A Clinical Trial Study to Determine the Effect of an Investigational Drug (SEP-363856) Has on the Way That the Drug Metformin Travels Through the Body in People With Schizophrenia.

Study Overview
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Brief Summary
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A clinical trial study to determine the effect of an investigational drug (SEP-363856) has on the way that the drug Metformin travels through the body in people with schizophrenia. This clinical trial will have approximately 24 subjects both male and female 18 year of age and older. This study will be conducted in approximately 2 study sites in the United States.

Detailed Description
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This is a randomized, single-blind, two-period crossover study in which each subject will receive both treatments and therefore act as their own control to minimize confounding covariates within the study population. Randomizing subjects to treatment sequence will assist with reducing the potential order effects that might confound the findings if all the subjects received the same treatment sequence. The single-blind method is used to keep subjects blind to treatment assignment throughout the study period, in order to avoid possible influence of the psychological factors of subjects on study assessments. This clinical study will evaluate whether SEP 363856 influences the PK of a concomitantly administered OCT2 substrate, metformin.

Official Title
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A Randomized, Single-blind, Two-period Crossover to Investigate the Effect of SEP-363856 on the Pharmacokinetics of Metformin in Subjects With Schizophrenia.

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: placebo
* Drug: SEP-363856
* Drug: metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subject between 18 and 65 years of age, inclusive, at the time of informed consent. Subject meets Diagnostic and Statistical Manual of Mental Disorders (DSM 5) criteria for a primary diagnosis of schizophrenia as established by clinical interview (using the DSM 5 as a reference and confirmed using the Structured Clinical Interview for DSM 5, Clinical Trials Version [SCID CT]). Subject must have a Clinical Global Impressions - Severity Scale (CGI S) score ≤ 4 (normal to moderately ill) at Screening. Subject must have a Positive and Negative Syndrome Scale (PANSS) total score ≤ 80 at Screening. Subject must have a score of ≤ 4 on the following PANSS items at Screening: P7 (hostility) G8 (uncooperativeness). Subject must have normal to mild symptoms on all individual items of the Simpson-Angus Scale (SAS) (< 2), Abnormal Involuntary Movement Scale (AIMS) (< 3) and Barnes Akathisia Rating Scale (BARS) (< 3) at Screening. Subject has been taking an antipsychotic for at least six weeks prior to Screening and has had no change in antipsychotic medication(s) (minor dose adjustments for tolerability purposes may be permitted after Medical Monitor and Sponsor review) for at least six weeks prior to Screening. Exclusion Criteria: 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, including any clinically significant hematological (including deep vein thrombosis) or bleeding disorder, renal, metabolic, endocrine, pulmonary, gastrointestinal, urological, cardiovascular, hepatic, neurologic or allergic disease (except for untreated seasonal allergies that are asymptomatic at the time of dosing). Subject has a disorder or history of a condition, or previous gastrointestinal surgery (eg, cholecystectomy, vagotomy, bowel resection) that may interfere with drug absorption, distribution, metabolism, excretion, gastrointestinal motility, or pH, or a history of clinically significant abnormality of the hepatic or renal system, or a history of malabsorption (uncomplicated cholecystectomy, appendectomy, and hernia repair will be acceptable). Subject has 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, 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 are not the primary focus of treatment. Subject answers yes to Suicidal Ideation Items 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 Columbia-Suicide Severity Rating Scale (C SSRS) at Screening (ie, in the past 1 month) or at any subsequent C SSRS assessment prior to dosing (ie since last visit).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a randomized, single-blind, two-period crossover study in adults with schizophrenia
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo and metformin<br>single dose of placebo + single dose of metformin-HCl 850 mg (approximately 663 mg metformin) (placebo will be dosed 1 hour prior to metformin administration) | Drug: placebo<br>* single dose of placebo<br>Drug: metformin<br>* metformin-HCl 850 mg<br>|
| Experimental: SEP-363856 and metformin<br>single dose of SEP 363856 100 mg + single dose of metformin-HCl 850 mg (SEP 363856 will be dosed 1 hour prior to metformin administration) | Drug: SEP-363856<br>* single dose of SEP 363856 100 mg<br>Drug: metformin<br>* metformin-HCl 850 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve | area under the plasma concentration-time curve from time zero to infinity (AUC0 ∞) or area under the plasma concentration-time curve from time zero to a defined time (AUC0-t), if appropriate | 72 hours | 
| • maximum observed plasma concentration | maximum observed plasma concentration (Cmax). | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| area under the plasma concentration-time curve | area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUC0-last) | 72 hours | 
| time of the maximum observed plasma concentration | time of the maximum observed plasma concentration (tmax) | 72 hours | 
| time of last quantifiable concentration | time of last quantifiable concentration (Tlast) | 72 hours | 
| • percentage of extrapolated AUC0-∞ | percentage of extrapolated AUC0-∞ (%AUCextrap) | 72 hours | 
| terminal elimination half-life | terminal elimination half-life(T1/2) | 72 hours | 
| apparent clearance | apparent clearance (CL/F) | 72 hours | 
| apparent volume of distribution | apparent volume of distribution (VZ/F) | 72 hours | 
| amount excreted in urine | amount excreted in urine (Ae) | 72 hours | 
| percentage excreted in urine | percentage excreted in urine (Fe) | 72 hours | 
| renal clearance | renal clearance (CLR) | 72 hours |