Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier:
NCT01423916
First received: August 8, 2011
Last updated: September 29, 2015
Last verified: September 2015
  Purpose

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

Condition Intervention Phase
Schizophrenia
Schizoaffective Disorder
Drug: OPC-34712 (4mg)
Drug: Moxifloxacin
Drug: OPC-34712 (12mg)
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Primary Outcome Measures:
  • Time-matched QTcI Change From Baseline (Day −1) Corrected for Placebo on Day 11 Following Brexpiprazole Treatment. [ Time Frame: Day 11 (Hours 1, 2, 3, 4, 5, 6, 8, 12, 16, 24) ] [ Designated as safety issue: Yes ]
    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).

  • Number of Participants With Adverse Events (AE) and Clinically Important Changes in Vital Signs, Physical Examinations, Laboratory Tests, and Standard ECGs (Electrocardiogram). [ 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 ] [ Designated as safety issue: Yes ]
    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.

  • Maximum Peak Plasma Concentration (Cmax) of Brexpiprazole and Moxifloxacin. [ Time Frame: Day 11 ] [ Designated as safety issue: Yes ]
    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 to Maximum (Peak) Plasma Concentration (Tmax) of Brexpiprazole and Moxifloxacin. [ Time Frame: Day 11 ] [ Designated as safety issue: Yes ]
    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.

  • Area Under the Plasma Concentration-time Curve During Dosing (AUCT). [ Time Frame: Day 11 ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • 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. [ Time Frame: Baseline, Day 11 ] [ Designated as safety issue: Yes ]
    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).

  • Change From Baseline in Summary of Maximum QTcI on Day 11 Minus Mean QTcI on Day -1 (Baseline). [ Time Frame: Baseline, Day 11 ] [ Designated as safety issue: Yes ]
    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.

  • Change From Baseline in Summary of Maximum QTcI on Day 11 Minus Maximum QTcI on Day -1 (Baseline). [ Time Frame: Baseline, Day 11 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With QTcI Interval Between 30 and 60 Msec on Day 11. [ Time Frame: Day 11 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With QTcI Interval > 60 Msec on Day 11. [ Time Frame: Day 11 ] [ Designated as safety issue: Yes ]
    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.

  • Number Participants Noted With New Incidence of QT Interval of > 500 Msec on Day 11. [ Time Frame: Day 11 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With New Incidence of ECG Morphology Abnormalities on Day 11. [ Time Frame: Day 11 ] [ Designated as safety issue: Yes ]
    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.

  • 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. [ Time Frame: Day 11 ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 218
Study Start Date: July 2011
Study Completion Date: March 2012
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm 1 (OPC-34712, placebo)
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)
Arms assigned to this intervention receive 4mg.
Drug: Placebo
OPC-34712 placebo
Active Comparator: Arm 2 (OPC-34712, placebo)
Arm 2 will be administered 12 mg OPC-34712 QD for 11 days and OPC-34712 placebo for 1 day.
Drug: OPC-34712 (12mg)
Arms assigned to this intervention receive 12mg.
Drug: Placebo
OPC-34712 placebo
Active Comparator: Arm 3 (moxifloxacin, placebo)
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
Arms assigned to this intervention will receive 400mg.
Drug: Placebo
OPC-34712 placebo
Active Comparator: Arm 4 (moxifloxacin, placebo)
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
Arms assigned to this intervention will receive 400mg.
Drug: Placebo
OPC-34712 placebo

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01423916

Locations
United States, California
Otsuka Investigational Site
Long Beach, California, United States, 90806
Otsuka Investigational Site
San Diego, California, United States, 92102
United States, Florida
Otsuka Investigational Site
Fort Lauderdale, Florida, United States, 33308
United States, Kansas
Otsuka Investigational Site
Overland Park, Kansas, United States, 66212
United States, Maryland
Otsuka Investigational Site
Rockville, Maryland, United States, 20850
United States, Missouri
Otsuka Investigational Site
St. Louis, Missouri, United States, 63118
United States, Pennsylvania
Otsuka Investigational Site
Philadelphia, Pennsylvania, United States, 19139
United States, Texas
Otsuka Investigational Site
Austin, Texas, United States, 78754
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
  More Information

Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT01423916     History of Changes
Other Study ID Numbers: 331-10-242 
Study First Received: August 8, 2011
Results First Received: August 4, 2015
Last Updated: September 29, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Schizophrenia
QTc Interval

Additional relevant MeSH terms:
Disease
Schizophrenia
Psychotic Disorders
Pathologic Processes
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Moxifloxacin
Fluoroquinolones
Norgestimate, ethinyl estradiol drug combination
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on September 30, 2016