Bipolar I Disorder, Metabolic Syndrome, Schizoaffective Disorder, Schizophrenia
Conditions
Brief summary
The purpose of this study was to determine whether patients with schizophrenia, schizoaffective disorder, or bipolar I disorder who also have metabolic syndrome have a larger decrease in fasting non-high density lipoprotein (non-HDL) cholesterol levels with aripiprazole than with their current atypical antipsychotic treatment (olanzapine, risperidone, or quetiapine).
Interventions
DRUGAripiprazole
Aripiprazole administered orally as tablets, 5 mg once daily (QD) in Week 1; 10 mg QD in Week 2. Flexible dosing allowed after Week 2, adjusted in 5-mg increments every 7 days within a range of 10 to 30 mg daily, for 16 weeks
DRUGOanzapine, risperidone, or quetiapine
Oanzapine, risperidone, or quetiapine administered orally as tablets at prior dosage for 16 weeks
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Competency in understanding nature of study and ability to sign informed consent form * A clinical diagnosis of schizophrenia, schizoaffective disorder, or bipolar I disorder (manic or mixed) that has been treated with antipsychotics (oral olanzapine, risperidone or quetiapine) for at least 3 months. * Treatment with any of the antipsychotic medications olanzapine, risperidone, or quetiapine for at least 3 months * A Clinical Global Impression-Severity Scale score of 4 or lower at baseline * Confirmed diagnosis of metabolic syndrome * Patients not receiving treatment specifically for any of the parameters related to metabolic syndrome at the time of randomization * Women of childbearing potential must be using an adequate method of contraception to avoid pregnancy throughout the study and up to 4 weeks after last dose of investigational product * Patients for whom it is clinically appropriate to switch from their current atypical antipsychotic to aripiprazole (determined by the investigator)
Exclusion criteria
* Risk of suicide (suicidal ideation or recently attempted suicide) * Meeting Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text revision criteria for any significant psychoactive substance use disorder within 3 months of screening * Diagnosis of type 1 or 2 diabetes mellitus * Current treatment for 1 of the components of metabolic syndrome * Use of medication for the purpose of weight loss * Diagnosis of bipolar disorders other than bipolar 1, depression with psychotic symptoms, or organic brain syndromes * History of neuroleptic malignant syndrome * Diagnosis of Parkinson's disease, Alzheimer's disease, multiple sclerosis, cerebral palsy, epilepsy, or mental retardation * History of seizures * Abnormal blood count for platelets, hemoglobin, absolute neutrophils, aspartate aminotransferase, alanine aminotransferase, creatinine, fasting glucose, and thyroid-stimulating hormone * Electrocardiogram recording with QTc interval \>475 msec * Detectable levels of cocaine or positive screen for stimulants or other drugs considered (determined by the investigator) to be of abuse or dependence * Blood alcohol levels superior or equal to 50 mg/dL \[or 10.9 mmol/L\] * Prior participation in an aripiprazole clinical trial * Treatment with aripiprazole within 1 month of enrollment * Predefined exclusionary laboratory tests * Patients with Bipolar Disorder treated with adjunctive therapy other than a stable dose of mood stabilizers (lithium or valproate) must undergo a 30-day washout period for adjunctive therapies, such as antidepressants, prior to randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change From Baseline in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Levels | Baseline to Weeks 4, 8, and 16 | Based on Last Observation Carried Forward data. Non-HDL cholesterol is defined as the difference between total cholesterol and high-density lipoprotein (HDL) cholesterol levels. Fasting non-HDL cholesterol is defined as the measured fasting HDL cholesterol level subtracted from the measured fasting total cholesterol level. |
| Mean Baseline Fasting Non-HDL Levels | At baseline (Day 1) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Changes From Baseline in Fasting Glucose Levels | Baseline to Week 16 | — |
| Percent of Participants Showing a Decrease or Increase in Body Weight of 7% or Greater From Baseline | Baseline and Weeks 4, 8, and 16 | — |
| Mean Changes From Baseline in Clinical Global Impression-Severity (CGI-S) Scale | Baseline and Weeks 4, 8, and 16 | The CGI-S scale is a 7-point scale that requires the clinician to rate the severity of a patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; or 7=extremely ill. |
| Number of Participants With Potentially Clinically Relevant Changes From Baseline in Blood Pressure, Heart Rate, Hemoglobin Levels, White Blood Cell Count, Differential Count, and Absolute Platelet Count | Baseline and Weeks 4, 8, and 16 | Any value falling outside of the normal range will be flagged for the attention of the investigator at the site. The investigator will indicate whether or not a flagged value is of clinical significance. |
| Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and 1 or More AEs | Baseline to Week 16, continuously | AE=any new untoward medical event or worsening of a preexisting medical condition that may or may not be causally related to treatment. SAE=any untoward medical occurrence that at any dose results in death; is life-threatening, a congenital anomaly/birth defect, or an important medical event; requires or prolongs inpatient hospitalization, or results in persistent or significant incapacity or drug dependency or abuse. |
| Mean Changes in Weight From Baseline | Baseline to Weeks 4, 8, and 16 | — |
