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

Inclusion Criteria:

1. Male or female between 18 to 65 years of age at Screening
2. 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.
3. 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.
4. MADRS score of 24 or higher at Screening as confirmed by an independent SAFER assessor.
5. 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.
6. Able and competent to read and sign the informed consent form (ICF).

Exclusion Criteria:

1. 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.
2. A high risk of suicide based on any of the following:

   1. Item 10 of MADRS score (suicidal thoughts) is 5 or higher at Screening or Baseline.
   2. Suicide attempt in the previous 6 months.
   3. Significant risk, as judged by the Investigator, based on the psychiatric interview or information collected with the C SSRS at Screening or Baseline.
3. 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).
4. Use of ketamine, esketamine, PCP, or dextromethorphan recreationally in the past 6 months.
5. History or current diagnosis of bipolar disorder, schizophrenia, or schizoaffective disorder or other schizophrenia spectrum disorders.
6. Dementia, delirium, amnesia, or any other significant cognitive disorder.
7. 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).