A Study to Evaluate the Efficacy, Safety and Tolerability of SEP-363856 in Subjects With Parkinson's Disease Psychosis

This is a multicenter, randomized, parallel-group, placebo-controlled study evaluating the efficacy, safety, and tolerability of double-blind SEP-363856 flexibly dosed at 25, 50, or 75 mg/day for 6 weeks followed by 12 weeks of open-label extension of SEP-363856 flexibly-dosed at 25, 50, or 75 mg/day in male and female subjects ≥ 55 years of age with a clinical diagnosis of PDP. The study will randomize approximately 36 subjects to 2 treatment groups in a 2:1 ratio (approximately 24 subjects to SEP-363856 and 12 to placebo). The study will consist of 4 periods: Screening/Washout Period (up to 14 days prior to Double-blind Treatment), Double-blind Treatment Period (6 weeks), Open-label SEP-363856 Treatment Period (12 weeks), and Follow-up Period (1 week after last dose) as shown in the following figure. All postBaseline clinic visits will have a window of ± 2 days relative to the date of the Baseline visit (Visit 3).

Inclusion criteria

• Subject, caregiver, and/or legally authorized representative understands and is willing to sign informed consent to participate in the study.
• Subject must be willing and able to comply with the study procedures and visit schedules and must be able to follow verbal and written instructions.
• Subject is male or postmenopausal female ≥ 55 years of age.
• Subject meets established diagnostic criteria for Parkinson's disease of at least one year duration, consistent with the UK Brain Bank criteria
• Subject has psychotic symptoms that began after the diagnosis of PD for at least one month, occurring at least weekly in the month prior to screening (according to subject or caregiver), and severe enough to warrant treatment with antipsychotics.
• Subject has a combined score of at least 6 or an individual score of at least 4 on the neuropsychiatric inventory (NPI) Item A (delusions) and/or Item B (hallucinations). This crieterion must be met at Visit 1 and Visit 3.
• Subject has a Mini-mental status examination (MMSE) score > 21 points out of 30.
• Subject has a caregiver (spouse or family member) who will be required to attend all visits and is able to provide study information on various scales such as the NPI.
• Subject is taking antiparkinsonian drugs or deep brain stimulation, with a stable dose/dose regimen and settings for 3 months before enrolment.
• Female subject must be postmenopausal defined as being amenorrheic for greater than two years with an appropriate clinical profile.
• Male subjects with female partner(s) of childbearing potential must agree to avoid fathering a child and use acceptable methods of birth control from screening until at least 30 days after the last study drug administration.
• Subject is, in the opinion of the Investigator, medically stable based on screening medical history, PE, neurological examination, vital signs, clinical laboratory values (hematology, serum chemistry, urinalysis, lipid panel, coagulation panel, thyroid panel, and serum prolactin).
• Subject has had a stable living arrangement at the time of screening.

Exclusion criteria

• Subject has psychosis secondary to other toxic or metabolic disorders.
• Subject has atypical Parkinson's disease, Parkinsonism secondary to medication or other neurodegenerative disorders, such as progressive supranuclear palsy or multiple system atrophy.
• Subject has dementia diagnosed concurrent with or before Parkinson's disease, motor symptoms that began less than one year before the onset of dementia or symptoms consistent with the diagnosis of lewy body dementia (LBD), or if the psychosis occurred after ablative stereotaxic surgery.
• Subject failed 2 or more antipsychotic agents given at adequate doses for at least 4 weeks within 1 year before screening.
• Subject has had a stroke or other uncontrolled serious medical or neurological illness within 6 months of baseline.
• Subject 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 at Screening (ie, in the past one month), or baseline (ie, since last visit).
• Subject does not tolerate venipuncture or has poor venous access that would cause difficulty for collecting blood samples.
• Subject has participated in an investigational drug study and received investigational drug within 30 days (or longer if the half-life is known to be ≥ 150 hours) prior to the screening visit, or who is currently participating in another clinical study. Subject has previously received SEP 363856.
• Subject has 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:
• Subject has hematological (including deep vein thrombosis) or bleeding disorder, renal, metabolic, endocrine, pulmonary, gastrointestinal, urological, cardiovascular, hepatic, neurologic, or allergic disease that is clinically significant or unstable (except for untreated, asymptomatic, seasonal allergies at time of dosing).
• Subject has a history of cancer or significant neoplasm.
• Subject has a disorder or history of a condition or previous gastrointestinal surgery (eg, cholecystectomy, vagotomy, bowel resection, or any surgical procedure) that may interfere with drug absorption, distribution, metabolism, excretion, gastrointestinal motility, or pH, or a clinically significant abnormality of the hepatic or renal system, or a history of malabsorption.
• Subject has Alcohol or Substance Abuse Disorder (DSM 5 criteria). The only exceptions are caffeine or nicotine.
• Subject has a clinically significant abnormal 12 lead ECG that may jeopardize the subject's ability to complete the study or a screening 12 lead ECG demonstrating any one of the following: heart rate > 100 beats per minute, QRS > 120 ms, QT interval corrected for heart rate using Fridericia's formula (QTcF) > 450 ms (males), QTcF > 470 ms (females), or PR > 220 ms.
• Subjects with known human immunodeficiency virus (HIV) seropositivity will be excluded.
• Female subject who is pregnant or lactating.
• Subject has a presence or history of a medically diagnosed, clinically significant psychiatric disorder.
• Subject is at significant risk of harming him/herself or others according to the Investigator's judgment.
• Subject has attempted suicide within 3 months prior to screening.
• Subject has a history of allergic reaction or suspected sensitivity to any substance that is contained in the formulation.
• Subject has any clinically significant abnormal laboratory values (hematology, serum chemistry, urinalysis, lipid panel, coagulation panel, thyroid panel, serum prolactin, and urine drug screen(Note: abnormal findings that may be clinically significant or of questionable significance will be discussed with the Medical Monitor prior to including subject).
• Subjects with serum alanine transaminase (ALT) or aspartate transaminase (AST) levels ≥ 3 times, serum blood urea nitrogen (BUN) or creatine ≥ 1.5 X the upper limit of the reference ranges provided by the central laboratory require retesting. If on retesting, the laboratory value remains equal to or above the ULN, the subject will be excluded.
• Subjects with a random (non-fasting) blood glucose at screening ≥ 200 mg/dL (11.1 mmol/L) and HbA1c ≥ 6.5% will be excluded.
• Subject has a prolactin concentration > 100 ng/mL at screening or has a history of pituitary adenoma.
• Subject's BMI is ≥ 30 mg/kg/m2.
• Subject has experienced significant blood loss (≥ 473 mL) or donated blood within 60 days prior to first dose of study drug; has donated plasma within 72 hours prior to the first dose of study drug or intends to donate plasma or blood or undergo elective surgery during study participation or within 60 days after the last study visit.
• Subject consumes more than 300 mg of caffeine per day (5 cups of coffee or equivalent in caffeinated beverages).
• Subject has used disallowed prescription medications or anticipates the need for any disallowed medication during their participation in this study. Subject is a staff member or the relative of a staff member.
• Subject is in the opinion of the Investigator, unsuitable in any other way to participate in this study.

Continuation into Open-label Extension Cirteria

• Subject must have completed the 6-week double-blind treatment.
• Subject has not taken any medication other than the study drug for the purpose of controlling PDD symptoms

. • There has been no clinically significant change in the subject's medical condition or Parkinson's disease, in the opinion of the investigator.

• Subject has not answered "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 any time during the DB treatment period.