Efficacy and Safety of Aticaprant as Adjunctive Therapy in Adults with Major Depressive Disorder and Anhedonia Unresponsive to Antidepressants

The primary objective of this study is to evaluate the **efficacy** of aticaprant 10 mg compared with placebo as adjunctive therapy to an antidepressant in improving depressive symptoms in adult participants with **Major Depressive Disorder (MDD)** with moderate-to-severe **anhedonia** who have had an inadequate response to current antidepressant therapy with a **Selective Serotonin Reuptake Inhibitor (SSRI)** or **Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)**. This is clinically relevant as it addresses the need for effective treatment options for patients with MDD who do not adequately respond to standard antidepressant therapies, potentially improving their quality of life and functional outcomes.

The clinical trial involves a total of **150 participants** diagnosed with **Major Depressive Disorder (MDD) with moderate-to-severe anhedonia**. The study population includes both male and female adults aged 18 to 64 years, who meet the DSM-5 diagnostic criteria for recurrent or single episode MDD without psychotic features. Participants are required to have a moderate to severe depressive episode, as indicated by a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 25 or higher at screening and baseline, and must exhibit symptoms of anhedonia. All participants have had an inadequate response to at least one and up to five oral antidepressant treatments, including current treatment with an SSRI or SNRI. The trial population was selected based on clinical assessments confirming the presence of anhedonia and stable symptom severity, with no significant improvement between site-rater assessments. Participants are medically stable, as determined by clinical assessments, vital signs, ECG, and laboratory evaluations. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring comprehensive evaluation of the adjunctive therapy's efficacy.

The clinical trial is designed to evaluate the **efficacy**, safety, and tolerability of **aticaprant** 10 mg as an adjunctive therapy in adult participants with **Major Depressive Disorder (MDD)** with moderate-to-severe anhedonia who have shown an inadequate response to current antidepressant therapy. This study is a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thus minimizing bias. The trial will include a placebo group receiving a matching placebo tablet to compare the effects of the active treatment. The trial is expected to commence recruitment on November 20, 2024, and conclude by July 15, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of MDD, and inadequate response to antidepressants. Following successful screening, participants will be randomized to receive either aticaprant or placebo. The primary endpoint is the change from baseline to Day 43 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, which will be assessed at various follow-up visits throughout the trial. The study will also include an end-of-study visit to evaluate the overall outcomes and any adverse events experienced by the participants.

The expected length of participant involvement is up to 43 days, corresponding to the maximum treatment period. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial will adhere to rigorous scientific and ethical standards to ensure the integrity of the data and the well-being of the participants.

The clinical trial involves the administration of **Aticaprant**, an experimental medication, as an adjunctive therapy for adult participants diagnosed with Major Depressive Disorder (MDD) exhibiting moderate-to-severe anhedonia and inadequate response to current antidepressant therapy. **Aticaprant** is provided in the form of a tablet, with a dosage of 10 mg per day. The route of administration is oral, and the treatment period extends up to a maximum of 43 days. The total maximum dose administered during the trial is 430 mg. The active substance in the experimental medication is chemically derived and is identified as **Aticaprant**. The pharmaceutical product is manufactured by Janssen-Cilag International N.V.

In addition to the experimental treatment, a **matching placebo tablet** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is designed to mimic the appearance and administration route of the **Aticaprant** tablet, ensuring blinding of both participants and investigators. The placebo is administered orally with the same frequency and duration as the experimental medication, maintaining consistency in the treatment protocol.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The study aims to evaluate the efficacy, safety, and tolerability of **Aticaprant** as an adjunctive therapy, with the primary objective of improving depressive symptoms in the target population. The trial design includes a long-term open-label extension phase to further assess the effects of **Aticaprant** over an extended period.

The efficacy of the investigational product, **aticaprant**, will be assessed in a randomized, double-blind, placebo-controlled clinical trial involving adult participants with Major Depressive Disorder (MDD) who exhibit moderate-to-severe anhedonia and have shown an inadequate response to current antidepressant therapy. The primary endpoint for evaluating efficacy is the change from baseline to Day 43 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. This scale is a validated tool commonly used to measure the severity of depressive episodes in patients with mood disorders.

Participants will receive aticaprant 10 mg as adjunctive therapy to their current antidepressant regimen, and their depressive symptoms will be monitored throughout the study. The MADRS assessments will be conducted at specified timepoints, including baseline and Day 43, to determine the efficacy of the treatment. The trial is designed to ensure that the efficacy assessments are conducted in a consistent and reliable manner, adhering to the highest standards of clinical research.