A Study to Evaluate the Efficacy and Safety of Flexible Doses of Extended-release (ER) Paliperidone Compared With Flexible Doses of Quetiapine and Placebo in Patients With Bipolar I Disorder
Condition: Bipolar Disorder; Mood Disorders
MeSH terms: Bipolar Disorder; Mood Disorders
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this study is to evaluate the effectiveness and safety of flexible-doses
      paliperidone ER (3 to 12 mg as needed) compared with placebo over 3 weeks in patients with
      Bipolar I Disorder who are experiencing an acute manic or mixed episode. This study will also
      evaluate the effects of paliperidone ER on global functioning, and will compare the
      effectiveness of flexible doses of paliperidone ER to that of quetiapine over 12 weeks.
    

Detailed description: 
      Several treatments are available for the treatment of acute manic and mixed episodes
      associated with bipolar disorder. Some of these treatments although used for many years, are
      associated with well-known problems such as poor tolerability, significant toxicities, narrow
      therapeutic ranges, and drug interactions. Often, several drugs must be used in combination
      to achieve the best clinical effect. More recently, a group of compounds known as atypical
      antipsychotics, such as risperidone, have been licensed for use in this indication.
      Paliperidone has similar properties as risperidone and is expected to be as effective in the
      treatment of acute manic and mixed episodes associated with bipolar disorder. Paliperidone ER
      has been shown to be effective in schizophrenia and it has an improved drug delivery system
      with a reduced potential for drug interactions.

      Study drug tablets are designed to deliver the appropriate amount of drug (3 mg or 6 mg)
      using a "Push-Pull" delivery system based on a patented oral osmotic pump technology (OROS)
      that allows the drug to be delivered at a relatively controlled rate for 24 hours. This study
      will test flexibly-dosed paliperidone ER (3 to 12 mg/day compared with placebo (inactive
      substance) or flexibly-dosed quetiapine (400 to 800 mg/day). There are 4 parts to the study:
      a screening and washout phase that lasts up to 7 days to determine if patients are eligible
      for the study and to discontinue all current medications, a double-blind (neither the patient
      nor the physician knows whether drug or placebo and what dosage is being taken) acute
      treatment phase that lasts for 3 weeks, a 9-week double-blind maintenance phase to see if the
      effects of paliperidone are maintained over a longer period, and a follow-up phase that lasts
      about 1 week after the final visit or early withdrawal from the study. During the acute
      treatment phase, patients are randomly assigned to receive treatment with placebo, 3 to 12
      mg/day of paliperidone ER, or 400 to 800 mg/day of quetiapine. The dosage of paliperidone ER
      or quetiapine may be adjusted to meet the patient's needs. Patients who receive placebo
      during the acute phase (first 3 weeks) will receive paliperidone ER (beginning with 6 mg/day)
      during the maintenance phase (last 9 weeks). All other patients receive the same drug, i.e.,
      either paliperidone ER or quetiapine, during both phases. The dosages during the acute phase
      begin at 6 mg/day for paliperidone ER and 100 mg/day for quetiapine, and may be adjusted
      thereafter by the study investigator to meet individual patient needs (after a forced
      titration of quetiapine to 400 mg/day). Patients will be hospitalized for at least the first
      7 days of double-blind treatment, and may be discharged on the seventh day and followed as
      outpatients based on the judgment of the study doctor. End-of-study/early withdrawal
      procedures will be done after the last dose of study drug has been received and blood samples
      have been taken, or if a patient withdraws early. Patients will have a follow-up visit with
      safety evaluations approximately 1 week later. The study, including the screening and washout
      phases, will last approximately 98 days or 14 weeks.

      Effectiveness will be primarily determined by the change in the total Young Mania Rating
      Scale (YMRS) score from the beginning (baseline) to the end of the acute treatment phase of
      the study. The YMRS is an 11-item established measure used to evaluate manic symptoms. A
      secondary measure of effectiveness is the change in the Global Assessment of Functioning
      (GAF) scale from baseline to the end of the acute treatment phase of the study. Other
      measures of effectiveness include the change from baseline to end of the maintenance phase in
      total YMRS score, the time to onset of therapeutic effect, responder rate (defined as 50% or
      more reduction from baseline in YMRS score) and changes from baseline to the end of the acute
      treatment phase in all other assessment scales. Additional assessment scales will be used to
      evaluate the clinical progress of the patient, psychotic features in bipolar disorder,
      quality of sleep and daytime drowsiness, health-related function, and rate the severity of
      the patient's bipolar disorder. Safety will be evaluated by the frequency, severity, and
      timing of side effects, clinical laboratory tests (including pregnancy tests), 12-lead
      electrocardiograms (ECGs), vital signs measurements, and physical and neurological
      examinations.

      The study hypotheses for the primary and secondary effectiveness measures are that 1)
      flexibly dosed (dosages of 3 to 12 mg/day) paliperidone ER have more effect than placebo on
      the change from baseline in the YMRS total score at the end of 3 weeks of treatment, 2)
      flexibly-dosed paliperidone ER has more effect than placebo on the change from baseline in
      GAF score at the end of 3 weeks of treatment, and 3), flexibly-dosed paliperidone ER is not
      worse than quetiapine in the change in YMRS score at 12 weeks. The potential effect on the
      variation in genes related to paliperidone ER may be evaluated separately in patients who
      consent to DNA (deoxyribonucleic acid) testing. All study drug will be administered twice
      daily. The dosages during the acute phase (first 3 weeks) begin at 6 mg/day for paliperidone
      ER and 400 mg/day for quetiapine (after a forced titration from 100 mg/day), and may be
      adjusted thereafter by the investigator to meet individual patient needs within the ranges of
      3-12 mg/day and 400-800 mg/day. Patients who receive placebo during the acute phase will
      receive paliperidone ER (starting with 6 mg/day) during the maintenance phase (last 9 weeks).
    

Intervention name(s): Placebo; Quetiapine; Paliperidone ER
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Daily for 3 weeks; 400 to 800 mg daily, initially titrated and flexibly dosed, for 12 weeks; 3 to 12 mg daily, flexibly dosed, for 12 weeks
Intervention MeSH terms: Quetiapine Fumarate; Paliperidone Palmitate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Affective psychosis; mixed-state; bipolar disorder; manic disorder; manic-depressive psychosis; mania; manic state; paliperidone; paliperidone ER.