Efficacy and Safety Evaluation of NBI-1065845 as Adjunctive Therapy in Adults with Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

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)**. This is assessed by measuring the improvement in symptoms of depression using the Montgomery-Asberg Depression Rating Scale (MADRS). The clinical relevance of this objective lies in its potential to enhance treatment outcomes for patients with MDD, a condition characterized by persistent and severe depressive symptoms that significantly impact daily functioning and quality of life.

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 reducing 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 **107 participants** diagnosed with **Major Depressive Disorder** (MDD). The study population includes both male and female subjects, aged 18 years and older, who have been confirmed to have recurrent moderate or severe MDD or persistent depressive disorder through a face-to-face evaluation using the Mini-International Neuropsychiatric Interview (MINI). Participants are required to be on oral antidepressant treatments and must have shown an inadequate response to these treatments, as assessed by the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH-ATRQ). 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 symptoms of depression using the Montgomery-Asberg Depression Rating Scale (MADRS). The trial is expected to last until July 2027, with recruitment starting in August 2025. Participants will be involved for a maximum of 56 days, during which they will receive either the active drug or a placebo in tablet form, administered orally.

The study will commence with an inclusion visit, where participants will undergo screening to confirm eligibility based on criteria such as age, diagnosis of MDD, and inadequate response to current antidepressant treatments. The diagnosis will be confirmed using the Mini-International Neuropsychiatric Interview (MINI). Participants must also have a Hamilton Depression Rating Scale-17 Item (HAM-D17) score of 22 or higher at screening and baseline. Following the inclusion visit, participants will be randomized to receive either NBI-1065845 or a placebo.

Throughout the trial, participants will attend follow-up visits to monitor their response to the treatment and any adverse effects. The primary endpoint will be the change from baseline in the total MADRS score at Day 56. Secondary endpoints include changes in the Sheehan Disability Scale (SDS) total score and the Clinical Global Impressions-Severity (CGI-S) score at Day 56. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the overall efficacy and safety of the treatment.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial is a Phase 3 study, indicating it involves a drug not currently authorized for the population involved. The study is not classified as low intervention, reflecting the rigorous nature of the trial design and the need for close monitoring of participants.

The clinical trial involves the administration of **NBI-1065845**, an experimental medication formulated as a tablet. The active substance in NBI-1065845 is **9-(4-cyclohexyloxyphenyl)-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide**, a chemical compound developed by Neurocrine Biosciences Inc. The tablets are administered orally. The dosing schedule and specific dosage amounts are not detailed in the provided data, but the maximum treatment period is specified as 56 days. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

The study also includes a placebo group, receiving tablets identical in appearance to the NBI-1065845 tablets but without the active drug. These placebo tablets serve as a control to evaluate the efficacy and safety of the experimental treatment. The placebo is administered in the same pharmaceutical form and via the same oral route as the active medication, ensuring blinding of both participants and investigators to the treatment assignments. The placebo administration follows the same dosing schedule as the experimental medication, with compliance monitoring in place to maintain the integrity of the study.

The efficacy of NBI-1065845 as an adjunctive treatment in subjects with 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, which is 56 days. 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 is the gold standard for minimizing bias and ensuring the validity of the results.