A Study to Evaluate the Efficacy and Safety of Adjustable Doses of Extended-release (ER) Paliperidone Compared With Placebo, in Combination With Lithium or Valproate, to Treat Manic and Mixed Episodes in Patients With Bipolar I Disorder
Condition: Affective Psychosis, Bipolar; Bipolar Disorder; Mania
MeSH terms: Bipolar Disorder; Psychotic Disorders; Mental Disorders; Affective Disorders, Psychotic
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this study is to evaluate the effectiveness and safety over a 6-week period of
      paliperidone ER compared with placebo in treating subjects with Bipolar I Disorder who are
      experiencing a manic or mixed episode while they are taking lithium or valproate. This study
      will also evaluate the effect of paliperidone ER compared with placebo on overall
      functioning, on how quickly a response is seen, on improvement in severity of illness, on
      health-related functional status, on depressive symptoms, and on psychotic symptoms. The
      relationship between blood levels and the effectiveness and safety of paliperidone ER will be
      evaluated, including the effect of food relative to time of taking the drug.
    

Detailed description: 
      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.
    

Intervention name(s): Paliperidone ER
Intervention type(s): Drug
Intervention MeSH terms: Paliperidone Palmitate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Affective psychosis; bipolar disorder; manic disorder; manic-depressive psychosis; mania; manic state; paliperidone; paliperidone ER; adjunctive therapy