Several treatments are available for the treatment of acute manic and mixed episodes
associated with bipolar disorder. Some of these treatments, including lithium, divalproex
sodium, and carbamazepine, have been used for many years. More recently, risperidone and a
number of atypical antipsychotics (olanzapine, quetiapine, ziprasidone, aripiprazole) have
been approved for use in the treatment of acute mania. Paliperidone has similar properties to
risperidone and is thus expected to have at least similar efficacy to risperidone in the
treatment of acute manic and mixed episodes associated with bipolar disorder. Paliperidone ER
has been shown to be effective in treating schizophrenia, and has an improved delivery system
(with delivery at a relatively controlled rate over 24 hours) and a reduced potential for
drug-drug interactions. Treatment of bipolar mania often involves more than a single
medication. Studies of mood stabilizers in combination with antipsychotic agents have
suggested greater efficacy or more rapid onset of action with these combinations than with
any of these agents alone. It is therefore of interest to evaluate the effectiveness of
paliperidone ER in combination with mood stabilizers for the treatment of acute manic and
mixed episodes associated with bipolar disorder.
This randomized (patients are randomly assigned to receive paliperidone ER or placebo),
double-blind (neither the patient nor the physician knows whether drug or placebo and what
dosage is being taken), placebo-controlled, parallel-group, multicenter study will evaluate
paliperidone ER compared with placebo over a 6-week period in patients with Bipolar I
Disorder who are experiencing an acute manic or mixed episode and are taking lithium or
valproate. A flexible dosing regimen will be used in this study to afford investigators the
ability to adjust the dosage of each subject to achieve rapid control of acute manic
symptoms. After a screening/washout phase of no more than 7 days to determine if patients are
eligible and to discontinue all medications excluded per protocol criteria(including any
mood-stabilizing medications other than lithium or valproate), patients will be randomly
assigned to either paliperidone ER or placebo for a 6-week, double-blind treatment phase.
Patients will be hospitalized for at least the first 7 days, and will be discharged and
followed as outpatients only if they are considered to be at no significant risk of violent
or suicidal behavior. An end-of-study visit will be conducted at the end of the double-blind
treatment phase or at early withdrawal, whichever comes first. A follow-up (post-treatment)
visit for safety evaluations will be scheduled approximately 1 week after the
end-of-study/early withdrawal visit. The study, including the screening/washout phase, will
last up to 56 days (8 weeks).
Effectiveness will primarily be determined by the change from baseline in the Young Mania
Rating Scale (YMRS) score to the end of the 6-week double-blind treatment phase or early
withdrawal. The YMRS is an established 11-item scale used to evaluate manic symptoms. A
secondary measure of effectiveness will be the change from baseline in the Global Assessment
of Functioning (GAF) score to the end of the 6 weeks of treatment. Additional measures of
effectiveness will measure severity of bipolar illness, psychotic symptoms, quality of sleep,
and health-related functional status. Safety will be measured by monitoring the frequency,
severity, and timing of side effects; monitoring the need for additional medications;
clinical laboratory tests (including pregnancy tests), 12-lead electrocardiograms;
measurement of vital signs (blood pressure, pulse, and temperature); and physical examination
(including height, weight, and waist circumference). Three scales will be used to assess
specific neurologic side effects; the Scale for Suicidal Ideation will be used to evaluate
any suicidal tendencies. The primary study hypothesis is that, in the treatment of patients
who experience an acute manic or mixed episode while they are taking lithium or valproate for
the treatment of Bipolar I Disorder, paliperidone ER is superior to placebo on the change
from baseline in the YMRS total score at the end of 6 weeks of double-blind treatment. The
secondary hypothesis is that, in these same patients, paliperidone ER is superior to placebo
on the change from baseline in GAF score at the end of 6 weeks of double-blind treatment.
Flexibly dosed oral paliperidone ER (3 to 12 mg/day) or matching placebo once daily. All
study drug will be administered before 10:00 a.m. Initial dosage will be 6 mg/day; adjustment
of the dosage will be based on assessment of the patient's response to and tolerance of the
study drug. Dosage may be increased in 3-mg/day increments or decreased as deemed necessary;
dosage should only be increased every 2 days unless a patient requires a higher dosage to
control manic symptoms.