A Phase 2/3, Multicenter, Randomized, Double blind, Placebo controlled Trial of the Safety and Efficacy of Flexible Doses of SEP 363856 as Adjunctive Therapy in the Treatment of Adults with Major Depressive Disorder.

The primary objective of this study is to compare the **efficacy** of SEP-363856, administered at doses ranging from 50 to 75 mg per day, to a placebo when used as an adjunctive therapy to an assigned open-label antidepressant therapy (ADT) in adults with Major Depressive Disorder (MDD) who have shown an inadequate response to a prospective 8-week trial of the same assigned open-label ADT. This objective is clinically relevant as it aims to determine the potential of SEP-363856 to enhance the therapeutic outcomes in patients with MDD who do not sufficiently respond to standard antidepressant treatments, thereby addressing a significant unmet need in the management of MDD.

Secondary objectives include evaluating the **safety** and **tolerability** of SEP-363856 at the specified doses as an adjunctive therapy to ADT in subjects with MDD. These objectives are crucial for understanding the risk-benefit profile of SEP-363856, ensuring that any potential therapeutic benefits are not outweighed by adverse effects, thus informing clinical decision-making regarding its use in this patient population.

The clinical trial involves a total of **779 participants** diagnosed with **major depressive disorder (MDD)**, who are currently experiencing a major depressive episode (MDE) as per DSM-5 criteria. The study population comprises adults aged 18 to 65 years, inclusive of both **male and female** subjects. Participants were selected based on their inadequate response to at least one and no more than three adequate antidepressant therapies (ADTs) for the current MDE, which must have persisted for a duration of at least 8 weeks but less than 2 years. All subjects were required to have a total score of 18 or higher on the 17-item Hamilton Depression Rating Scale (HAM-D17) at both the screening and baseline visits. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity were highlighted in the selection criteria. The sponsor has not provided additional information regarding the general health status or specific lifestyle habits of the participants.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the safety and efficacy of flexible doses of SEP-363856 as adjunctive therapy in adults with **major depressive disorder** (MDD). The trial aims to compare the efficacy of SEP-363856 (50 to 75 mg/day) to placebo when used alongside an assigned open-label antidepressant therapy (ADT) in subjects with MDD who have shown an inadequate response to an 8-week trial of the same ADT. The study is expected to run from February 15, 2023, to March 24, 2025, with participant involvement lasting approximately 14 weeks.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age (18 to 65 years), diagnosis of MDD according to DSM-5 criteria, and a history of inadequate response to at least one but no more than three adequate ADTs. The screening will include assessments like the 17-item Hamilton Depression Rating Scale (HAM-D17) to ensure a total score of ≥ 18. Following the screening, eligible participants will enter Phase A, an 8-week period where they will receive open-label ADT. At the end of Phase A, participants will be randomized to receive either SEP-363856 or placebo for an additional 6 weeks (Phase B).

Throughout the trial, participants will attend regular follow-up visits for safety and efficacy assessments. Primary endpoints include the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from the end of Phase A to the end of Phase B. Secondary endpoints will evaluate standard safety variables such as adverse events, physical examinations, vital signs, ECGs, and laboratory assessments. Additional safety evaluations will include scales like the Columbia-Suicide Severity Rating Scale (C-SSRS) and the Simpson-Angus Scale (SAS).

The trial will conclude with an end-of-study visit, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial is not categorized as low intervention and is considered a therapeutic confirmatory trial for an unapproved product.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. The primary experimental medication is **Ulotaront**, also known by its sponsor product code SEP-363856. Ulotaront is provided in tablet form and is administered orally. The dosage ranges from 50 to 75 mg per day, with a maximum daily dose of 75 mg. The treatment period for Ulotaront is up to 14 days. The chemical origin of the active substance is confirmed, and the medication is not a paediatric formulation.

In addition to Ulotaront, the trial includes a **placebo** group, which receives a matching placebo for SEP-363856. The placebo is used to maintain the double-blind nature of the study and is administered in a manner consistent with the active treatment group.

Several **non-experimental treatments** are used as standard-of-care therapy in this trial. These include **Citalopram**, **Paroxetine**, **Venlafaxine**, **Fluoxetine**, and **Sertraline**. Each of these medications is administered orally in their respective pharmaceutical forms. Citalopram is provided in a form coded as PHF00082MIG, with a maximum daily dose of 20 mg and a total dose of 1960 mg over the treatment period. Paroxetine, also in the PHF00082MIG form, has a maximum daily dose of 62.5 mg and a total dose of 6125 mg. Venlafaxine is administered in the PHF00209MIG form, with a maximum daily dose of 225 mg and a total dose of 22050 mg. Fluoxetine and Sertraline are both provided in the PHF00006MIG form, with maximum daily doses of 60 mg and 200 mg, respectively, and total doses of 5880 mg and 19600 mg over the treatment period. Each of these medications is chemically derived and not formulated for paediatric use.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial is designed to assess the efficacy of Ulotaront as an adjunctive therapy in adults with Major Depressive Disorder who have shown an inadequate response to an 8-week trial of the assigned open-label antidepressant therapy.

Efficacy in this clinical trial will be assessed by evaluating the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from the end of Phase A (Week 8 visit) to the end of Phase B (Week 14 visit). The MADRS is a widely used and validated scale for assessing the severity of depressive episodes in patients with Major Depressive Disorder (MDD). This primary endpoint will provide a quantitative measure of symptom improvement in participants receiving SEP-363856 as adjunctive therapy compared to placebo.