| Eligibility |
Inclusion Criteria:
1. Subjects able to give informed consent, and/or consent obtained from a legally
acceptable representative (as required by IRB/IEC) prior to the initiation of any
protocol required procedures;
2. Subjects with Bipolar I Disorder, manic or mixed episode, with or without psychotic
features, as defined by DSM-IV-TR and confirmed by the M.I.N.I.;
3. Subjects who are able to understand the nature of the study and follow protocol
requirements including the prescribed dosage regimens, capsule/tablet ingestion,
discontinuation of prohibited concomitant medications, and who can be reliably rated
on assessment scales;
4. Subjects willing to discontinue all medication starting from the signing of the
informed consent and during the study phases (allowed exceptions noted in Section
6.4.2);
5. Men or women aged = 18 and = 65 years;
6. Subjects with YMRS total score = 20 (to be assessed prior entry into open-label acute
treatment phase);
7. YMRS total score = 12 for 2 consecutive visits (to be assessed at Week 5 and/or Week6
prior entry into double-blind treatment phase).
Exclusion Criteria:
1. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for
the entire study period and for up to four weeks after completion of the study.
Acceptable methods include oral, injectable or implanted contraceptives, intrauterine
devices or barrier methods such as condoms, diaphragm, and spermicides;
2. Women who are pregnant or breast-feeding;
3. Subjects presenting clinically with a current DSM-IV-TR diagnosis of delirium,
dementia, amnestic or other cognitive disorders, or a psychotic disorder (e.g.,
schizophrenia or schizoaffective disorder). Also, subjects with borderline, paranoid,
histrionic, schizotypal, schizoid, or antisocial personality disorder;
4. Subjects with a current Axis I (DSM-IV-TR) diagnosis of Bipolar II Disorder, rapid
cyclers (experiencing four or more manic or depressive episodes per year), Bipolar
Disorder NOS, or any other primary psychiatric disorder other than Bipolar I Disorder;
5. Subjects with documented evidence of first manic episode;
6. Subjects considered treatment refractory for manic symptoms; (Note: if a subject has
failed = 2 antimanic treatments, e.g., antipsychotic, lithium, valproate or
carbamazepine at therapeutic dose and duration, exclusive of the current episode,
obtain permission from the Otsuka medical monitor to include the subject)
7. Subjects previously nonresponsive to aripiprazole for manic symptoms;
8. Subjects with a significant risk of committing suicide based on history, mental status
exam, or investigator's judgment;
9. Subjects who have met DSM-IV-TR criteria for substance abuse within the past three
months, or substance dependence* within the past 6 months, including benzodiazepines;
(* exceptional for subjects with substance dependence on nicotine or caffeine);
10. Subjects with thyroid pathology (e.g., hypothyroidism or hyperthyroidism) unless
condition has been stabilized with medications for at least the past three months;
(Note: Subjects with an abnormal thyroid function test may be retested prior to the
start of study medication. Subjects with an abnormal thyroid function test at
screening will not be eligible for the study, unless permission is obtained from
Otsuka);
11. Subjects who have a history or evidence of a medical condition that would expose them
to an undue risk of a significant adverse event or interfere with assessments of
safety or efficacy during the course of the trial, including but not limited to
hepatic, renal, respiratory, cardiovascular, endocrine (e.g., Addison's Disease),
immune, neurologic, or hematologic disease as determined by the clinical judgment of
the investigator;
12. Subjects with a significant history of seizure disorder (e.g., epilepsy);
13. The following laboratory tests results, vital signs, and ECG findings are
exclusionary:
- Platelets = 75000/mm3
- Hemoglobin = 9g/dL
- Neutrophils, absolute = 1000/ mm3
- SGOT (AST) > 3x Upper Limit of Normal
- SGPT (ALT) > 3x Upper Limit of Normal
- Creatinine = 2 mg/dL
- QTc > 475 msec
14. Subjects with a recent antipsychotic use who have a CPK = 550 IU (Otsuka should be
contacted to discuss any elevated CPK levels);
15. Subjects who are known to be allergic, intolerant, or unresponsive to valproate or to
aripiprazole;
16. Subjects with a history of neuroleptic malignant syndrome from antipsychotic agents;
17. Subjects likely to require prohibited concomitant therapy during the study as
indicated in Section 6.4 of the protocol;
18. Recent treatment of their most recent manic or mixed acute episode with a long acting
antipsychotic in which the last dose was less than one full cycle plus one week prior
to entering Phase 2 (haloperidol decanoate treatment within the past five weeks,
fluphenazine decanoate treatment within the past three weeks or Risperdal ConstaTM
treatment within the past three weeks);
19. Subjects likely to require the initiation of intensive individual psychotherapy during
the course of the study (Note: Group and supportive therapy is allowed, if part of the
subject's ongoing treatment. Individual psychotherapy is allowed if the subject has
consistently received psychotherapy for at least 3 months prior to the study and will
continue during the study);
20. ECT treatment within the current episode or within two months prior to the study;
21. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (e.g., infectious disease) illness must
not be enrolled into this study.
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