, where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer [4.9% Alc/Vol], 100 mL wine [12% Alc/Vol], or 30 mL spirit [40% Alc/Vol]).
• 15. Patient smokes more than 5 cigarettes or equivalent nicotine-containing products per week, and/or the volunteer is unwilling to abstain from smoking or the use of nicotine-containing products. Note: 1 average cigar = approx. 5 average cigarettes; 1 average pipe session = approx. 5 average cigarettes; 1 average nicotine liquid vape session = 1 average e-cigarette = 1 average cigarette.
• 16. Females who are breastfeeding or planning to breastfeed from pre-dose to 90 days post last dose
• 17. Is not able to reliably and regularly swallow liquid oral medications on a daily basis.
• 18. Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medication within 10 days prior to first dose of study drug.
• 19. Use of live vaccines within 30 days prior to screening. Use of (non-live) booster vaccines is acceptable for enrolment.
• 20. Participation in another clinical study of an investigational drug or investigational device within 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to screening.
• 21. Any other condition or prior therapy that in the opinion of the PI (or delegate) would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.
• 22. History or current presence of unexplained recurrent vomiting that may confound safety or tolerability assessments.
• 23. Hemodynamic instability, including clinically significant hypotension, hypertension, syncope, tachycardia or symptomatic orthostatic hypotension.
• 24. Patients with evidence of serious risk of suicide at screening based on the C-SSRS

• Answers "Yes" on items 4 or 5 (C-SSRS - ideation) with the most recent episode occurring within the 2 months before Screening or,
• Answers "Yes" to any of the 5 items (C-SSRS - behavior) with an episode occurring within the 12 months before Screening, except for the participant having responded "Yes" to engaging in non-suicidal injurious behavior