Efficacy and Safety Evaluation of ITI-1284 in Treating Agitation in Alzheimer's Dementia: 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 **agitation associated with Alzheimer's dementia**. This is measured by the change from baseline to the end of Week 12 in the Cohen-Mansfield Agitation Inventory (CMAI) total score. This objective is clinically relevant as it aims to address the management of agitation, a common and challenging symptom in patients with Alzheimer's dementia, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Evaluating the efficacy of ITI-1284 in the treatment of **psychosis** in patients with Alzheimer's disease, as measured by the change from baseline to the end of Week 12 in the Clinical Global Impression-Severity (CGI-S) score.
• Assessing the **safety and tolerability** of ITI-1284, compared with placebo, through the evaluation of adverse events, vital signs, electrocardiograms, clinical laboratory tests, modified physical examinations, cognitive assessments using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Columbia-Suicide Severity Rating Scale (C-SSRS), and extrapyramidal symptoms assessed by the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson-Angus Scale (SAS).
• Evaluating the **pharmacokinetics** of ITI-1284 by measuring plasma concentrations of ITI-1284 and its metabolites following sublingual administration once daily.

The clinical trial involves a total of **183 participants** diagnosed with **agitation associated with Alzheimer’s dementia**. The study population includes both male and female subjects aged **55 years and older**. Participants were selected based on specific criteria, including a **Mini Mental State Examination** score between 6 and 24, and a **body mass index** ranging from 18 to 40 kg/m². All participants meet the clinical criteria for Alzheimer’s disease and exhibit symptoms of agitation for at least two weeks prior to screening. The trial includes individuals living at home or in assisted living facilities, provided they have a caregiver to accompany them to study visits. The population is characterized by a vulnerable status due to the nature of the disease. Lifestyle considerations such as diet and physical activity are not specified, but participants must have been residing in their current location for at least four weeks prior to screening and plan to remain there for the trial's duration. The trial does not specify any additional lifestyle or health status requirements beyond those related to the primary condition under investigation.

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 **agitation associated with Alzheimer's dementia**. The trial will involve a flexible-dose regimen and is set to last for a total duration of 12 weeks. Participants will be randomly assigned to receive either ITI-1284 or a matching placebo, with the primary objective being the assessment of changes in the Cohen-Mansfield Agitation Inventory (CMAI) total score from baseline to the end of Week 12. Secondary endpoints include changes in the Clinical Global Impression-Severity (CGI-S) score over the same period.

The study will commence with an inclusion (screening) visit, where eligibility criteria such as age, **Mini Mental State Examination** scores, and clinical criteria for Alzheimer's disease will be assessed. Participants must be 55 years or older, have a body mass index between 18 and 40 kg/m², and exhibit symptoms of agitation for at least two weeks prior to screening. Following successful screening, participants will enter the treatment phase, which includes regular follow-up visits to monitor safety, efficacy, and adherence to the study protocol. These visits will occur at specified intervals throughout the 12-week period.

The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted to evaluate the overall impact of the treatment. The expected length of participant involvement is approximately 12 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide valuable insights into the management of agitation in Alzheimer's dementia, contributing to the development of effective therapeutic strategies.

The clinical trial involves the administration of **ITI-1284**, an investigational 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, and it is administered via the sublingual route. The dosing regimen for ITI-1284 is flexible, with a maximum daily dose of 20 mg and a total maximum dose of 1690 mg over a treatment period of up to 88 days. The primary objective of the trial is to evaluate the efficacy of ITI-1284 in treating agitation associated with Alzheimer's dementia, as measured by the change in the Cohen-Mansfield Agitation Inventory (CMAI) total score from baseline to the end of Week 12.

In addition to the experimental treatment, the study includes the use of **placebo tablets** that match the ITI-1284 10 mg and 20 mg active tablets. These placebo tablets are used as a comparator to assess the efficacy and safety of ITI-1284. The placebo tablets are identical in appearance to the active medication but do not contain the active substance. The administration of placebo tablets follows the same sublingual route and dosing schedule as the ITI-1284 tablets, ensuring blinding and maintaining the integrity of the double-blind study design.

The efficacy of ITI-1284 in the treatment of agitation associated with Alzheimer's dementia will be assessed through a primary efficacy endpoint and a key secondary efficacy endpoint. The primary efficacy endpoint is defined as the change from baseline to the end of Week 12 in the Cohen-Mansfield Agitation Inventory (CMAI) total score. This endpoint will measure the reduction in agitation symptoms over the course of the trial. The key secondary efficacy endpoint involves the change from baseline to the end of Week 12 in the Clinical Global Impression-Severity (CGI-S) score, which will provide additional insights into the overall severity of the patient's condition.

Data collection for these endpoints will occur at specified timepoints, with baseline measurements taken prior to the initiation of treatment and follow-up assessments conducted at the end of Week 12. The CMAI and CGI-S are validated scales commonly used in clinical trials to evaluate agitation and overall clinical status, respectively. These tools will ensure the reliability and validity of the efficacy assessments. The trial is designed as a multicenter, randomized, double-blind, placebo-controlled, flexible-dose study, which will enhance the robustness of the efficacy data collected.