A Clinical Trial to Evaluate the Efficacy and Safety of SEP-363856 in Acutely Psychotic People With Schizophrenia, Followed by an Open-label Extension Phase

A Phase 2/3 Randomized, Double-blind, Parallel-group, Placebo-controlled, Fixed-dose, Multicenter Study to Evaluate the Efficacy and Safety of SEP-363856 in Acutely Psychotic Patients with Schizophrenia, Followed by an Open-label Extension Phase.

The double-blind phase is to evaluate the efficacy and safety of 2 doses of SEP-363856 (50 and 75 mg/day) versus placebo over 6 weeks in acutely psychotic patients with schizophrenia. This phase is projected to randomize approximately 480 subjects to 3 treatments (SEP-363856 50 mg/day, SEP-363856 75 mg/day, placebo) in a 1:1:1 ratio. The completers of the double-blind phase will be able to enroll into the 12-week open-label phase during which the long term safety and effectiveness of-SEP 363856 will be evaluated.

• SEP-363856 50 mg (Drug): Subjects will take one tablet of study drug per day at approximately the same time each evening at bedtime. Study drug may be taken orally with or without food.
• SEP-363856 75 mg (Drug): Subjects will take one tablet of study drug per day at approximately the same time each evening at bedtime. Study drug may be taken orally with or without food.
• Placebo (Drug): Subjects will take one tablet of study drug per day at approximately the same time each evening at bedtime. Study drug may be taken orally with or without food.

Primary outcomes

• Change from Baseline in Positive and negative syndrome scale (PANSS) total score at Week 6 [Week 6]: PANSS is comprised of 30 items and 3 subscales (Positive, Negative, General Psychopathology). An anchored Likert scale from 1 - 7, where values of 2 and above indicate the presence of progressively more severe symptoms, is used to score each item. Individual items are then summed to determine scores for the 3 subscales, as well as a total score. PANSS Positive subscale score range: 7-49. PANSS Negative subscale score range: 7-49. PANSS General Psychopathology subscale score range: 16-112. PANSS total score range: 30-210.

Secondary outcomes

• Change from Baseline in Clinical Global Impressions - Severity (CGI-S) score at Week 6 [Week 6]: The CGI-S is a single-item clinician-rated assessment of the subject's current illness state on a 7-point scale (score range: 1-7), where a higher score is associated with greater illness severity.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

1. Must be fully informed of and understand the objectives, procedures, and possible benefits and risks of the study, and give written informed consent prior to performing any study related activities. If the subject is considered a minor according to local regulations at the time of collection of the informed consent, written consent will be obtained from a legally acceptable representative (guardian) in addition to that obtained from the subject.
2. Male or female between 18 to 65 years of age (inclusive) at the time of consent.
3. Must meet DSM 5 criteria for schizophrenia as established by clinical interview at Screening
4. Must have a CGI S score ≥ 4 (moderately ill) at Screening and Baseline.
5. Must have a PANSS total score ≥ 80 and a PANSS item score ≥ 4 (moderate) on 2 or more of the following PANSS items: delusions (P1), conceptual disorganization (P2), hallucinations (P3), and unusual thought content (G9) at Screening and Baseline.
6. Must have an acute exacerbation of psychotic symptoms (no longer than 2 months prior to providing informed consent for this study). The acute exacerbation should include:

   a. Marked deterioration of functioning in one or more areas, such as occupational, social, or personal care or hygiene.
7. In the opinion of the Investigator, subjects must be generally healthy based on Screening medical history, physical examination (PE), vital signs, ECG, and clinical laboratory values (hematology, chemistry, and urinalysis).

Exclusion Criteria:

1. Have a DSM 5 diagnosis or presence of symptoms consistent with a DSM 5 diagnosis other than schizophrenia. Exclusionary disorders include but are not limited to alcohol use disorder (within past 12 months), substance (other than nicotine or caffeine) use disorder within past 12 months, or lifetime history of significant substance abuse that, in the opinion of the Investigator, may have had a significant and potentially permanent impact on the brain or other body systems, major depressive disorder, bipolar I or II disorder, schizoaffective disorder, obsessive compulsive disorder, and posttraumatic stress disorder. Symptoms of mild to moderate mood dysphoria or anxiety are allowed so long as these symptoms have not been a focus of primary treatment
2. At significant risk of harming self, others, or objects based on Investigator's judgment.
3. Have any clinically significant unstable medical condition or any clinically significant chronic disease that in the opinion of the Investigator, would limit the subject's ability to complete and/or participate in the study.
4. Female subjects who are pregnant or lactating.
5. Have any clinically significant abnormal laboratory value(s) at Screening (hematology, chemistry, and urinalysis) as determined by the Investigator.