| Median Changes in Body Mass Index From Baseline | Baseline to Weeks 4, 8, and 16 | — |
| Mean Changes in Serum Prolactin Levels From Baseline | Baseline to Weeks 4, 8. and 16 | — |
| Mean Change From Baseline in Impact of Weight on Quality of Life (IWQoL-Lite) Scores | Baseline to Weeks 4, 8, and 16 | The IWQoL-Lite is a 31-item self-report survey that assesses the impact of weight on quality of life (QoL) in obese patients. Total score=the sum of scores(ranging from 1-5 for each item) for all 31 items. The sum is then rescaled to a 0-100 scoring, with 0 representing the poorest and 100 the best QoL. The survey also assesses improvements in QoL that occur with weight losses of 5% or greater and deteriorations in QoL with weight gain of 5% or greater. A change of 7.8 to 12.0 points from baseline=meaningful improvement. A change of -4.5 to -7.6 points from baseline=meaningful deterioration. |
| Mean Percent Changes From Baseline in Fasting Triglyceride and Total, High-Density Lipoprotein, and Low-Density Lipoprotein Cholesterol Levels | Baseline to Week 16 | — |
Countries
Canada
Participant flow
Pre-assignment details
Of 64 patients enrolled, 36 were screen failures, and 28 were randomized. Of those randomized, 26 received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Aripiprazole 5 mg once daily (QD) in Week 1; 10 mg QD in Week 2. Flexible dosing allowed after Week 2, adjusted in 5-mg increments every 7 days in a range of 10 to 30 mg daily. | 14 |
| Control Group (Olanzapine, Risperidone, or Quetiapine) Participants were to continue to receive the same dose of their current antipsychotic treatment (either olanzapine, risperidone, or quetiapine) for 16 weeks. | 14 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Investigator decision | 1 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Sponsor terminated study | 6 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 4 |
Baseline characteristics
| Characteristic | Control Group (Olanzapine, Risperidone, or Quetiapine) | Total | Aripiprazole |
|---|---|---|---|
| Age Continuous | 32.9 years STANDARD_DEVIATION 9.1 | 35.9 years STANDARD_DEVIATION 10.06 | 39.0 years STANDARD_DEVIATION 10.36 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 24 Participants | 12 Participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 2 Participants |
| Sex: Female, Male Male | 9 Participants | 21 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 14 | 6 / 12 |
| serious Total, serious adverse events | 2 / 14 | 0 / 12 |
Outcome results
Primary
Mean Baseline Fasting Non-HDL Levels
Time frame: At baseline (Day 1)
Population: All randomized patients who took at least 1 dose of study medication during the treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Mean Baseline Fasting Non-HDL Levels | 176.07 mg/dL | Standard Error 13.76 |
| Control Group (Olanzapine, Risperidone, or Quetiapine) | Mean Baseline Fasting Non-HDL Levels | 167.14 mg/dL | Standard Error 14.01 |
Primary
Mean Percent Change From Baseline in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Levels
Based on Last Observation Carried Forward data. Non-HDL cholesterol is defined as the difference between total cholesterol and high-density lipoprotein (HDL) cholesterol levels. Fasting non-HDL cholesterol is defined as the measured fasting HDL cholesterol level subtracted from the measured fasting total cholesterol level.
Time frame: Baseline to Weeks 4, 8, and 16
Population: All randomized patients who took at least 1 dose of study medication during the treatment period. The Last Observation Carried Forward (LOCF) data set included data recorded at a given visit. If no observation was recorded at that visit, data was carried forward from the previous visit. .
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aripiprazole | Mean Percent Change From Baseline in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Levels | Week 4 | -7.54 Percentage of change | Standard Error 3.22 |
| Aripiprazole | Mean Percent Change From Baseline in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Levels | Week 8 | -18.45 Percentage of change | Standard Error 2.37 |
| Aripiprazole | Mean Percent Change From Baseline in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Levels | Week 16 | -14.72 Percentage of change | Standard Error 3.86 |
| Control Group (Olanzapine, Risperidone, or Quetiapine) | Mean Percent Change From Baseline in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Levels | Week 4 | 0.19 Percentage of change | Standard Error 3.6 |
| Control Group (Olanzapine, Risperidone, or Quetiapine) | Mean Percent Change From Baseline in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Levels | Week 8 | -4.44 Percentage of change | Standard Error 2.86 |
| Control Group (Olanzapine, Risperidone, or Quetiapine) | Mean Percent Change From Baseline in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Levels | Week 16 | -2.47 Percentage of change | Standard Error 4.55 |
Secondary
Mean Change From Baseline in Impact of Weight on Quality of Life (IWQoL-Lite) Scores
The IWQoL-Lite is a 31-item self-report survey that assesses the impact of weight on quality of life (QoL) in obese patients. Total score=the sum of scores(ranging from 1-5 for each item) for all 31 items. The sum is then rescaled to a 0-100 scoring, with 0 representing the poorest and 100 the best QoL. The survey also assesses improvements in QoL that occur with weight losses of 5% or greater and deteriorations in QoL with weight gain of 5% or greater. A change of 7.8 to 12.0 points from baseline=meaningful improvement. A change of -4.5 to -7.6 points from baseline=meaningful deterioration.
