Evaluation of NMRA-335140 Efficacy in Major Depressive Disorder: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of 80 mg/day of NMRA-335140, a kappa opioid receptor antagonist, compared to placebo in alleviating symptoms of depression in adult participants diagnosed with **Major Depressive Disorder** (MDD) over a 6-week double-blind treatment period. This is clinically relevant as it aims to determine the potential of NMRA-335140 as a therapeutic option for MDD, a condition with significant impact on quality of life and functional capacity.

Secondary objectives include:

• Assessing participant-reported symptoms of **anhedonia** using the Snaith-Hamilton Pleasure Scale (SHAPS) and changes from baseline to week 6.
• Evaluating the **MADRS** response rate, defined as a ≥50% reduction in total score from baseline.
• Monitoring changes in MADRS scores over time.
• Clinical assessment of MDD severity and improvement using the Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I) scores.
• Evaluating participant-reported symptoms of MDD using the Patient Health Questionnaire-9 (PHQ-9) total score.
• Assessing participant-reported severity of anhedonia using PHQ-9 Anhedonia Item #1.
• Clinician-reported symptoms of **anxiety** using the Hamilton Anxiety Rating Scale (HAMA) total score.
• Participant-reported assessment of functional impairment using the Sheehan Disability Scale (SDS) total score.
• Determining the MADRS remission rate, defined as a total score of 10 or less.

The clinical trial involves a total of **205 participants** diagnosed with **Major Depressive Disorder** (MDD). The study population includes both male and female adults, with an age range corresponding to category code 3, typically representing individuals aged 18 to 65 years. Participants were selected based on a primary diagnosis of MDD without psychotic features, confirmed by a structured clinical interview. The trial includes individuals whose current major depressive episode has been present for more than four weeks but no longer than 12 months prior to the screening visit. Participants must have a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 25 or higher at screening and baseline, with a change in MADRS total score between screening and baseline of 20% or less. The trial population includes a vulnerable population, indicating that additional ethical considerations are in place. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of the investigational drug NMRA-335140 in adult participants diagnosed with **Major Depressive Disorder** (MDD). The trial aims to assess the effects of an 80 mg daily dose of NMRA-335140, a kappa opioid receptor antagonist, compared to a placebo over a treatment period of six weeks. The primary endpoint is the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week six, while the secondary endpoint involves the change in the Snaith-Hamilton Pleasure Scale (SHAPS) total score over the same period.

The trial will commence with a screening visit to confirm eligibility based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) criteria for MDD, ensuring the absence of psychotic features. Participants must have a MADRS total score of 25 or higher at both screening and baseline, with a change in MADRS score between these visits not exceeding 20%. The current depressive episode should have persisted for more than four weeks but not longer than 12 months prior to the screening visit.

Following the screening, eligible participants will be randomly assigned to receive either NMRA-335140 or a placebo, administered orally in the form of a film-coated tablet. The study will include regular follow-up visits to monitor the participants' progress and assess the efficacy and safety of the treatment. The total duration of participant involvement is expected to be approximately six weeks, with the possibility of early termination if significant adverse effects occur or if the participant withdraws consent.

The trial is scheduled to begin recruitment on July 15, 2024, and is estimated to conclude by June 2, 2025. Participants will be closely monitored throughout the study to ensure adherence to the protocol and to evaluate the therapeutic potential of NMRA-335140 in alleviating symptoms of MDD. The study's design and procedures are structured to maintain the integrity of the double-blind methodology, with the placebo being identical in appearance to the active drug to ensure blinding is preserved.

The clinical trial involves the administration of **NMRA-335140**, an experimental medication 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 per day. The maximum treatment period is six weeks. The primary objective of the trial is to evaluate the efficacy of NMRA-335140, a kappa opioid receptor antagonist, in alleviating symptoms of major depressive disorder (MDD) in adult participants.

The study also includes a **placebo** group to maintain blinding and ensure the reliability of the results. The placebo is identical in appearance to the NMRA-335140 film-coated tablet but does not contain the active drug substance. This design allows for a direct comparison between the effects of the active medication and the placebo, thereby assessing the true efficacy of NMRA-335140 in treating MDD.

Efficacy in this clinical trial will be assessed by evaluating the effects of the investigational product, NMRA-335140, a kappa opioid receptor antagonist, compared to placebo in participants with **Major Depressive Disorder** (MDD). The primary endpoint for efficacy evaluation is the treatment difference in the change from Baseline to Week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. This scale is a validated tool used to measure the severity of depressive episodes in patients with mood disorders. The secondary endpoint involves assessing the change from Baseline to Week 6 in the Snaith-Hamilton Pleasure Scale (SHAPS) total score, which evaluates anhedonia, a core symptom of depression.

Data collection will occur at specified timepoints, including Baseline and Week 6, to ensure accurate measurement of changes in the MADRS and SHAPS scores. The trial is designed as a randomized, double-blind, placebo-controlled study, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thus maintaining the integrity of the data collected. The efficacy assessments will be conducted over a 6-week double-blind treatment period, with the primary focus on symptom improvement as measured by the aforementioned scales.