A Clinical Study to Test the Effectiveness of an Investigational Drug to Treat People That Have Major Depressive Episodes When They Have Bipolar 1 Depression

This is a randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study designed to evaluate the efficacy, safety, and tolerability of treatment with SEP-4199 monotherapy given as 200 mg/day or 400 mg/day compared with placebo for the treatment of major depressive episodes associated with bipolar I disorder (bipolar I depression).

Inclusion criteria

• Subject is 18 to 65 years of age, inclusive, at the time of informed consent with bipolar I disorder, current episode depressed with or without rapid cycling disease course (≥ 4 episodes of mood disturbance but < 8 episodes in the previous 12 months) with or without psychotic features (diagnosed by DSM 5 criteria, and confirmed by the SCID 5 CT). The current episode of major depression associated with bipolar I disorder must be confirmed by the Investigator and noted in the source records.
• Subject provides written informed consent and is willing and able to comply with the protocol in the opinion of the investigator.
• Subject or legally acceptable representative must possess an educational level and degree of understanding of English or the local language that enables them to communicate suitably with the Investigator and the study coordinator.
• Subject must have a lifetime history of at least one bipolar manic or mixed manic episode. It is strongly recommended that a reliable informant (e.g., family member or caregiver) be available to confirm this history.
• Subject's current major depressive episode is ≥ 4 weeks and less than 12 months in duration at Screening.
• Subject has a MADRS total score ≥ 22 at both Screening and Baseline.
• Subject has a YMRS total score ≤ 12 at Screening.
• Female subjects of childbearing potential must have a negative serum ß-hCG test at Screening.
• Females who participate in this study must be . one of the following:

• unable to become pregnant (e.g., postmenopausal, surgically sterile, etc.) -OR-
• Practicing abstinence or part of an abstinent lifestyle
• using and willing to continue using a highly effective form of birth control for at least 28 days prior to administration of the first dose of study drug, during the treatment period, and 2 months after completion or premature discontinuation from the study drug.
• Male subjects with partners of child bearing potential must be practicing abstinence, part of an abstinent life style or using protocol-specified methods of birth control. See Section 10.4 for further information on acceptable methods of birth control.
• Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening.
• Subjects with type 2 diabetes are eligible for study inclusion only if all of the following conditions are met within 30 days prior to Screening:

• Subject's random screening glucose is < 200 mg/dL (11.1 mmol/L).
• Subject's Hemoglobin A1c (HbA1c) ≤ 7.0%.
• If a subject is currently being treated with oral anti-diabetic medication(s), the dose must have been stable for at least 30 days prior to screening. Such medication may be adjusted or discontinued during the study, as clinically indicated.
• Subject has not required hospitalization for diabetes or related complications in the past 12 months.
• Note: Subjects with type 2 diabetes that is newly diagnosed during screening are ineligible for the study.
• Subject who requires concomitant medication treatment with the following agents may be included if they have been on stable doses for the specified times: 1) oral hypoglycemics must be stabilized for at least 30 days prior to baseline; 2) thyroid hormone replacement must be stable for at least 90 days prior to baseline; 3) anti hypertensive agents must be stable for at least 30 days prior to baseline. The subject's medical condition should be deemed clinically stable following consultation with the Medical Monitor as needed.

Exclusion criteria

• Subject has a lifelong history or presence of symptoms consistent with a major psychiatric disorder other than bipolar I disorder as defined by DSM 5. Exclusionary disorders include but are not limited to moderate to severe alcohol use disorder (within past 12 months), substance use disorder (other than nicotine or caffeine) within past 12 months, bipolar II disorder, schizoaffective disorder, obsessive compulsive disorder, posttraumatic stress disorder.
• Subject demonstrates a decrease (improvement) of ≥ 25% in MADRS total score from Screening to Baseline, or subject's MADRS total score is < 22 at Baseline.
• Subject has received treatment with antidepressants within 3 days of randomization, fluoxetine at any time within 28 days, an MAO inhibitor within 21 days or clozapine within 120 days. All other psychotropic medications with the exceptions of lorazepam, temazepam,eszopiclone, zopiclone, zolpidem and zolpidem CR require 3 days minimum washout. Depot neuroleptics must be discontinued at least one treatment cycle prior to randomization.
• Subject has suspected/confirmed Borderline Personality Disorder
• Subject currently has a clinically significant neurological, metabolic (including type 1 diabetes), hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorder such as unstable angina, congestive heart failure (uncontrolled), or central nervous system (CNS) infection that would pose a risk to the subject if they were to participate in the study or that might confound the results of the study. Subjects with a known history of HIV seropositivity will be excluded.

