Efficacy and Safety Evaluation of 9-(4-Cyclohexyloxyphenyl)-7-Methyl-3,4-Dihydropyrazino[2,1-c][1,2,4]Thiadiazine 2,2-Dioxide as Adjunctive Therapy in Major Depressive Disorder

The primary objective of this study is to evaluate the **efficacy** of NBI-1065845 compared with placebo as an adjunctive treatment in subjects with **Major Depressive Disorder (MDD)**, focusing on improving symptoms of depression. This is measured by the Montgomery-Asberg Depression Rating Scale (MADRS), which is clinically relevant as it provides a standardized assessment of depression severity, aiding in the determination of treatment effectiveness.

Secondary objectives include:

• Evaluating the efficacy of NBI-1065845 compared with placebo in improving overall functioning, as measured by the Sheehan Disability Scale (SDS), and in improving the overall severity of depression, as measured by the Clinical Global Impression-Severity Scale (CGI-S).
• Assessing the safety and tolerability of NBI-1065845 as an adjunctive treatment in subjects with MDD.

The clinical trial involves a total of **118 participants** diagnosed with **Major Depressive Disorder** (MDD). The study population includes both male and female subjects, aged 18 years and older, who have a primary diagnosis of recurrent MDD, either moderate or severe, or persistent depressive disorder. Participants are required to have an inadequate response to oral antidepressant treatments, as assessed by the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire. The trial population was selected based on their ability to comply with study procedures and restrictions, as determined by the investigator. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that special considerations are in place to ensure the safety and ethical treatment of all participants.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of NBI-1065845 as an adjunctive treatment in subjects with **Major Depressive Disorder** (MDD). The primary objective is to assess the improvement in depressive symptoms using the Montgomery-Asberg Depression Rating Scale (MADRS). The trial will span a total duration of 56 days, with the primary endpoint being the change from baseline in the total MADRS score at Day 56. Secondary endpoints include changes from baseline in the Sheehan Disability Scale (SDS) total score and the Clinical Global Impressions-Severity (CGI-S) score at Day 56.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of recurrent MDD or persistent depressive disorder, and inadequate response to current oral antidepressant treatments. The diagnosis will be confirmed using the Mini-International Neuropsychiatric Interview (MINI). Following the screening, participants will be randomized to receive either NBI-1065845 or a placebo, both administered orally in tablet form. The study includes follow-up visits to monitor safety and efficacy, with assessments conducted at regular intervals throughout the trial period. The end-of-study visit will occur on Day 56, where final evaluations will be conducted to assess the primary and secondary endpoints.

The expected length of participant involvement is approximately 8 weeks, from the screening visit to the end-of-study visit. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events, or withdrawal of consent. Participants must be willing and able to comply with all study procedures and restrictions as determined by the investigator. The trial is a Phase 3 study, indicating it involves a drug not currently authorized for the population involved in the planned clinical trial.

The clinical trial involves the administration of **NBI-1065845**, an experimental medication, as an adjunctive treatment for subjects with Major Depressive Disorder (MDD). **NBI-1065845** is formulated as a tablet and contains the active substance **9-(4-cyclohexyloxyphenyl)-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide**. The pharmaceutical form is a tablet, and the route of administration is oral. The maximum treatment period for this medication is 56 days. The dosage is measured in milligrams, although specific dosing details are not provided. The medication is produced by Neurocrine Biosciences Inc.

The study also includes a **placebo** group, where participants receive tablets identical in appearance to the **NBI-1065845** tablets but without the active drug. The placebo tablets are administered orally, following the same schedule as the experimental medication, to maintain the double-blind nature of the trial. The placebo serves as a comparator to evaluate the efficacy of **NBI-1065845** in improving symptoms of depression, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS).

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. The trial is designed to assess the safety and efficacy of **NBI-1065845** compared to placebo, with the primary objective being the improvement of depressive symptoms in subjects with MDD.

The efficacy of NBI-1065845 as an adjunctive treatment for Major Depressive Disorder (MDD) will be assessed using the **Montgomery-Asberg Depression Rating Scale (MADRS)**. The primary endpoint is the change from baseline in the total MADRS score at Day 56. Secondary endpoints include changes from baseline in the Sheehan Disability Scale (SDS) total score and the Clinical Global Impressions-Severity (CGI-S) score, both also measured at Day 56.

Data collection will involve the use of validated scales, with assessments scheduled at baseline and at the end of the treatment period. The MADRS, SDS, and CGI-S are established tools for evaluating symptom severity and functional impairment in depression, ensuring reliable and consistent measurement of treatment efficacy. The trial is designed as a randomized, double-blind, placebo-controlled study, which will facilitate a robust comparison of the efficacy of NBI-1065845 against placebo in improving depressive symptoms.