A Phase 2/3, Randomized, Double-blind, Parallel-group, Placebo-controlled, Flexible-dose, Multicenter Study to Evaluate the Efficacy and Safety of SEP 363856 in the Treatment of Adults with Generalized Anxiety Disorder

The primary objective of this study is to evaluate the **efficacy** of flexible doses of SEP-363856 (50 – 75 mg/day) compared with placebo in subjects with **generalized anxiety disorder** (GAD), as measured by the Hamilton Anxiety Rating Scale (HAM-A) total score. This is clinically relevant as it aims to determine the potential of SEP-363856 in reducing anxiety symptoms, which could offer a new therapeutic option for individuals with GAD.

Secondary objectives include evaluating the efficacy of flexible doses of SEP-363856 (50 - 75 mg/day) compared with placebo in subjects with GAD, as measured by the Clinical Global Impression-Severity (CGI-S) score. This assessment provides additional insights into the overall severity of the disorder and the impact of the treatment on the patient's global functioning.

The clinical trial involves a total of **179 participants** diagnosed with **generalized anxiety disorder** (GAD). The study population comprises both male and female subjects, aged between 18 to 65 years, who meet the DSM-5 criteria for GAD. Participants were selected based on their willingness and ability to comply with study procedures and visit schedules, as well as their capacity to understand and follow verbal and written instructions. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity were highlighted. The selection criteria ensure a diverse representation of adults within the specified age range, without any gender bias.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **Ulotaront** in adults diagnosed with **generalized anxiety disorder**. The trial will employ a parallel-group, flexible-dose approach, with participants receiving either Ulotaront or a placebo. The study is set to span a period of approximately two years, with an estimated recruitment start date of August 25, 2023, and an anticipated end date of August 26, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (18 to 65 years) and a confirmed diagnosis of generalized anxiety disorder according to DSM-5 criteria. Following successful screening, participants will be randomized to receive either Ulotaront or placebo. The primary endpoint of the study is the change from baseline in the Hamilton Anxiety Rating Scale (HAM-A) total score at the endpoint, while secondary endpoints include changes in the Clinical Global Impression-Severity (CGI-S) score.

Throughout the trial, participants will attend regular follow-up visits to monitor their response to treatment and any potential adverse effects. These visits will ensure compliance with the study protocol and allow for the collection of necessary data to evaluate the trial's objectives. The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted to gather endpoint data.

The expected length of participant involvement in the study is contingent upon the treatment period, which may vary based on the flexible dosing regimen. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or choose to withdraw consent. The trial's design and procedures are structured to ensure the collection of robust data while maintaining participant safety and adherence to ethical standards.

The clinical trial involves the administration of **Ulotaront**, a chemical compound with the active substance name Ulotaront, also known by its synonyms SEP-363856, (S)-1-(4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine, and SEP-856. Ulotaront is provided in a **tablet** form and is manufactured by Otsuka Pharmaceutical Co., Ltd. The medication is administered **orally**. The trial includes three different dosing regimens of Ulotaront: a maximum daily dose of 25 mg with a total dose of 75 mg over a 3-week period, a maximum daily dose of 75 mg with a total dose of 3900 mg over a 52-week period, and a maximum daily dose of 50 mg with a total dose of 200 mg over a 4-week period. The dosing schedule is flexible, allowing for adjustments within the specified range to evaluate efficacy and safety in the treatment of adults with Generalized Anxiety Disorder (GAD).

The study also includes a **placebo** group, which is administered a placebo formulation known as Placebo SEP-365856. The placebo is used as a comparator to evaluate the efficacy of Ulotaront. The placebo is administered in a manner identical to the active treatment, ensuring blinding and maintaining the integrity of the double-blind study design. The placebo is also provided in a tablet form and is administered orally. The use of a placebo control is essential in determining the true therapeutic effect of Ulotaront by comparing outcomes between the active treatment and placebo groups.

Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the prescribed treatment schedule. This monitoring is crucial for maintaining the validity of the trial results and for accurately assessing the efficacy and safety of Ulotaront in the target population. The trial is designed to assess the impact of Ulotaront on the Hamilton Anxiety Rating Scale (HAM-A) total score, providing a quantitative measure of its efficacy in reducing anxiety symptoms in individuals with GAD.

The efficacy of SEP-363856 in the treatment of adults with Generalized Anxiety Disorder (GAD) will be assessed in a Phase 2/3, randomized, double-blind, parallel-group, placebo-controlled, flexible-dose, multicenter study. The primary endpoint for evaluating efficacy is the change from baseline in the Hamilton Anxiety Rating Scale (HAM-A) total score at the endpoint. The secondary endpoint includes the change from baseline in the Clinical Global Impression-Severity (CGI-S) score at the endpoint. These assessments will be conducted using validated scales to ensure the reliability and accuracy of the data collected.

The study will involve flexible doses of SEP-363856, ranging from 50 to 75 mg per day, compared with a placebo. The efficacy parameters will be measured at the endpoint, with the primary focus on the reduction of anxiety symptoms as indicated by the HAM-A total score. The CGI-S score will provide additional insights into the overall severity of the disorder and the treatment's impact. The trial is designed to ensure that the data collected is robust and can provide meaningful insights into the efficacy of SEP-363856 for treating GAD.