Trial to Evaluate the Effects of OPC-34712 on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder

Study Overview
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Brief Summary
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The purpose of this study is to establish pharmacodynamics (PD), pharmacokinetics (PK), and adverse event (AE) profile of OPC-34712 administered to schizophrenic/schizoaffective subjects. The goals of this trial are three-fold: To determine the effect of OPC-34712 on the individual QT interval (QTcI) corrected for placebo To determine the effect of moxifloxacin on QTcI To examine the concentration-effect relationship of OPC-34712 and moxifloxacin on QTcI

Official Title
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A Parallel-arm, Double-blind, Placebo and Positive Controlled Multiple Oral Dose Administration Trial to Evaluate the Effects of OPC-34712 on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder

Conditions
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Schizophrenia, Schizoaffective Disorder

Intervention / Treatment
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* Drug: OPC-34712 (4mg)
* Drug: Moxifloxacin
* Drug: OPC-34712 (12mg)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects between 18 and 55 years of age, inclusive, with a diagnosis of schizophrenia or schizoaffective disorder as defined by DSM-IV-TR criteria. Body mass index of 19 to 35 kg/m2. Exclusion Criteria: Females who are pregnant or lactating. A negative serum pregnancy test must be confirmed prior to the first dose of trial medication for all female subjects. Subjects presenting with a first episode of schizophrenia or schizoaffective disorder based on the clinical judgment of the investigator. Subjects who have received continuous medication therapy to treat schizophrenia or schizoaffective disorder for less than 6 months prior to washout. Subjects with schizophrenia or schizoaffective disorder that are considered resistant/refractory to antipsychotic treatment by history, who have a history of failure to clozapine, or who are responsive only to clozapine treatment. Subjects with a current DSM-IV-TR Axis I diagnosis other than schizophrenia or schizoaffective disorder. Hospitalization for an exacerbation of schizophrenia or schizoaffective disorder within 3 months prior to randomization. Subjects who have a history of or who have evidence of other medical and/or neurological conditions that would expose them to an undue risk of a significant AE or interfere with assessments of safety or efficacy during the course of the trial. Subjects with a history of neuroleptic malignant syndrome. Subjects with a history of seizure disorder. Subjects who meet DSM-IV-TR criteria for substance dependence within 6 months prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1 (OPC-34712, placebo)<br>Arm 1 will be administered 4 mg OPC-34712 once daily (QD) for 11 days and OPC-34712 placebo for 1 day. | Drug: OPC-34712 (4mg)<br>* Arms assigned to this intervention receive 4mg.<br>Drug: Placebo<br>* OPC-34712 placebo<br>|
| Active Comparator: Arm 2 (OPC-34712, placebo)<br>Arm 2 will be administered 12 mg OPC-34712 QD for 11 days and OPC-34712 placebo for 1 day. | Drug: OPC-34712 (12mg)<br>* Arms assigned to this intervention receive 12mg.<br>Drug: Placebo<br>* OPC-34712 placebo<br>|
| Active Comparator: Arm 3 (moxifloxacin, placebo)<br>Arm 3 will be administered 400 mg moxifloxacin (positive control) plus OPC-34712 placebo for 1 day and OPC-34712 placebo QD for 11 days. | Drug: Moxifloxacin<br>* Arms assigned to this intervention will receive 400mg.<br>Drug: Placebo<br>* OPC-34712 placebo<br>|
| Active Comparator: Arm 4 (moxifloxacin, placebo)<br>Arm 4 will be administered OPC-34712 placebo QD for 11 days and 400 mg moxifloxacin (positive control) plus OPC-34712 placebo for one day. | Drug: Moxifloxacin<br>* Arms assigned to this intervention will receive 400mg.<br>Drug: Placebo<br>* OPC-34712 placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-matched QTcI Change From Baseline (Day -1) Corrected for Placebo on Day 11 Following Brexpiprazole Treatment. | Pharmacodynamics endpoint is the time-matched corrected QT interval (QTcI) change from baseline (Day -1) corrected for placebo on Day 11 following brexpiprazole treatment. The primary QT to QTc correction formula (QTcI) was determined for each participant using the participant's baseline (Day -1 placebo) ECG data. The QT correction formula QT / (RR)k was derived using log-log-linear regression, where log (QT) = a + k × log (RR) + ε to estimate the exponent (k). | Day 11 (Hours 1, 2, 3, 4, 5, 6, 8, 12, 16, 24) | 
| Number of Participants With Adverse Events (AE) and Clinically Important Changes in Vital Signs, Physical Examinations, Laboratory Tests, and Standard ECGs (Electrocardiogram). | Clinically important changes in vital signs, physical examinations, laboratory tests and ECGs were by and large reflected in AE/SAE (which are presented in safety section) of this report. | AEs were recorded from Screening (informed consent was signed) during the 12-day treatment period to follow-up 30 (+ 2) days post-last dose of study medication | 
| Maximum Peak Plasma Concentration (Cmax) of Brexpiprazole and Moxifloxacin. | Pharmacokinetics endpoint is the maximum (peak) plasma concentration (Cmax) of brexpiprazole and moxifloxacin. Values for Cmax were determined directly from the observed data. Blood samples were collected on Days -1, 1, 11, and 12 at predose, and 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours postdose or at ET. | Day 11 | 
