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

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.

Time frame: Day 11

Population: PK analysis dataset consisted of all evaluable PK parameters from randomized participants who had plasma concentrations. For Moxifloxacin group, area under the plasma concentration-time curve was calculated to the last observable concentration.

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.

Time frame: Day 11

Population: Pharmacokinetics (PK) analysis dataset consisted of all evaluable PK parameters from randomized participants who had plasma concentrations.

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.

Time frame: 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

Population: Safety dataset of randomized participants received 1 dose of study medication after Day 1.

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).

Time frame: Day 11 (Hours 1, 2, 3, 4, 5, 6, 8, 12, 16, 24)

Population: The dataset quantitates effect of brexpiprazole on individual QTcI corrected for placebo of the completer population where participants received study medication from Day 1 to Day 11 (placebo at Day 1) had 1 Predose and Post-dose time-matched ECG assessments on Day 1 and Day 11. The first 5 time points for moxifloxacin arm only were 2-sided 98% CI.

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.

Time frame: Day 11

Population: PK analysis dataset consisted of all evaluable PK parameters from randomized participants who had plasma concentrations.

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.

Time frame: Baseline, Day 11

Population: Assay sensitivity dataset demonstrated the effect of moxifloxacin on QTcI from randomized participants in moxifloxacin and placebo arms who had evaluable time-matched ECG assessments on Days -1, 1, 11, and 12. Number of participants analyzed included those who had observations in QTc at both Days -1 and 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). The change form Baseline in summary of maximun QTcI on Day 11 minus mean QTcI on Day -1 (Baseline) is presented here.

Time frame: Baseline, Day 11

Population: Assay sensitivity dataset shows the effect of moxifloxacin on QTcI from randomized participants in moxifloxacin and placebo arms who had evaluable time-matched ECG assessments on Days -1, 1, 11, and 12. Number of participants analyzed were total number of participants with both Baseline and at least one observation of the given parameter.

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).

Time frame: Baseline, Day 11

Population: Assay sensitivity dataset demonstrated the effect of moxifloxacin on QTcI from randomized participants in moxifloxacin and placebo arms who had evaluable time-matched ECG assessments on Days -1, 1, 11, and 12. Number of participants analyzed included those who had observations in QTc at both Days -1 and 11.

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.

Time frame: Day 11

Population: Electrocardiograms 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.

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.

Time frame: Day 11

Population: Number of participants who took at least one dose of study drug post Day -1, and had evaluations of the ECG parameters at Baseline and Post 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). Participants with QTcI interval change of \> 60 msec on Day 11 were presented here.

Time frame: Day 11

Population: Assay sensitivity dataset demonstrated the effect of moxifloxacin on QTcI from randomized participants in moxifloxacin and placebo arms who had evaluable time-matched ECG assessments on Days -1, 1, 11, and 12. Number of participants analyzed included those who had observations in QTc at both Days -1 and 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.

Time frame: Day 11

Population: Assay sensitivity dataset shows the effect of moxifloxacin on QTcI from randomized participants in moxifloxacin and placebo arms who had evaluable time-matched ECG assessments on Days -1, 1, 11, and 12. Number of participants analyzed were total number of participants with both Baseline and at least one observation of the given parameter.

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.

Time frame: Day 11

Population: Assay sensitivity sample dataset demonstrated the ability of the trial that detected the effect of moxifloxacin on the QTcI that consisted from randomized participants in moxifloxacin and placebo arms, who had evaluable time-matched ECG assessments in both periods (Day -1/1 or Day 11/12) in placebo and moxifloxacin on Days -1, 1, 11, and 12.