Efficacy and Safety Evaluation of Lumateperone as Adjunctive Therapy in Major Depressive Disorder Patients with Inadequate Antidepressant Response

The primary objective of this study is to evaluate the **efficacy** of lumateperone 42 mg administered once daily compared with placebo as an adjunctive treatment to antidepressant therapy in patients with **Major Depressive Disorder** (MDD) who have an inadequate response to ongoing antidepressant therapy. This is measured by the change from baseline to Day 43 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. This objective is clinically relevant as it aims to address the unmet need for effective treatment options in patients with MDD who do not adequately respond to standard antidepressant therapies.

Secondary objectives include:

• Evaluating the efficacy of lumateperone 42 mg compared with placebo as adjunctive treatment to ADT in patients with MDD, measured by change from baseline to Day 43 in the Clinical Global Impression Scale-Severity (CGI-S).
• Determining the proportion of patients who are treatment responders, defined as a ≥ 50% decrease from baseline in MADRS total score at Day 43.
• Assessing the proportion of remitters, where remission is defined as a MADRS total score ≤ 10 at Day 43.
• Evaluating by-visit change from baseline in the MADRS total score.
• Assessing by-visit change from baseline in the Hamilton Anxiety Rating Scale (HAM-A) total score.
• Evaluating by-visit change from baseline in CGI-S score.
• Assessing change from baseline in the Changes in Sexual Functioning Questionnaire-14 item version (CSFQ-14) total score at each assessment time point, including Day 43.
• Evaluating change from baseline in MADRS individual item scores at each assessment time point, including Day 43.
• Determining the safety and tolerability of lumateperone 42 mg compared with placebo, assessed by adverse events, clinical laboratory results, vital sign measures, ECG results, suicidality as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), and extrapyramidal symptoms as assessed by the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson Angus Scale (SAS).

The clinical trial involves a total of **327 participants** diagnosed with **Major Depressive Disorder** (MDD). The study population comprises both male and female subjects, aged between 18 and 65 years, who have been identified as having an inadequate response to ongoing antidepressant therapy. Participants were selected based on their ability to provide written informed consent and their diagnosis confirmed by the DSM-5 criteria for MDD, including those with psychotic features. The trial specifically targets individuals experiencing a major depressive episode lasting between 12 weeks and 18 months prior to screening, with a moderate severity of illness as indicated by a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 24 or higher. Additionally, participants must have a Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score of 14 or higher and a Clinical Global Impressions-Severity (CGI-S) score of 4 or higher. The trial includes individuals who have shown less than 50% improvement with at least two antidepressant therapies during the current depressive episode, while taking a minimum effective dose of specified antidepressants for at least six weeks. The study does not exclude vulnerable populations, ensuring a comprehensive evaluation of the adjunctive treatment's efficacy.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **lumateperone** as an adjunctive therapy in patients with **Major Depressive Disorder** (MDD) who have an inadequate response to ongoing antidepressant therapy. The trial will involve the administration of lumateperone 42 mg once daily, compared to a placebo, over a period of 43 days. The primary endpoint is the change from baseline to Day 43 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary endpoints include changes in the Clinical Global Impressions-Severity (CGI-S) score, the proportion of treatment responders, and safety parameters.

The trial will commence with a screening visit to confirm eligibility based on inclusion criteria, such as age between 18 and 65 years, a diagnosis of MDD according to DSM-5 criteria, and an inadequate response to at least two antidepressant therapies. Following the screening, eligible participants will be randomized to receive either lumateperone or placebo. Study visits will occur at regular intervals to monitor efficacy and safety, with assessments including MADRS, CGI-S, and other relevant scales. The end-of-study visit will occur on Day 43, marking the conclusion of the participant's involvement in the trial.

Participants are expected to be involved in the study for approximately 6 weeks, from the screening visit to the end-of-study visit. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial is anticipated to conclude by October 31, 2025, with recruitment starting on February 1, 2024.

The clinical trial involves the administration of **lumateperone** as the experimental medication. Lumateperone is provided in the form of capsules, with each capsule containing 42 mg of the active substance. The route of administration is oral, and the medication is to be taken once daily. The maximum treatment period for lumateperone is six weeks. The active substance, lumateperone, is a chemical small molecule, and the product is manufactured by Intra-Cellular Therapies, Inc. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind study. The placebo capsules are identical in appearance to the lumateperone capsules but do not contain the active substance. The placebo is also administered orally once daily, following the same schedule as the lumateperone treatment. The use of a placebo allows for the assessment of the efficacy and safety of lumateperone as an adjunctive therapy in patients with Major Depressive Disorder (MDD) who have an inadequate response to ongoing antidepressant therapy. Participant compliance with the placebo regimen is similarly monitored to maintain the integrity of the study results.

Efficacy in this clinical trial will be assessed by evaluating the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to Day 43. This primary endpoint will measure the efficacy of **lumateperone** 42 mg administered once daily as an adjunctive treatment to antidepressant therapy in patients with Major Depressive Disorder (MDD) who have an inadequate response to ongoing antidepressant therapy. The MADRS is a validated scale used to quantify the severity of depressive episodes in patients with mood disorders.

Secondary efficacy endpoints include the change from baseline to Day 43 in the Clinical Global Impressions-Severity (CGI-S) score, the proportion of patients who are treatment responders (defined as a ≥ 50% decrease from baseline in MADRS total score at Day 43), and the proportion of remitters (defined as a MADRS total score ≤ 10 at Day 43). Additional assessments will include by-visit mean changes from baseline in the MADRS total score, Hamilton Anxiety Rating Scale (HAM-A) total score, and Changes in Sexual Functioning Questionnaire-14 (CSFQ-14) total score, as well as by-visit mean changes from baseline in the CGI-S score. Changes from baseline in MADRS individual item scores at each assessment time point, including Day 43, will also be evaluated.