Bipolar I Disorder
Conditions
Brief summary
The primary objective of this trial is to evaluate the clinical efficacy and safety of aripiprazole in comparison to placebo in patients with Bipolar I Disorder experiencing a manic or mixed episode.
Interventions
DRUGAripiprazole
oral, 24mg/day
DRUGplacebo
oral, 0mg(4tablets)/day
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Trial subjects will be men and women of age 18 or above and below the age of 65 who will not be turning 65 during the trial. * Patients have the ability to understand and to provide informed consent to the examination, observation, and evaluation processes specified in this protocol, and have signed the informed consent form based on a full understanding of the trial. * Patients who meet DSM-IV-TR criteria for manic or mixed episodes and have been diagnosed as having 296.4x Bipolar I Disorder in which the most recent episode was manic or 296.6x Bipolar I Disorder in which the most recent episode was mixed * Patients with a YMRS total score of 20 or more
Exclusion criteria
* Patients presenting with a clinical picture and/or history that is consistent with a DSM-IV-TR diagnosis of: * Delirium, dementia, amnestic disorder, or other cognitive disorders * Schizophrenia or other psychotic disorder * Personality disorder * Patients experiencing their first manic or mixed episode * Patients whose current manic episode has lasted for more than 4 weeks * Patients with psychotic symptoms that are clearly due to another general medical condition or direct physiological effects of a substance * Patients who have met DSM-IV-TR criteria for a substance-related disorder within 3 months (90 days) prior to informed consent (excluding caffeine- and nicotine-related disorders, but including abuse of benzodiazepines) * Patients who have received ECT treatment within 8 weeks prior to informed consent * Patients who are expected to require administration of ultrashort-acting or short-acting benzodiazepine receptor agonist hypnotics and antianxiety drugs (See (1) of 4.2.2) at doses exceeding the equivalent of 15 mg/day of diazepam (Only for those patients using such drugs) * Patients at significant risk of developing a severe adverse event. Patients who have a medical condition that would interfere with assessments of safety or efficacy during the course of the trial, or who have a history of such a condition. * Patients who have received any of the following treatments during the screening period: * Reserpine * Levodopa, dopamine receptor stimulants * Monoamine oxidase inhibitors * Psychostimulants * Thyroid hormones, antithyroid drugs * Corticosteroids (other than topical preparations) * Adrenaline * All other investigational or unapproved agents * ECT * Light therapy * For patients who take lithium, valproate, or carbamazepine within 3 days prior to commencement of investigational product administration, those patients with serum concentrations of lithium greater than 0.6 mmol/L, serum concentrations of valproate greater than 50 µg/mL, or serum concentrations of carbamazepine greater than 4 µg/mL * Patients judged to have a diabetic blood glucose level (judgment based on use of a self-monitoring blood glucose meter permissible), or patients whose HbA1c is 6.5% or higher * Patients with a history or a complication of diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Young Mania Rating Scale (YMRS) | Day1, Day21 | Using LOCF datasets, change in YMRS total score from baseline (Day 1) to endpoint (Day 21) was evaluated through analysis of covariance(ANCOVA). YMRS is composed of 11 evaluation items with 5 rating levels each. Items rated on a scale of 0 to 4 (comprising 5 rating levels of one point each) are 1) elevated mood, 2) increased motor activity/energy, 3) sexual interest, 4) sleep, 7) language-thought disorder, 10) appearance, and 11) insight. Items rated on a scale of 0 to 8 (comprising 5 rating levels of two points each) are 5) irritability, 6) speech (rate and amount), 8) content, and 9) disruptive-aggressive behavior. YMRS ranges from 0 (best possible outcome) to 60 (worst possible outcome). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression - Bipolar Version (CGI-BP), Severity of Illness Score (Mania) | Day1, Day21 | CGI-BP severity of illness is a scale for overall evaluation of the severity of bipolar disorder; it comprises 3 components-mania, depression, and overall bipolar illness. CGI-BP severity of illness score (mania) ranges form 1 (normal, not ill) to 7 (very severely ill). Using LOCF datasets, change in CGI-BP severity of illness score (mania) from baseline (Day 1) to endpoint (Day 21) was evaluated through ANCOVA. |