Time frame: Baseline to Weeks 4, 8, and 16
Population: Due to low enrollment, the study was terminated early. This endpoint was not analyzed because there were insufficient data to draw meaningful conclusions.
Secondary
Mean Changes From Baseline in Clinical Global Impression-Severity (CGI-S) Scale
The CGI-S scale is a 7-point scale that requires the clinician to rate the severity of a patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; or 7=extremely ill.
Time frame: Baseline and Weeks 4, 8, and 16
Population: Due to low enrollment, the study was terminated early. This endpoint was not analyzed because there were insufficient data to draw meaningful conclusions.
Secondary
Mean Changes From Baseline in Fasting Glucose Levels
Time frame: Baseline to Week 16
Population: Due to low enrollment, the study was terminated early. This endpoint was not analyzed because there were insufficient data to draw meaningful conclusions.
Secondary
Mean Changes in Serum Prolactin Levels From Baseline
Time frame: Baseline to Weeks 4, 8. and 16
Population: Due to low enrollment, the study was terminated early. This endpoint was not analyzed because there were insufficient data to draw meaningful conclusions.
Secondary
Mean Changes in Weight From Baseline
Time frame: Baseline to Weeks 4, 8, and 16
Population: Due to low enrollment, the study was terminated early. This endpoint was not analyzed because there were insufficient data to draw meaningful conclusions.
Secondary
Mean Percent Changes From Baseline in Fasting Triglyceride and Total, High-Density Lipoprotein, and Low-Density Lipoprotein Cholesterol Levels
Time frame: Baseline to Week 16
Population: Due to low enrollment, the study was terminated early. This endpoint was not analyzed because there were insufficient data to draw meaningful conclusions.
Secondary
Median Changes in Body Mass Index From Baseline
Time frame: Baseline to Weeks 4, 8, and 16
Population: Due to low enrollment, the study was terminated early. This endpoint was not analyzed because there were insufficient data to draw meaningful conclusions.
Secondary
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and 1 or More AEs
AE=any new untoward medical event or worsening of a preexisting medical condition that may or may not be causally related to treatment. SAE=any untoward medical occurrence that at any dose results in death; is life-threatening, a congenital anomaly/birth defect, or an important medical event; requires or prolongs inpatient hospitalization, or results in persistent or significant incapacity or drug dependency or abuse.
Time frame: Baseline to Week 16, continuously
Population: All randomized subjects who took at least 1 dose of study medication during the treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aripiprazole | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and 1 or More AEs | Deaths | 0 Participants |
| Aripiprazole | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and 1 or More AEs | SAEs | 2 Participants |
| Aripiprazole | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and 1 or More AEs | AEs leading to discontinuation | 3 Participants |
| Aripiprazole | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and 1 or More AEs | 1 or more AEs | 11 Participants |
| Control Group (Olanzapine, Risperidone, or Quetiapine) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and 1 or More AEs | 1 or more AEs | 6 Participants |
| Control Group (Olanzapine, Risperidone, or Quetiapine) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and 1 or More AEs | Deaths | 0 Participants |
| Control Group (Olanzapine, Risperidone, or Quetiapine) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and 1 or More AEs | AEs leading to discontinuation | 0 Participants |
| Control Group (Olanzapine, Risperidone, or Quetiapine) | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and 1 or More AEs | SAEs | 0 Participants |
Secondary
Number of Participants With Potentially Clinically Relevant Changes From Baseline in Blood Pressure, Heart Rate, Hemoglobin Levels, White Blood Cell Count, Differential Count, and Absolute Platelet Count
Any value falling outside of the normal range will be flagged for the attention of the investigator at the site. The investigator will indicate whether or not a flagged value is of clinical significance.
Time frame: Baseline and Weeks 4, 8, and 16
Population: Due to low enrollment, this study was terminated early, and these data were not summarized.
Secondary
Percent of Participants Showing a Decrease or Increase in Body Weight of 7% or Greater From Baseline
Time frame: Baseline and Weeks 4, 8, and 16
Population: Due to low enrollment, the study was terminated early. This endpoint was not analyzed because there were insufficient data to draw meaningful conclusions.