Clinical trial NCT01854944: PET Trial to Assess the Receptor Occupancy of Brexpiprazole in Adult Subjects With Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Schizophrenia
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
First posted: 2013-05-16
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine how low and high does of brexpiprazole binds to certain receptors in the brain. This will be determined by PET scans taken pre-dose and post-dose.


Eligibility criteria: Inclusion Criteria:

* A diagnosis of Schizophrenia.
* Ability to provide written informed consent.
* Ability to understand the protocol and meet the protocol requirements.
* Must be in good physical health determined by ECG and laboratory values, medical history and physical examinations.
* Has stable disease, defined as meeting all of the following criteria: A CGI-S score \<= 4 (moderately ill); A PANSS total score \<= 60; A score of \<= 4 (moderate) on any of the following PANSS items: (P7 (hostility); G8 (uncooperativeness)).
* Body mass index of 19 to 35 kg/m2

Exclusion Criteria:

* Sexually active males and females of childbearing potential who are not practicing double-barrier birth control, or who will not remain abstinent, during the trial and for 30 days following the last dose of trial medication. If employing birth control, 2 of the following precautions must be used: vasectomy, partner who uses hormonal contraception, tubal ligation, vaginal diaphragm, nonhormonal intrauterine device, condom, or sponge with spermicide.
* 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 based on the clinical judgment of the investigator.
* Subjects who have received continuous medication therapy to treat schizophrenia for less than 6 months prior to the drug-free interval.
* Subjects with schizophrenia who 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 including MDD, bipolar disorder, delirium, dementia, amnestic, or other cognitive disorders or subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
* Subjects who, in the opinion of the investigator, cannot be rated reliably on the battery of movement rating scales required by the protocol.
* Subjects with a significant risk of violent behavior, a significant risk of committing suicide based on history or investigator's judgment, or who have attempted suicide within 2 years of cohort assignment.
* Subjects with clinically significant tardive dyskinesia at enrollment.
* Subjects who experience clinical deterioration during the drug-free interval, such that they require prohibited rescue therapy, will not meet the trial criteria and will be replaced.
* Subjects who experienced an acute exacerbation requiring hospitalization within 3 months prior to the Screening Visit or between the Screening and Baseline Visits.
* Subjects who experienced an acute exacerbation requiring change in antipsychotic medication (with reference to drug or dose) within the last 4 weeks prior to baseline.
* Subjects who have a history of myocardial infarction, hypertension, or diabetes or who have evidence of other medical 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, including, but not limited to, hepatic, renal, respiratory, cardiovascular, endocrine, neurologic, hematologic, or immunologic disease. The medical monitor must be contacted to discuss any such condition prior to cohort assignment.
* Subjects who have any of the following neurologic diagnoses, whether under treatment or not, whether stable or not: migraine, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, residual of stroke, transient cerebral ischemic attacks, cerebral palsy, or any condition that requires intermittent or maintenance treatment or which is manifested by any abnormality on neurologic examination. A subject with tardive dyskinesia or other nonclinically significant symptoms of EPS due solely to the current or prior use of antipsychotic medications is not excluded by this criterion. Single-nerve peripheral palsies are also not excluded by this criterion: eg, Bell's palsy or radial-nerve palsy or fixed residuals from traumatic injury.

History of or current hepatitis or acquired immunodeficiency syndrome or carriers of HBsAg and/or anti-HCV or HIV antibodies.

* Subjects with a history of thyroid pathology (unless the condition has been stabilized with medications for at least the past 3 months) and/or abnormal thyroid laboratory results.
* 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 cohort assignment (excluding caffeine and nicotine), including alcohol and benzodiazepines, and/or a positive alcohol (breath or urine) test or a positive urine screen for drugs of abuse. (In the case where a subject had a positive screen for stimulants and/or marijuana and was therefore excluded, the medical monitor should be contacted to determine if rescreening is an option.)
* Subjects who had any major surgery, any blood transfusion, or donated blood or plasma within 30 days prior to enrollment.
* The following laboratory test, vital sign, and ECG results are exclusionary:

  1. Platelets \<= 75,000/mm3
  2. Hemoglobin \<= 9 g/dL
  3. Neutrophils, absolute \<= 1000/mm3
  4. AST \> 2 times upper limit of normal
  5. ALT \> 2 times upper limit of normal
  6. Creatinine \>= 2 mg/dL
* Subjects with electrolytes outside of the normal range will not be enrolled in the trial without prior review and approval from the medical monitor.
* Subjects who have sitting (performed first) or supine blood pressure, after resting for \>= 3 minutes, higher than 140/90 mmHg or lower than 100/50 mmHg. Upon standing from the supine position, subjects who have a fall in systolic blood pressure \>= 20 mmHg or a fall in diastolic blood pressure \>= 10 mm Hg after 1 to 3 minutes in the standing position. (Any repeated out-of-range values not deemed clinically significant need to be discussed with the medical monitor to determine eligibility.)
* Subjects who have a supine pulse rate, after resting for \>= 3 minutes, outside the range of 40 to 90 bpm.
* Subjects with any ECG abnormality at Screening, prior to dosing, will be excluded, including but not limited to, a PR interval \> 220 msec, QRS interval \> 110 msec, QTc \> 450 msec, QTcF \> 450 msec, QTcB \> 450 msec or the increase in QTcB is considered significant by the investigator, abnormal U waves, or other minor ST-T wave changes which are considered clinically significant.
* Prohibited concomitant medications/therapies used for the following time period prior to Day -1 and for the duration of the trial include:
* Antipsychotics

  1. Use of oral antipsychotics within 21 days prior to Day -1;
  2. Use of long-acting injectable antipsychotics within 6 months.
* Anxiolytics and Sleep Aids

