A Study to Assess the Efficacy, Safety and Tolerability of VLS-01 Buccal Film, Compared to Placebo in Patients With Treatment Resistant Depression (ELUMINA)

Inclusion Criteria:

• Participant must be 18 to 65 years of age inclusive at the time of signing theInformed Consent.

• Has a diagnosis of recurrent moderate or severe MDD without psychotic features orsingle- episode MDD with duration greater than or equal to 3 months withoutpsychotic features and is currently experiencing a major depressive episode.

• Onset of first episode of MDD occurred before age 55.

• Has not responded to an adequate dose and duration of at least two and no more thanfive antidepressant medications for the current depressive episode, as determined bythe Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH- ATRQ).

• Capable of giving signed informed consent which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in theprotocol.

Exclusion Criteria:

• Has a current or prior DSM-5-TR diagnosis of a schizophrenia spectrum and otherpsychotic disorder, substance/medication-induced psychotic disorder, bipolar andrelated disorder, or any disorder with psychotic features.

• Has a moderate or severe substance use disorder (drug, alcohol, or tobacco) withinthe 6 months before Screening and/or history of moderate or severe substance usedisorder (drug alcohol) within the previous 1 year before Screening

• Has a history of, or current signs and symptoms of, diseases or conditions thatwould make participation not be in the best interest (e.g., compromise thewellbeing) of the participant or that could prevent, limit, or confound theprotocol-specified assessments.

• Has suicidal ideation with some intent to act within 6 months before Screening or ahistory of suicidal behavior within the past 1 year before Screening.

• Has a history of clinically significant cardiovascular, cerebrovascular, orperipheral vascular disease or condition, including but not limited to unstableangina, myocardial infarction, congestive heart failure, cardiac arrhythmia,valvular heart disease, obstructive coronary artery disease, hypertension,hypotension, bradycardia, tachycardia, or risk factors for long QT Syndrome.

• Has an active malignancy, or history of malignancy, excluding basal or squamous cellcarcinoma of the skin, within 2 years before Screening.

• Has any known allergy or hypersensitivity to VLS-01 or to any of the excipients inthe formulation.

• Has recently initiated and is currently undergoing directive psychotherapy (e.g.,cognitive behavioral therapy, interpersonal psychotherapy, psychodynamicpsychotherapy) within the past 30 days before Screening. Participants planning toinitiate individual or group therapy during the study are also not eligible.

• Has received any prohibited therapies.

• Has clinically significant laboratory abnormalities at Screening.