Efficacy and Safety Evaluation of ITI-1284 in Psychosis Associated with Alzheimer's Disease: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of ITI-1284, administered once daily, compared with placebo in the treatment of **psychosis** in patients with Alzheimer's disease (AD). This is measured by the change from baseline to the end of Week 6 in the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) psychosis subscale score. This objective is clinically relevant as it aims to determine the potential of ITI-1284 to alleviate psychotic symptoms in AD, which can significantly impact patient quality of life and caregiver burden.

Secondary objectives include:

• To evaluate the efficacy of ITI-1284 administered once daily compared with placebo in the treatment of psychosis in patients with AD, as measured by change from baseline to end of Week 6 in Clinical Global Impression-Severity (CGI-S) score.

The clinical trial involves a total of **172 participants** diagnosed with **psychosis associated with Alzheimer's disease**. The study population includes both male and female subjects aged 55 years and older, with a body mass index (BMI) ranging from 18 to 40 kg/m². Participants were selected based on their ability to provide informed consent, either personally or through a legally authorized representative, and their diagnosis of Alzheimer's disease confirmed by specific biomarker criteria. The trial includes individuals who meet the clinical criteria for psychosis as per the International Psychogeriatric Association's provisional consensus definition. Participants are required to have a Mini-Mental State Examination score between 6 and 24, indicating a certain level of cognitive function necessary for compliance with study procedures. The study population comprises individuals living at home or in assisted living/long-term care facilities, with the condition that those living at home do not reside alone. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The inclusion of a vulnerable population is acknowledged, ensuring that ethical considerations are addressed throughout the study.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy, safety, and tolerability of ITI-1284 in patients with **psychosis associated with Alzheimer's disease**. The trial will involve a flexible-dose regimen and is set to last for a total duration of six weeks. Participants will be randomly assigned to receive either ITI-1284 or a placebo, with the primary objective being the assessment of changes in the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) psychosis subscale score from baseline to the end of Week 6. Secondary endpoints include changes in the Clinical Global Impression-Severity (CGI-S) score over the same period.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed, including age, body mass index, and confirmation of Alzheimer's disease and psychosis criteria. Following successful screening, participants will proceed to the baseline visit, where initial assessments and randomization occur. Subsequent follow-up visits will be conducted at regular intervals to monitor safety, efficacy, and any adverse events. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the primary and secondary endpoints.

Participant involvement is expected to last for the entire six-week duration of the trial, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial is structured to ensure rigorous adherence to scientific and ethical standards, with all procedures conducted in accordance with applicable regulations and guidelines.

The clinical trial involves the administration of **ITI-1284**, an experimental medication, in the form of a tablet. ITI-1284 is a chemical substance developed by INTRA-CELLULAR THERAPIES, INC. The pharmaceutical form of ITI-1284 is a tablet, intended for **sublingual use**. The dosing regimen for ITI-1284 is flexible, with a maximum daily dose of 20 mg and a total maximum dose of 770 mg over a treatment period of up to 6 weeks. The administration of ITI-1284 is conducted once daily, and participant compliance is monitored throughout the study duration.

In addition to the experimental treatment, the study includes the use of a placebo. The **ITI-1284 placebo tablets** are designed to match the active tablets in appearance, being yellow to off-yellow-cream, circular, freeze-dried units, debossed with a diamond. The placebo is formulated to match both the 10 mg and 20 mg active tablets, ensuring blinding in the double-blind study design. The placebo is administered in the same manner as the active treatment, with the same frequency and route of administration.

The efficacy of ITI-1284 in the treatment of **psychosis associated with Alzheimer's disease** will be assessed through a multicenter, randomized, double-blind, placebo-controlled, flexible-dose study. The primary endpoint for evaluating efficacy is the change from baseline to the end of Week 6 in the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) psychosis subscale score. This scale is a validated tool used to measure psychotic symptoms in patients with Alzheimer's disease.

Secondary efficacy assessments will include the change from baseline to the end of Week 6 in the Clinical Global Impression-Severity (CGI-S) score. The CGI-S is a widely used scale that provides a clinician's view of the patient's global functioning prior to and after initiating a study treatment. These efficacy parameters will be collected and analyzed at specified timepoints, including baseline and the end of Week 6, to determine the treatment's impact on psychosis symptoms in the study population.