Countries
China, Japan, South Korea, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aripiprazole Subjects were administered 24 mg/day of aripiprazole once daily for 21 days. If there was a problem with tolerability, the dose could be reduced to 12 mg/day. | 122 |
| Placebo Subjects were administered placebo once daily for 21 days. | 125 |
| Total | 247 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 12 |
| Overall Study | Change of residence or other commitments | 1 | 1 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lack of Efficacy | 28 | 35 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Progression to depressive phase | 1 | 1 |
| Overall Study | Protocol Violation | 3 | 3 |
| Overall Study | Withdrawal by Subject | 11 | 13 |
Baseline characteristics
| Characteristic | Aripiprazole | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 119 Participants | 123 Participants | 242 Participants |
| Age, Continuous | 37.5 years STANDARD_DEVIATION 12.46 | 37.8 years STANDARD_DEVIATION 12.69 | 37.6 years STANDARD_DEVIATION 12.5 |
| Region of Enrollment China | 28 participants | 28 participants | 56 participants |
| Region of Enrollment Indonesia | 7 participants | 8 participants | 15 participants |
| Region of Enrollment Japan | 39 participants | 40 participants | 79 participants |
| Region of Enrollment Malaysia | 12 participants | 13 participants | 25 participants |
| Region of Enrollment Philippines | 19 participants | 18 participants | 37 participants |
| Region of Enrollment Taiwan | 17 participants | 18 participants | 35 participants |
| Sex: Female, Male Female | 70 Participants | 75 Participants | 145 Participants |
| Sex: Female, Male Male | 52 Participants | 50 Participants | 102 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 69 / 123 | 45 / 125 |
| serious Total, serious adverse events | 5 / 123 | 9 / 125 |
Outcome results
Primary
Young Mania Rating Scale (YMRS)
Using LOCF datasets, change in YMRS total score from baseline (Day 1) to endpoint (Day 21) was evaluated through analysis of covariance(ANCOVA). YMRS is composed of 11 evaluation items with 5 rating levels each. Items rated on a scale of 0 to 4 (comprising 5 rating levels of one point each) are 1) elevated mood, 2) increased motor activity/energy, 3) sexual interest, 4) sleep, 7) language-thought disorder, 10) appearance, and 11) insight. Items rated on a scale of 0 to 8 (comprising 5 rating levels of two points each) are 5) irritability, 6) speech (rate and amount), 8) content, and 9) disruptive-aggressive behavior. YMRS ranges from 0 (best possible outcome) to 60 (worst possible outcome).
Time frame: Day1, Day21
Population: Full analysis set (FAS): The FAS consisted of subjects who had received at least one dose of investigational product and for whom the post-dosing efficacy parameter data had been obtained. Cases of GCP violation were excluded from analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Young Mania Rating Scale (YMRS) | -11.3 scores on a scale | Standard Error 1.31 |
| Placebo | Young Mania Rating Scale (YMRS) | -5.3 scores on a scale | Standard Error 1.29 |
p-value: <0.00195% CI: [-9.4, -2.7]ANCOVA
Secondary
Clinical Global Impression - Bipolar Version (CGI-BP), Severity of Illness Score (Mania)
CGI-BP severity of illness is a scale for overall evaluation of the severity of bipolar disorder; it comprises 3 components-mania, depression, and overall bipolar illness. CGI-BP severity of illness score (mania) ranges form 1 (normal, not ill) to 7 (very severely ill). Using LOCF datasets, change in CGI-BP severity of illness score (mania) from baseline (Day 1) to endpoint (Day 21) was evaluated through ANCOVA.
Time frame: Day1, Day21
Population: FAS: The FAS consisted of subjects who had received at least one dose of investigational product and for whom the post-dosing efficacy parameter data had been obtained. Cases of GCP violation were excluded from analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Clinical Global Impression - Bipolar Version (CGI-BP), Severity of Illness Score (Mania) | -1.4 scores on a scale | Standard Error 0.15 |
| Placebo | Clinical Global Impression - Bipolar Version (CGI-BP), Severity of Illness Score (Mania) | -0.7 scores on a scale | Standard Error 0.15 |
p-value: <0.00195% CI: [-1.1, -0.3]ANCOVA