Long-term Safety and Efficacy of Aticaprant as Adjunctive Therapy in Adults and Elderly with Major Depressive Disorder: An Open-label Study

The primary objective of this study is to assess the long-term **safety** and tolerability of **aticaprant** when administered as adjunctive therapy to a current antidepressant, specifically selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), in adult and elderly participants diagnosed with **Major Depressive Disorder** (MDD). This evaluation is clinically relevant as it aims to determine the potential benefits and risks associated with the prolonged use of aticaprant in combination with standard antidepressant treatments, which could inform future therapeutic strategies for managing MDD.

The clinical trial involves a total of **711 participants** diagnosed with **Major Depressive Disorder** (MDD). The study population includes both male and female subjects, aged between 18 to 74 years. Participants are required to be medically stable, as determined by physical examinations, medical history, vital signs, and 12-lead ECG results. The trial includes individuals who have either completed previous related studies or are directly entering the study. All participants must meet the DSM-5 diagnostic criteria for recurrent or single episode MDD without psychotic features. Additionally, participants aged 65 or older must have experienced their first onset of depression before the age of 55. A key lifestyle consideration is that participants must be receiving and tolerating a stable dose of a **SSRI/SNRI** for depressive symptoms for at least six weeks prior to screening. The trial population was selected based on their inadequate response to at least one oral antidepressant treatment during the current episode of depression. The study also includes a vulnerable population, ensuring comprehensive safety and tolerability assessments of aticaprant as an adjunctive therapy to current antidepressants.

The clinical trial is designed to evaluate the long-term safety and efficacy of **aticaprant** as an adjunctive therapy in adult and elderly participants with **Major Depressive Disorder** (MDD). This is a Phase 3, open-label study, which will involve participants who have either completed previous double-blind treatment phases or are directly entering the study. The trial will span an estimated duration from August 2023 to December 2025, with a maximum treatment period of 52 weeks for each participant. The study will involve the administration of aticaprant in tablet form, taken orally, with a maximum daily dose of 10 mg.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, medical stability, and a diagnosis of MDD according to DSM-5 criteria. The screening process will also ensure that participants have had an inadequate response to at least one oral antidepressant treatment in their current episode of depression. Following the screening, participants will enter the treatment phase, where they will receive aticaprant in addition to their current stable dose of an SSRI or SNRI. Regular follow-up visits will be conducted to monitor safety and efficacy, including assessments of adverse events, vital signs, weight, body mass index, and laboratory parameters. The Columbia Suicidality Severity Rating Scale (C-SSRS) and the Physician Withdrawal Checklist (PWC-20) will be used to assess suicidality and withdrawal symptoms, respectively.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the long-term impact of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The primary endpoints of the study include the incidence of adverse events, changes in vital signs, and the proportion of participants with clinically relevant sexual dysfunction over time. The study aims to provide valuable insights into the safety profile of aticaprant when used as an adjunctive treatment for MDD.

The clinical trial involves the administration of the experimental medication **JNJ-67953964**, which contains the active substance **aticaprant**. This medication is provided in the form of a **tablet** and is intended for **oral use**. The maximum daily dose of aticaprant is 10 mg, with the same amount being the maximum total dose per day. The treatment period for this study is set to a maximum of 52 weeks. The primary objective of the trial is to evaluate the long-term safety and tolerability of aticaprant when used as an adjunctive therapy in adult and elderly participants diagnosed with Major Depressive Disorder (MDD). The medication is administered in conjunction with a current antidepressant, specifically a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

In addition to the experimental treatment, participants will continue their standard-of-care therapy, which includes the use of antidepressants such as SSRIs or SNRIs. These medications are not experimental and are part of the routine treatment for MDD. The trial does not include a placebo or comparator treatment, as the focus is on assessing the adjunctive use of aticaprant alongside existing antidepressant therapy. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

The efficacy of the clinical trial will be assessed through a series of primary endpoints designed to evaluate the impact of **aticaprant** as adjunctive therapy in participants with Major Depressive Disorder (MDD). The primary endpoints include the assessment of adverse events (AEs), including those of special interest (AESI), changes from baseline in vital signs, weight/body mass index (BMI), and suicidality using the Columbia Suicidality Severity Rating Scale (C-SSRS). Additionally, laboratory parameters and 12-lead ECG results will be monitored. Withdrawal symptoms will be evaluated using the Physician Withdrawal Checklist, 20-item (PWC-20), and the proportion of participants experiencing clinically relevant sexual dysfunction will be measured over time using the Arizona Sexual Experiences Scale (ASEX).