Safety and Tolerability Study of Single-dose Administration of Brexpiprazole in Adult Subjects With Schizophrenia

Study Overview
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Brief Summary
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To determine the pharmacokinetics, safety and tolerability of brexpiprazole administered subcutaneously or intramuscularly in adults with schizophrenia.

Detailed Description
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This trial is designed to assess the pharmacokinetics, safety and tolerability of brexpiprazole in the treatment of subjects with schizophrenia. The trial will consist of two parts across 13-36 months. The trial population will include approximately 110 male & female subjects between 18 and 64 years of age (inclusive) with a diagnosis of schizophrenia as defined by DSM-V criteria.

Official Title
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A Phase 1, Two-part, Open-label, Randomized, Exploratory and Single Ascending Dose, Parallel Arm Trial to Determine the Pharmacokinetics, Safety, and Tolerability of Brexpiprazole Long-acting Injectable Administered Subcutaneously or Intramuscularly in Adult Subjects With Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Brexpiprazole, OPDC-34712


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females between 18 and 64 years of age, inclusive, at the screening visit with a diagnosis of schizophrenia as defined by DSM-V criteria. Body mass index between 18 and 35 kg/m^2 at the screening visit. Good physical health as determined by no clinically significant deviation from normal. Ability to provide informed consent and/or consent obtained from a legally acceptable representative (as required by IRB), prior to the initiation of any protocol-required procedures. Male and female subjects who are surgically sterile, female subjects who have been postmenopausal for at least 12 consecutive months prior to the screening visit, or male subjects/female subjects (of childbearing potential) who agree to remain abstinent or to practice 2 of the approved birth control methods from the screening visit and for at least 150 days after the dose of IMP for a female subject or 180 days after the dose of IMP for a male subject. Exclusion Criteria: Subjects who have: Met DSM-V criteria for substance use disorder within the past 180 days; including alcohol and benzodiazepines, excluding caffeine/nicotine. A positive drug screen for drugs of abuse (excluding stimulants, other prescribed medications, and marijuana [if in investigator's documented opinion the subject does not meet DSM-V criteria for substance use disorder]). Use of more than 1 psychotropic medication at the screening or baseline visit, except for oral brexpiprazole administered during the brexpiprazole tolerability testing (if applicable) and current oral antipsychotic medication. Use of varenicline beyond screening. Subjects who have participated in any clinical trial involving a psychotropic medication within 1 month prior to the administration of IMP or 5 half-lives from last IMP administration whichever is longer. Subjects who have a significant risk of committing suicide based on history, routine psychiatric status examination, investigator's judgment, or who have an answer of yes on questions 4 or 5 on the Baseline Version of the C-SSRS. Subjects currently in an acute relapse of schizophrenia as assessed by the investigator. Subjects with a current DSM-V diagnosis other than schizophrenia. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Single Dose Injection: Subcutaneous<br>Drug: Brexpiprazole, OPDC-34712 Once, subcutaneous | Drug: Brexpiprazole, OPDC-34712<br> <br> |
| Experimental: Part A: Single Dose Injection: Intramuscular<br>Drug: Brexpiprazole, OPDC-34712 Once, subcutaneous | Drug: Brexpiprazole, OPDC-34712<br> <br> |
| Experimental: Part B: Cohort 1<br>Drug: Brexpiprazole, OPDC-34712 Once, SC or IM | Drug: Brexpiprazole, OPDC-34712<br> <br> |
| Experimental: Part B: Cohort 2<br>Drug: Brexpiprazole, OPDC-34712 Once, SC or IM | Drug: Brexpiprazole, OPDC-34712<br> <br> |
| Experimental: Part B: Cohort 3<br>Drug: Brexpiprazole, OPDC-34712 Once, SC or IM | Drug: Brexpiprazole, OPDC-34712<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Suicidality via Columbia-Suicide Severity Rating Scale | Baseline version and Since Last Visit version of CSSRS will be completed by trained trial center staff | Part A: Screening to Day 182; Part B: Screening to Day 126 | 
| Number of reported Adverse Events (AE) |  | Part A: 182 days; Part B: 126 days | 
| Clinical Laboratory Tests | Hematology, serum chemistry, urinalysis, drug screen, etc. will be performed. | Part A: 182 days; Part B: 126 days | 
| Change in physical exam results | Investigator or designee will perform complete physical exam and document any clinically significant conditions. Body height and weight will also be measured for BMI calculation and weight will be measured as part of all subsequent physical exams. | Part A: Screening to Day 182; Part B: Screening to Day 126 | 
| Change in Systolic/Diastolic blood pressure from screening to end of study | Heart rate and body temperature will also be obtained prior to PK blood draws and ECG. | Part A: Screening to Day 182; Part B: Screening to Day 126 | 