| Time to Maximum (Peak) Plasma Concentration (Tmax) of Brexpiprazole and Moxifloxacin. | Pharmacokinetics endpoint is the time to maximum (peak) plasma concentration (tmax) of brexpiprazole and moxifloxacin. Values for tmax were determined directly from the observed data. Blood samples were collected on Days -1, 1, 11, and 12 at predose, and 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours postdose or at ET. | Day 11 | 
| Area Under the Plasma Concentration-time Curve During Dosing (AUCT). | Pharmacokinetics endpoint is the area under the concentration-time curve from time zero to 24 hours (AUC0-24h) of brexpiprazole and moxifloxacin. Area under the plasma concentration-time curve during the dosing interval at steady-state (AUCT) value was estimated using the linear trapezoidal rule; the value reported represent the area under the curves to the last time point during that day. Blood samples were collected on Days -1, 1, 11, and 12 at predose, and 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours postdose or at ET. | Day 11 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Noted With Time-matched Change in Mean QTcI Change From Baseline for Assay Sensitivity of Moxifloxacin Treatment Corrected for Placebo at Day 11. | New onset (> 450, > 480, or > 500 msec) in QTc was defined as a participant who attained a QTc > 450, > 480, > 500 msec during Day 11 but not on Day -1. The number of participants were noted with time-matched change in mean QTcI change from Baseline for assay sensitivity of moxifloxacin treatment corrected for placebo. The primary QT to QTc correction formula (QTcI) were determined for each participant using the participant's Baseline (Day -1 placebo) ECG data. The QT correction formula QT / (RR)k were derived using log-log-linear regression, where log (QT) = a + k × log (RR) + ε to estimate the exponent (k). | Baseline, Day 11 | 
| Change From Baseline in Summary of Maximum QTcI on Day 11 Minus Mean QTcI on Day -1 (Baseline). | The primary QT to QTc correction formula (QTcI) were determined for each participant using the participant's Baseline (Day -1 placebo) ECG data. The QT correction formula QT / (RR)k were derived using log-log-linear regression, where log (QT) = a + k × log (RR) + ε to estimate the exponent (k). The change form Baseline in summary of maximun QTcI on Day 11 minus mean QTcI on Day -1 (Baseline) is presented here. | Baseline, Day 11 | 
| Change From Baseline in Summary of Maximum QTcI on Day 11 Minus Maximum QTcI on Day -1 (Baseline). | The primary QT to QTc correction formula (QTcI) were determined for each participant using the participant's Baseline (Day -1 placebo) ECG data. The QT correction formula QT / (RR)k were derived using log-log-linear regression, where log (QT) = a + k × log (RR) + ε to estimate the exponent (k). The change from Baseline in summary of maximum QTcI on Day 11 minus maximum QTcI on Day -1 (Baseline) is presented here. | Baseline, Day 11 | 
| Number of Participants With QTcI Interval Between 30 and 60 Msec on Day 11. | The primary QT to QTc correction formula (QTcI) were determined for each participant using the participant's Baseline (Day -1 placebo) ECG data. The QT correction formula QT / (RR)k were derived using log-log-linear regression, where log (QT) = a + k × log (RR) + ε to estimate the exponent (k). Participants with QTcI interval change between 30 to 60 msec were presented here. | Day 11 | 
| Number of Participants With QTcI Interval > 60 Msec on Day 11. | The primary QT to QTc correction formula (QTcI) were determined for each participant using the participant's Baseline (Day -1 placebo) ECG data. The QT correction formula QT / (RR)k were derived using log-log-linear regression, where log (QT) = a + k × log (RR) + ε to estimate the exponent (k). Participants with QTcI interval change of > 60 msec on Day 11 were presented here. | Day 11 | 
| Number Participants Noted With New Incidence of QT Interval of > 500 Msec on Day 11. | The number of participants who were noted with new incidence of QT interval of > 500 msec on Day 11 and a 12-lead ECG was used. | Day 11 | 
| Number of Participants With New Incidence of ECG Morphology Abnormalities on Day 11. | Participants with incidence of ECG morphology abnormalities on Day 11 (participants who had abnormalities during Day 11 but not at Day -1) were noted. Types of abnormalities included appearance of abnormal U waves, negative T waves, elevation of ST segment, depression of ST segment, second degree heart block, third degree heart block, right bundle branch block, and left bundle branch block. ECGs were sampled at predose and approximately 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours postdose on Days -1, 1, 11, and 12. | Day 11 | 
| Number of Participants With Maximum Change From Baseline to the On-treatment ECG Values on Day 11 for Heart Rate (HR), PR Interval, and QRS Interval. | Changes in HR with values 25% decrease from Day -1 and HR < 50 bpm and 25% increase from Day -1 and HR > 100 bpm; PR interval of greater than or equal to 25% change from Day -1 and PR > 200 msec; QRS interval of Greater than or equal to 25% change from Day -1 and > 100 msec were noted on Day 11. Maximum change from baseline to the on-treatment ECG values on Day 11 for heart rate. | Day 11 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, QTc Interval