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

• Time to Recurrence of Manic Symptoms Associated With Bipolar I Disorder [ Time Frame: Date of randomization into the maintenance phase until the first occurrence of recurrence of manic symptoms or discontinuation from the study, assessed over a period of 41 months. ] [ Designated as safety issue: No ]
  This was the key secondary efficacy end-point. Pali/Pali and Pali/Placebo were compared with each other with respect to time to recurrence of manic symptoms. The criterias used for this analysis were similar to criterias used for primary analysis.
• Time to Recurrence of Depressive Symptoms Associated With Bipolar I Disorder [ Time Frame: Date of randomization into the maintenance phase until the first occurrence of recurrence of depressive symptoms or discontinuation from the study, assessed over a period of 41 months. ] [ Designated as safety issue: No ]
  Pali/Pali and Pali/Placebo were compared with each other with respect to time to recurrence of depressive symptoms. The criterias used for this analysis were similar to criterias used for primary analysis.

• Young Mania Rating Scale (YMRS): Change From Baseline [ Time Frame: From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization). ] [ Designated as safety issue: No ]
  This is method by which condition of patient suffering with mania is checked. In this scale patient's condition is assessed using 11 items. A severity rating is assigned to each of 11 items based on the how subject feels of his or her condition and the physicians observation of patients behavior. The range of the scale is 0 to 60. A higher score indicates a more severe condition. Change from baseline (Day 105) in the double‑blind maintenance phase to the last postbaseline assessment.
• Montgomery-Asberg Depression Rating Scale (MADRS) [ Time Frame: From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization). ] [ Designated as safety issue: No ]
  The MADRS consists of 10 items covering all the important complaints which patient with depression have (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). Item is scored from 0 (normal) to 6 (severe). Total score (0 to 60) is calculated by adding the scores of all 10 items. A higher score represents a more severe condition. Negative Change in Score Indicates Improvement.
• Global Assessment of Functioning (GAF): Change From Baseline [ Time Frame: From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization). ] [ Designated as safety issue: No ]
  This scale is used when the clinical progress of a subject needs to be assessed in global terms, using a single measure. The GAF scale is rated with respect to psychological, social, and occupational functioning at the time of the assessment only. A higher score indicates a better functioning, with an overall range from 1 to 100. Positive Change in Score Indicates Improvement.
• Clinical Global Impression - Bipolar Disorder - Severity of Illness (CGI-BP-S): Change From Baseline [ Time Frame: From 1st randomization into acute phase to end of acute/continuation phase (ie, up to 15 weeks after 1st randomization), or from randomization into maintenance (MA) phase to the end of MA phase (ie, up to 175 weeks (or 41 months) after 2nd randomization). ] [ Designated as safety issue: No ]
  The CGI-BP-S rating scale is used to rate the severity of bipolar disorder, including both depressed and manic components, on a 7-point scale ranging from 1 (not ill) to 7 (very severely ill). This scale permits a global evaluation of the subject's bipolar condition at a given time. Negative Change in Score Indicates Improvement.

The purpose of this study is to evaluate the effectiveness and safety of oral extended-release (ER) paliperidone compared with placebo in the prevention of the recurrence of mood symptoms in patients with Bipolar I Disorder who initially respond to treatment of an acute manic or mixed episode with paliperidone ER. Olanzapine was included as an active control arm, although the study is not designed to allow for a direct comparison of olanzapine with paliperidone.

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.

• Drug: Olanzapine
  Once daily in dose range of 5 to 20 mg/day for 15 weeks, then until recurrence
• Drug: Paliperidone ER
  Once daily in dose range of 3 to 12 mg/day for 15 weeks, then until recurrence
• Drug: Placebo
  Once daily until recurrence (only after initial 15 weeks on paliperidone ER)

• Experimental: Paliperidone ER
  Intervention: Drug: Paliperidone ER
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo
• Active Comparator: Olanzapine
  Intervention: Drug: Olanzapine

Inclusion Criteria:

• Meet DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) criteria for Bipolar I Disorder Most Recent Episode Manic or Mixed (with or without psychotic features)
• have a history of at least 2 previously documented mood episodes associated with Bipolar I Disorder (1 of which must be a manic or mixed episode) that required medical treatment within the past 3 years
• a total score of at least 20 on the YMRS at screening and at Day 1 of the study.

Exclusion Criteria:

• Meet DSM-IV criteria for any type of episode associated with bipolar disorder other than Bipolar I Disorder Most Recent Episode Manic or Mixed
• Meet DSM-IV criteria for rapid cycling
• Meet DSM-IV criteria for schizoaffective disorder
• Known or suspected borderline or antisocial personality disorder
• be, in the opinion of the investigator, at significant immediate risk for suicidal or violent behavior during the course of the study based on current status or prior history (e.g., suicide attempts during previous episodes).