A Study of CLE-100 (Oral Esketamine) as an Adjunctive Treatment to Standard Antidepressants for Major Depressive Disorder

This is a Phase 2 study in subjects with MDD currently treated with an oral antidepressant medication with an inadequate response to at least 2 antidepressants. SOLEO will be an outpatient study to assess the safety, efficacy, and tolerability of CLE-100 as compared to placebo.

Eligible subjects will be randomized to receive either placebo or CLE-100 (oral esketamine) once daily in addition to their current oral antidepressant monotherapy for 4 weeks. All subjects who adequately completed the 4-week Double-Blind Treatment Period and who meet the eligibility criteria will be offered the option to roll-over to a 6-month Open-label Extension (OLE) Treatment Period with CLE-100.

Inclusion criteria

• Male or female between 18 to 65 years of age at Screening
• Diagnosis of MDD, single or recurrent, without psychotic features, in the current or previous episode(s), according to the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5). The diagnosis of MDD must be supported by the Mini International Neuropsychiatric Interview (MINI) Screen 7.0.2 for DSM-5.
• Currently experiencing a Major Depressive Episode (MDE) that began at least 12 weeks but no more than 5 years prior to Screening. The current MDE must be confirmed by the independent SAFER assessor.
• MADRS score of 24 or higher at Screening as confirmed by an independent SAFER assessor.
• At Screening, a history of inadequate response to at least 2 antidepressant medications in the current MDE. Inadequate response is defined as less than 50% improvement of depression symptoms following at least 6 weeks of treatment with a therapeutic dose and is assessed by the site using the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ). Inadequate response to at least 2 antidepressant medications must be verified by documented medical or pharmacy records and confirmed by an independent SAFER assessor.
• Able and competent to read and sign the informed consent form (ICF).

Exclusion criteria

• At Screening, a history of inadequate response (as defined in inclusion criterion #5) to more than 5 antidepressant medications in the current MDE using MGH-ATRQ and confirmed by the independent SAFER assessor.
• A high risk of suicide based on any of the following:

• Item 10 of MADRS score (suicidal thoughts) is 5 or higher at Screening or Baseline.
• Suicide attempt in the previous 6 months.
• Significant risk, as judged by the Investigator, based on the psychiatric interview or information collected with the C SSRS at Screening or Baseline.
• Current or lifetime history of substance use disorder with ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3.4-methylenedioxymethamphetamine (MDMA) hallucinogen-related use disorders or has any other current substance use disorder or history within 12 months prior to Screening (Substance Use Disorder is diagnosed per DSM-5 criteria and does not include tobacco use disorder).
• Use of ketamine, esketamine, PCP, or dextromethorphan recreationally in the past 6 months.
• History or current diagnosis of bipolar disorder, schizophrenia, or schizoaffective disorder or other schizophrenia spectrum disorders.
• Dementia, delirium, amnesia, or any other significant cognitive disorder.
• Any medical condition for which an increase in blood pressure or intracranial pressure or intraocular pressure or tachycardia poses a serious risk (e.g., aneurysmal vascular disease, arteriovenous malformation, or history of intracerebral hemorrhage).