A Study to Evaluate the Effectiveness and Safety of Extended-Release (ER) Paliperidone Compared With Placebo in Delaying the Recurrence of Symptoms in Bipolar I Disorder

This is a randomized (patients are assigned different treatments based on chance), double-blind (neither the patient nor the physician knows whether drug or placebo is being taken), active- and placebo-controlled, parallel-group, multicenter study to evaluate the efficacy (effectiveness) and safety of paliperidone ER relative to placebo in the prevention of recurrent mood symptoms associated with Bipolar I Disorder.

There are 5 phases in this study: a screening phase (lasting up to 7 days) to establish a subject's eligibility for the study,; a 3-week double-blind acute treatment phase to treat the acute or manic episode; a 12-week double-blind treatment continuation phase to establish a patient's clinical stability,; a double-blind treatment maintenance phase to measure the time to symptom recurrence that will last until the patient experiences a recurrence,; and a follow-up phase consisting of a visit approximately 1 week after the last study visit. All antipsychotic drugs and all mood stabilizers other than study drug must be discontinued before the first study drug administration.

Hospitalization is required for at least the first 7 days of the acute treatment phase. At the beginning of the acute treatment phase, patients will be randomly assigned to receive ER paliperidone or olanzapine in a 4:1 ratio. Patients in the ER paliperidone group who have a clinical response at the end of the acute treatment phase, remain clinically stable throughout the continuation phase, and achieve remission for each of the last 3 weeks of the continuation phase will again be randomly assigned: they will be assigned in a 1:1 ratio to receive ER paliperidone or placebo in the maintenance phase. Patients in the olanzapine treatment group who fulfill the same criteria will continue receiving double-blind treatment with olanzapine in the maintenance phase.

Measures of efficacy used are the Young Mania Rating Scale (YMRS), Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression - Bipolar Disorder - Severity of Illness Scale (CGI-BP-S), Global Assessment of Functioning (GAF), the Short Form-36 to measure health-related functional status, and the sleep visual analog scale (VAS).

Safety evaluations include monitoring of adverse events, clinical laboratory tests (including urine pregnancy testing and hemoglobin A1c), 12-lead ECG, vital signs measurements, measurement of orthostatic changes in pulse and blood pressure, physical examinations (including height, body weight, and waist circumference), and monitoring of extrapyramidal symptoms using the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), and the Simpson Angus Scale (SAS). In addition, the Scale for Suicidal Ideation will be administered to assess suicidality.

The primary hypothesis for this study is that, during the long-term treatment of patients with Bipolar I Disorder who maintain clinical stability after an acute manic or mixed episode, ER paliperidone is superior to placebo in delaying the time to recurrence of any mood symptoms associated with Bipolar I Disorder. Patients begin the acute treatment phase at 6.0 mg/day of oral ER paliperidone or 10 mg/day of oral olanzapine. Dosages may be adjusted, as needed, between 3 to 12 mg/day of ER paliperidone or 5 to 20 mg/day of olanzapine, through the end of the continuation phase. Then, in the maintenance phase, patients receive the dosage of ER paliperidone (or ER paliperidone placebo) or olanzapine reached at the end of the continuation phase. They remain on those dosages until the end of the study.