| ECG Reading | 12-lead ECG will be collected in triplicate (5 minutes apart). heart rate, ventricular rate, RR interval, PR interval, QRS duration and QT intervals will be recorded. QTcF and corrected QT interval using Bazett's formula will be calculated. | Part A: 182 days; Part B: 126 days | 
| Extrapyramidal Symptoms (EPS) Rating Scale | SAS, AIMS & BARS will be assess by trained trial center staff | Part A: 182 days; Part B: 126 days | 
| Investigator's assessment of injection site | Injection site will be assessed. Injection site will also be inspected for seepage after needle is withdrawn. | Part A: 182 days; Part B: 126 days | 
| Visual analog scale (VAS) scores for pain reception |  | Part A: 182 days; Part B: 126 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum peak plasma concentration (Cmax) [Pharmacokinetics] | Samples will also be collected on Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112, 126, 154, and 182/ET or until plasma concentrations of brexpiprazole are BLQ, whichever is longer based on monthly PK sampling (samples will be collected between 8 AM and 2 PM on the indicated nondosing day). If a PK blood sample cannot be drawn at the designated time on Day 1, a window of ± 15 minutes for each blood draw is acceptable with the exact time recorded. PK parameters will be assessed for plasma brexpiprazole and its metabolite(s) including DM-3411. | Day 1 (predose [within 2 hours prior to dosing] and 4, 8 , and 12 hours postdose) | 
| Time of Cmax (tmax) [Pharmacokinetics] | Samples will also be collected on Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112, 126, 154, and 182/ET or until plasma concentrations of brexpiprazole are BLQ, whichever is longer based on monthly PK sampling (samples will be collected between 8 AM and 2 PM on the indicated nondosing day). If a PK blood sample cannot be drawn at the designated time on Day 1, a window of ± 15 minutes for each blood draw is acceptable with the exact time recorded. PK parameters will be assessed for plasma brexpiprazole and its metabolite(s) including DM-3411 | Day 1 (predose [within 2 hours prior to dosing] and 4, 8 , and 12 hours postdose) | 
| Area under the concentration-time curve (AUC) from time zero to time t (Last observable concentration; AUCt) [Pharmacokinetics] | Samples will also be collected on Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112, 126, 154, and 182/ET or until plasma concentrations of brexpiprazole are BLQ, whichever is longer based on monthly PK sampling (samples will be collected between 8 AM and 2 PM on the indicated nondosing day). If a PK blood sample cannot be drawn at the designated time on Day 1, a window of ± 15 minutes for each blood draw is acceptable with the exact time recorded. PK parameters will be assessed for plasma brexpiprazole and its metabolite(s) including DM-3411 | Day 1 (predose [within 2 hours prior to dosing] and 4, 8 , and 12 hours postdose) | 
| AUC from time zero to infinity (AUC∞) [Pharmacokinetics] | Samples will also be collected on Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112, 126, 154, and 182/ET or until plasma concentrations of brexpiprazole are BLQ, whichever is longer based on monthly PK sampling (samples will be collected between 8 AM and 2 PM on the indicated nondosing day). If a PK blood sample cannot be drawn at the designated time on Day 1, a window of ± 15 minutes for each blood draw is acceptable with the exact time recorded. PK parameters will be assessed for plasma brexpiprazole and its metabolite(s) including DM-3411 | Day 1 (predose [within 2 hours prior to dosing] and 4, 8 , and 12 hours postdose) | 
| Terminal-phase elimination half-life (t1/2,z) [Pharmacokinetics] | Samples will also be collected on Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112, 126, 154, and 182/ET or until plasma concentrations of brexpiprazole are BLQ, whichever is longer based on monthly PK sampling (samples will be collected between 8 AM and 2 PM on the indicated nondosing day). If a PK blood sample cannot be drawn at the designated time on Day 1, a window of ± 15 minutes for each blood draw is acceptable with the exact time recorded. PK parameters will be assessed for plasma brexpiprazole and its metabolite(s) including DM-3411 | Day 1 (predose [within 2 hours prior to dosing] and 4, 8 , and 12 hours postdose) | 
| Apparent clearance of drug from plasma after extravascular administration (CL/F; brexpiprazole only) [Pharmacokinetics] | Samples will also be collected on Days 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 98, 112, 126, 154, and 182/ET or until plasma concentrations of brexpiprazole are BLQ, whichever is longer based on monthly PK sampling (samples will be collected between 8 AM and 2 PM on the indicated nondosing day). If a PK blood sample cannot be drawn at the designated time on Day 1, a window of ± 15 minutes for each blood draw is acceptable with the exact time recorded. PK parameters will be assessed for plasma brexpiprazole and its metabolite(s) including DM-3411 | Day 1 (predose [within 2 hours prior to dosing] and 4, 8 , and 12 hours postdose) |