Efficacy and Safety Evaluation of ITI-1284 as Adjunctive Therapy in Generalized Anxiety Disorder Patients with Inadequate Response to Standard Treatment

The primary objective of this study is to evaluate the **efficacy** of two doses of ITI-1284 (10 mg and 20 mg) administered once daily compared with placebo as adjunctive therapy in patients with **Generalized Anxiety Disorder** (GAD) who have an inadequate response to ongoing GAD treatment. This is measured by the change from baseline to the end of Week 6 in the Hamilton Anxiety Rating Scale (HAM-A) total score. The clinical relevance of this objective lies in its potential to improve treatment outcomes for patients with GAD who do not respond adequately to standard therapies, thereby addressing a significant unmet need in this patient population.

The secondary objective is to assess the efficacy of the same doses of ITI-1284 compared with placebo, as adjunctive therapy, by measuring the change from baseline to the end of Week 6 in the Clinical Global Impression-Severity (CGI-S) score. This objective aims to provide additional insights into the therapeutic potential of ITI-1284 in enhancing the overall clinical impression of severity in patients with GAD.

The clinical trial involves a total of **477 participants** diagnosed with **Generalized Anxiety Disorder** (GAD). The study population includes both male and female subjects aged 18 years and older, with a **body mass index (BMI)** ranging from 19 to 40 kg/m². Participants were selected based on their inadequate response to ongoing GAD treatment, as evidenced by less than 50% improvement in anxiety symptoms with at least one GAD-approved medication. The trial includes individuals who are currently outpatients and are expected to maintain this status throughout the study. Participants are required to continue their current GAD treatment regimen for the study's duration. The trial population is diverse, including individuals of childbearing potential who agree to use highly effective birth control methods. The study also considers the lifestyle and usual habits of participants, allowing for abstinence as a form of birth control based on the investigator's judgment. The trial does not exclude vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across a broad demographic.

The clinical trial is designed to evaluate the efficacy, safety, and tolerability of **ITI-1284** as an adjunctive treatment in patients with **Generalized Anxiety Disorder** (GAD) who have an inadequate response to existing GAD treatments. This is a multicenter, randomized, double-blind, placebo-controlled study. Participants will be randomly assigned to receive either ITI-1284 at doses of 10 mg or 20 mg, or a placebo, administered once daily for a period of six weeks. The primary efficacy endpoint is the change from baseline to Week 6 in the Hamilton Anxiety Rating Scale (HAM-A) total score. Secondary endpoints include changes in the Clinical Global Impressions-Severity (CGI-S) score and other measures of anxiety and quality of life.

The trial will commence with a screening visit to confirm eligibility based on inclusion criteria such as age, body mass index, and a confirmed diagnosis of moderate or severe GAD. Participants must have a history of inadequate response to at least one GAD-approved treatment and currently be experiencing inadequate response to another GAD-approved treatment. Following the screening, eligible participants will proceed to the baseline visit, where initial assessments will be conducted. Subsequent study visits will occur weekly to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will take place at the conclusion of the six-week treatment period.

Participant involvement is expected to last approximately six weeks, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The study is anticipated to start recruitment in December 2024 and is estimated to conclude by July 2026. Participants are required to provide written informed consent and adhere to study instructions throughout the trial duration. The trial is not classified as low intervention and is categorized as a Phase IIb clinical trial.

The clinical trial involves the administration of **ITI-1284**, a chemical small molecule, as an adjunctive treatment for patients with Generalized Anxiety Disorder (GAD) who have an inadequate response to existing GAD treatment. **ITI-1284** is provided in a **tablet** form and is administered via **sublingual use**. The trial evaluates two dosages of **ITI-1284**: 20 mg and 10 mg. The 20 mg dosage is administered once daily, with a maximum daily dose of 20 mg and a total maximum dose of 840 mg over a treatment period of 6 weeks. Similarly, the 10 mg dosage is administered once daily, with a maximum daily dose of 10 mg and a total maximum dose of 420 mg over the same treatment period. The pharmaceutical form of the medication is a **tablet**, and it is not a pediatric formulation. The active substance, **ITI-1284**, is of chemical origin and is developed by INTRA-CELLULAR THERAPIES, INC.

The study also includes a **placebo** group to serve as a comparator. The placebo is used to assess the efficacy of **ITI-1284** by providing a baseline for comparison. The placebo does not contain any active substance and is not associated with any specific pharmaceutical form or route of administration. The inclusion of a placebo group allows for a double-blind, placebo-controlled study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias in the assessment of the treatment's efficacy and safety.

The efficacy of ITI-1284 as an adjunctive treatment for patients with **Generalized Anxiety Disorder** (GAD) will be assessed through a multicenter, randomized, double-blind, placebo-controlled study. The primary efficacy endpoint is the change from baseline to Week 6 in the Hamilton Anxiety Rating Scale (HAM-A) total score. This scale is a widely used and validated tool for measuring the severity of anxiety symptoms. The primary objective is to evaluate the efficacy of two doses of ITI-1284 (10 mg and 20 mg) administered once daily compared with placebo in patients who have an inadequate response to ongoing GAD treatment.

Secondary efficacy endpoints include the change from baseline to Week 6 in the Clinical Global Impressions-Severity (CGI-S) score. Additional secondary endpoints may involve changes from baseline in HAM-A total score, CGI-S score, and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) score by visit. Other measures include a ≥ 50% reduction from baseline in HAM-A total score, HAM-A remission (HAM-A total score ≤ 7), CGI-Improvement (CGI-I) scale score, change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and Patient Global Impression of Change (PGI-C) scale score. These assessments will be conducted at specified timepoints throughout the study to ensure comprehensive evaluation of the treatment's efficacy.