Long-term Evaluation of NMRA-335140 for Safety and Efficacy in Major Depressive Disorder Patients

The primary objective of this open-label, 52-week extension study is to evaluate the long-term **safety** and tolerability of NMRA-335140, administered at a dose of 80 mg once daily, in the treatment of **Major Depressive Disorder** (MDD). This is clinically relevant as it aims to ensure that the therapeutic benefits of NMRA-335140 can be sustained over an extended period without compromising patient safety, which is crucial for chronic conditions like MDD.

The secondary objective is to assess the long-term effectiveness of NMRA-335140 80 mg QD. This evaluation is important to determine the sustained efficacy of the treatment in managing symptoms of MDD over a prolonged duration, thereby providing insights into its potential as a long-term therapeutic option.

The clinical trial involves a total of **375 participants** diagnosed with **Major Depressive Disorder**. The study population includes both male and female subjects, with an age range that encompasses adults. Participants were selected based on their completion of a previous NMRA-335140 Phase 3 study, ensuring continuity in the evaluation of the long-term safety and tolerability of NMRA-335140 80mg once daily. The trial includes a vulnerable population, indicating that special considerations are in place to address their specific needs. Participants are required to adhere to certain lifestyle considerations, such as compliance with contraception requirements and restrictions on concomitant medication or therapy, as outlined in the parent study protocol. The study does not specify additional lifestyle factors such as diet or physical activity. The inclusion of a caregiver for participants in the Czech Republic highlights the importance of monitoring compliance and safety, particularly for those with severe depression.

The clinical trial is designed as an open-label, 52-week extension study to evaluate the long-term safety and tolerability of **NMRA-335140** in participants with **Major Depressive Disorder** (MDD). The trial employs a non-randomized, open-label methodology, allowing all participants to receive the investigational product, NMRA-335140, at a dose of 80 mg once daily. The study is structured to include an initial screening visit, followed by regular follow-up visits, and concludes with an end-of-study visit. The primary objective is to assess safety and tolerability through various measures, including adverse events, clinical laboratory parameters, electrocardiograms, vital signs, physical examinations, ophthalmologic examination, corneal specular microscopy, Columbia Suicide Severity Rating Scale, and the Change in Sexual Functioning Questionnaire-14.

Participants are expected to be involved in the study for the entire 52-week duration unless conditions necessitate early termination. Such conditions include non-compliance with study protocols, withdrawal of consent, or the occurrence of adverse events that warrant discontinuation. The study visits are sequenced to monitor the participants' health and response to the treatment, with assessments conducted at each visit to ensure participant safety and data integrity. The inclusion criteria require participants to have completed a previous NMRA-335140 Phase 3 MDD study and to have signed an informed consent form. The study also mandates compliance with contraception requirements and restrictions on concomitant medication or therapy as outlined in the parent study protocol.

Secondary endpoints focus on changes from baseline in various scales, including the Montgomery-Åsberg Depression Rating Scale, Snaith-Hamilton Pleasure Scale, Patient Health Questionnaire-9, Hamilton Anxiety Rating Scale, Clinical Global Impression of Severity, and Sheehan Disability Scale. The trial is anticipated to start recruitment on August 26, 2024, and is estimated to conclude by May 6, 2026. Participants are required to attend all scheduled visits and adhere to the study protocol to ensure the collection of comprehensive and reliable data.

The clinical trial involves the administration of the experimental medication **NMRA-335140**, which is formulated as a **film-coated tablet**. The active substance in NMRA-335140 is **1-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine**, a chemical compound. The medication is administered orally at a dosage of 80 mg once daily. The maximum treatment period for this study is 52 weeks. The primary objective of this open-label, 52-week extension study is to evaluate the long-term safety and tolerability of NMRA-335140 in the treatment of **major depressive disorder**.

In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The study focuses solely on the administration of NMRA-335140. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial is designed to assess the safety and effectiveness of NMRA-335140 over an extended period, providing valuable data on its long-term use in individuals with major depressive disorder.

Efficacy in the clinical trial assessing NMRA-335140 for the treatment of **Major Depressive Disorder** will be evaluated using several secondary endpoints. These include changes from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, Snaith-Hamilton Pleasure Scale (SHAPS) total score, Patient Health Questionnaire-9 (PHQ-9) total score, and the Hamilton Anxiety Rating Scale (HAM-A) total score over time. Additionally, changes in the Clinical Global Impression of Severity (CGI-S) score and the Sheehan Disability Scale (SDS) will be assessed. The Clinical Global Impression of Improvement (CGI-I) score will be evaluated at each timepoint. The percentage of participants whose MADRS total score decreases by 50% or more from baseline, as well as those whose score decreases to 10 or less, will also be measured.

The efficacy parameters will be collected and analyzed at various timepoints throughout the study. The tools and instruments used for these assessments include validated scales such as the MADRS, SHAPS, PHQ-9, HAM-A, CGI-S, CGI-I, and SDS. These assessments will provide a comprehensive evaluation of the treatment's impact on depressive symptoms, anhedonia, anxiety, and overall clinical impression of severity and improvement.