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
Condition: Depressive Episode; Bipolar 1 Depression
MeSH terms: Depression; Depressive Disorder
Intervention: SEP-4199 200 mg; SEP-4199 400 mg; Placebo
Intervention description: SEP-4199 200 mg/day (supplied in two 100mg tablets); SEP-4199 400 mg/day (supplied in two 200mg tablets; Placebo (supplied in two tablets/day)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: double blind
Enrollment: 344.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Depression, Depressive episode, Bipolar, Bipolar 1, Bipolar 1 depression

Summary:

      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
    

Eligibility criteria:

        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.