  1) Regular use of benzodiazepines for 2 weeks (lorazepam \[\<= 6 mg daily up to 48 hours prior to PK and PD assessments\] can be used as rescue therapy during the 21 days prior to Day -1 and \[\<= 4 mg daily up to 48 hours prior to PK and PD assessments or up to 24 hours prior to the completion of the EPS rating scales or C-SSRS\] during the treatment period).
* Mood Stabilizers

  1) Use of lamotrigine within 14 days.
* Selective Serotonin Reuptake Inhibitors

  1. Use of Prozac within 28 days;
  2. Use of Paxil within 14 days;
  3. Use of Zoloft, Luvox, or Celexa within 7 days.
* Serotonin and Norepinephrine Reuptake Inhibitors

  1. Use of Effexor within 3 days;
  2. Use of duloxetine within 14 days.
* Other

  1. Use of Symbyax within 28 days;
  2. Use of CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers within 14 days;
  3. Use of electroconvulsive therapy within 2 months.
* Use and discontinuation of any other therapy (prescription medication, over-the counter, herbal medication, or vitamins) not listed above must be approved by the sponsor and the medical monitor.
* Subjects who received brexpiprazole in a prior clinical trial.
* Subjects who received any investigational agent in a clinical trial within 90 days prior to Screening.
* Consumption of alcohol and/or food and beverages containing methylxanthines, grapefruit, grapefruit juice, Seville oranges, or Seville orange juice within 72 hours prior to dosing and for the duration of the trial.
* Subjects who are heavy smokers (ie, \> 21 cigarettes per day). Other
* Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious disease) illness must not be enrolled into this trial.
* Subjects with a history of allergy to more than one class of medications.
* Any subject who, in the opinion of the investigator, should not participate in the trial.
* A history of difficulty in donating blood.
* Exposure to any substances known to stimulate hepatic microsomal enzymes within 30 days prior to Screening through the end of the trial (eg, occupational exposure to pesticides, organic solvents).
* Additionally, subjects who meet the following imaging exclusion criteria will not be included in this trial:

  1. Subjects who suffer from claustrophobia.
  2. Subjects with MRI-incompatible implants and other contraindications for MRI, such as pacemaker, artificial joints, nonremovable body piercings, tattoos larger than 1 cm in diameter, metal fragments, claustrophobia, etc.
  3. Subjects who have received a diagnostic or therapeutic radiopharmaceutical within 7 days prior to participation in this trial.
  4. Participation in other research trials involving ionizing radiation within 1 year of the PET scans that would cause the subject to exceed the yearly dose limits for normal subjects.
  5. Subjects with history of IV drug use which would prevent venous access for PET tracer injection.
  6. Severe motor problems that prevent the subject from lying still for PET and MRI.
  7. Subjects who complain of chronic pain (eg, as the result of rheumatoid arthritis).

Primary outcomes:
measure: Change in Percentage Dopamine D2/D3 Receptor Occupancy
timeFrame: Baseline to 4 hours post-last dose on Day 10
measure: Change in Percentage 5-HT1A Receptor Occupancy
timeFrame: Baseline to 4 hours post-last dose on Day 10
measure: Change in Percentage 5-HT2A Receptor Occupancy
timeFrame: Baseline and 4 hours post-last dose on Day 10
measure: Change in Occupancy at Serotonin Transporter (SERT)
timeFrame: Baseline to 4 hours post-last dose on Day 10
Secondary outcomes:
measure: Area Under the Concentration-time Curve (AUCτ) During a Dosing Interval at Steady-state for Brexpiprazole and Its Metabolite DM-3411
timeFrame: Baseline to Day 10
measure: Peak (Maximal) Concentration of Drug in Plasma (Cmax) for Brexpiprazole and Its Metabolite DM-3411
timeFrame: Baseline to Day 10
measure: Apparent Clearance of Drug From Plasma After Extravascular Administration (CL/F; Only Brexpiprazole)
timeFrame: Baseline to Day 10
measure: Time to Maximum (Peak) Plasma Concentration (Tmax) for Brexpiprazole and Its Metabolite DM-3411
timeFrame: Baseline to Day 10
measure: Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Score
timeFrame: Baseline to Day 6, 11 and Last Visit
measure: Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score
timeFrame: Baseline to Day 6, 11 and Last Visit
measure: Mean Change From Baseline in Barnes Akathisia Rating Scale (BARS) Score
timeFrame: Baseline to Day 6, 11 and Last Visit
measure: Percentage of Participants Who Reported at Least One Occurrence of Suicidality, Suicidal Behavior and Suicidal Ideation on the Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Baseline to Last Visit
measure: Mean Change From Baseline in Positive and Negative Symptom Scale (PANSS) Total Score
timeFrame: Baseline to Day 6, 11 and Last Visit
measure: Mean Change From Baseline in PANNS Positive Subscale Score
timeFrame: Baseline to Day 6, 11 and Last Visit
measure: Mean Change From Baseline in PANSS Negative Subscale Score
timeFrame: Baseline to Day 6, 11 and Last Visit
measure: Mean Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score
timeFrame: Baseline to Day 6, 11 and Last Visit
measure: Mean Change From Baseline in Clinical Global Impression-Improvement (CGI-I) Score
timeFrame: Baseline to Day 6, 11 and Last Visit
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University
state: New York
Study officials:
References:
citation: Girgis RR, Forbes A, Abi-Dargham A, Slifstein M. A positron emission tomography occupancy study of brexpiprazole at dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors, and serotonin reuptake transporters in subjects with schizophrenia. Neuropsychopharmacology. 2020 Apr;45(5):786-792. doi: 10.1038/s41386-019-0590-6. Epub 2019 Dec 17.