Note: Active medical conditions that are minor or well-controlled are not exclusionary if they do not affect risk to the subject or the study results. In cases in which the impact of the condition upon risk to the subject or study results is unclear, the Medical Monitor should be consulted. Any subject with a known cardiovascular disease or condition (even if under control) must be discussed with the Medical Monitor before being randomized in the study.

• Subject has evidence of any chronic organic disease of the CNS such as tumors, inflammation, active (or history of) seizure disorder, vascular disorder, Parkinson's disease, Alzheimer's disease or other forms of dementia, myasthenia gravis, or other degenerative processes. In addition, subjects must not have a history of intellectual disability or persistent neurological symptoms attributable to serious head injury. Past history of febrile seizure, is not exclusionary.
• Subject has a history of malignancy < 5 years prior to signing the informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Subjects with pituitary tumors of any duration are excluded.
• Subject demonstrates evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of clinically significant impaired hepatic function through clinical and laboratory evaluation (use screening values for laboratory evaluation). Subject has a history of stomach or intestinal surgery or any other condition that could interfere with absorption, distribution, metabolism, or excretion of medications.
• Subject has knowledge of any kind of cardiovascular disorder/condition known to increase the possibility of QT prolongation or history of additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome or Brugada Syndrome) or cardiac conduction disorders, or requires treatment with an antiarrhythmic medication.
• Subject has family history of QTc prolongation or of unexplainable sudden death at < 50 years of age.
• Abnormal 12 lead ECG at Screening, including:

• QTcF > 450 ms (male subjects) or > 470 ms (female subjects)
• QRS > 110 ms
• PR > 200 ms
• Second- or third-degree atrioventricular block
• Any rhythm other than sinus rhythm, which is interpreted by the Investigator to be clinically significant
• Subject has a history of neuroleptic malignant syndrome (NMS).
• Subject exhibits evidence of severe tardive dyskinesia, severe dystonia, or any other severe movement disorder. Severity is to be determined by the investigator.
• Subject has been diagnosed with type 1 diabetes, or insulin-dependent diabetics.
• Subject who has any abnormal laboratory parameter at screening that indicates a clinically significant medical condition as determined by the investigator. Subjects with fasting blood glucose at screening ≥ 126 mg/dL (7.0 mmol/L) will be excluded from the study. Subjects with fasting blood glucose from 100-125 mg/dL (5.6-6.9 mmol/L) may enter the study based on the approval of the Medical Monitor. Subjects with HbA1c > 7.0% will be excluded. Subjects who are found to have been non-fasting at Screening may be allowed if their blood glucose is < 200 mg/dL. Subjects with random (nonfasting) blood glucose at screening ≥ 200 mg/dL (11.1 mmol/L) must be retested in a fasted state. Subjects with HbA1c > 7.0% will be excluded.
• Subject has a prolactin concentration > 100 ng/mL at screening or have a history of pituitary adenoma.
• Subject has a body mass index (BMI) ≥ 40 or < 18 kg/m2.
• Subject has a history of non-response to an adequate (6-week) trial of three or more antidepressants (with or without mood stabilizers) during the current episode.
• Subject is considered by the Investigator to be at imminent risk of suicide or injury to self, others, or answers "yes" to "Suicidal Ideation" item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) on the C-SSRS assessment at the Screening visit (in the past month [30 days]) or Baseline.
• Subject tests positive for drugs of abuse at screening or baseline. In the event a subject tests positive for cannabinoids (tetrahydrocannabinol), the investigator will evaluate the subject's ability to abstain from cannabis during the study. This information will be discussed with the Medical Monitor for study enrollment consideration.
• Subject has a history of hypersensitivity to more than two distinct chemical classes of drug (e.g., sulfas and penicillins).
• Subjects have received depot neuroleptics unless the last injection was at least one treatment cycle before randomization.
• Subject requires treatment with a drug that consistently prolongs the QTc interval
• Subject has received ECT within 90 days prior to randomization or is expected to require ECT during the study course.
• Subject is currently participating, or has participated in a study with an investigational or marketed compound or device within 6 months prior to signing the informed consent, or has participated in 3 or more studies within 18 months prior to signing the informed consent.