Clinical Trial of Lumateperone as Adjunctive Therapy in the Treatment of Patients With Major Depressive Disorder

The study will be conducted in three periods:

• Screening Period (up to 2 weeks) during which patient eligibility will be assessed;
• Double-blind Treatment Period (6 weeks) in which all patients will be randomized to receive placebo or lumateperone 42mg/day in 1:1 ratio.
• Safety Follow-up Period (1 week) in which all patients will return to the clinic for a safety follow-up visit approximately one week after the last dose of study treatment.

Inclusion criteria

• Male or female patients between the ages of 18 and 65 years, inclusive;
• Meet DSM-5 diagnostic criteria for MDD (a diagnosis of MDD with psychotic features will be acceptable) as confirmed by the Investigator or Sponsor-approved rater using the Mini-International Neuropsychiatric Interview (MINI), and meet all the following criteria:

• The start of the current major depressive episode (MDE) is at least 8 weeks but not more than 18 months prior to Screening;
• Has at least moderate severity of illness based on rater-administered MADRS total score ≥ 24 at Screening and at Baseline;
• Has at least moderate severity of illness based on CGI-S score ≥ 4 at Screening and at Baseline;
• Has a Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score ≥14 at Screening and at Baseline;
• Has sufficient history and medical record confirmation verifying the ADT and the current MDE is causing clinically significant distress or impairment in social, occupational, or other important areas of functioning.
• Currently having an inadequate response to ADT (less than 50% improvement) as confirmed by the Investigator and taking at least the minimum effective dose (per package insert) of one of the following antidepressants as monotherapy treatment for at least 6 weeks duration:

• citalopram/escitalopram
• fluoxetine
• paroxetine
• sertraline
• duloxetine
• levomilnacipran/milnacipran (if locally approved for MDD)
• venlafaxine/desvenlafaxine
• buproprion
• vilazodone
• vortioxetine

Exclusion criteria

• Within the patient's lifetime, has a confirmed DSM-5 psychiatric diagnosis other than MDD, including:

• Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder or other psychotic disorder;
• Bipolar Disorder;
• Within 6 months of Screening, has a confirmed DSM-5 psychiatric diagnosis other than MDD including:

• Anxiety disorders such as Panic Disorder or Generalized Anxiety Disorder; Obsessive-compulsive Disorder; Posttraumatic Stress Disorder as primary diagnoses.
• Eating disorder;
• Substance use disorders (excluding nicotine);
• Personality disorder of sufficient severity to have a major impact on the patient's psychiatric status;
• Within 12 months of Screening, has had any other psychiatric condition (other than MDD) that has been the main focus of treatment;
• The patient experiences a ≥ 25% decrease in the MADRS total score between Screening and Baseline;
• The patient experiences a ≥ 25% decrease in the QIDS-SR-16 total score between Screening and Baseline;
• In the opinion of the Investigator, the patient has a significant risk for suicidal behavior during participation in the study or:

• At Screening, the patient scores "yes" on Suicidal Ideation Items 4 or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) within 6 months prior to Screening, or at Baseline, the patient scores "yes" on Suicidal Ideation Items 4 or 5 since the Screening Visit;
• At Screening, the patient has had 1 or more suicide attempts within 2 years prior to Screening;
• At Screening or Baseline, the patient scores ≥ 5 on MADRS Item 10 (Suicidal Thoughts), or
• The patient is considered to be in imminent danger to him/herself or others.
• The patient has a first MDE at age 60 years or older.