A Study to Evaluate the Efficacy and Safety of Risperidone for the Prevention of Mood Episodes in the Treatment of Patients With Bipolar I Disorder
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this randomized, double blind, double dummy, multicenter study was to evaluate
      the efficacy of risperidone long-acting injectable (LAI) monotherapy in comparison with
      placebo in the prevention of a mood episode in treatment of patients with bipolar I disorder.
      Oral olanzapine was used to assess the validity of the study design. The primary objective of
      this study is to evaluate the efficacy of risperidone LAI versus placebo in the prevention of
      a mood episode (recurrence event) in patients with bipolar I disorder after a 12-week (3
      month) stabilization period on risperidone LAI, as measured by the time to recurrence of any
      mood episode. Risperidone LAI has been approved by the FDA in the USA for the treatment of
      patients with schizophrenia and for the prevention of mood recurrences in bipolar I disorder,
      as monotherapy or add-on treatment. It is approved at EMEA and other European and
      non-European health authorities for the treatment of patients with schizophrenia, too.
    

Detailed description: 
      This is a randomized, double-blind, double-dummy multicenter study with 3 parallel arms
      (risperidone long-acting injectable (LAI), placebo, and olanzapine) to evaluate the efficacy
      and safety of risperidone LAI versus placebo in the prevention of a mood episode (recurrence
      event). The primary objective of this study is to evaluate the efficacy of risperidone LAI
      monotherapy versus placebo in the prevention of a mood episode (recurrence event) in patients
      with bipolar I disorder after a 12-week (3 month) stabilization period on risperidone LAI, as
      measured by the time to recurrence of any mood episode. This study includes 3 periods - the
      screening period (Period I, lasting up to 2 weeks); the open-label treatment period (Period
      II, lasting 12 weeks); and the double-blind treatment period (Period III, lasting up to 18
      months and at least 9 months). In the open -label treatment period (Period II) treatment with
      risperidone LAI will be started with injection of a recommended dose of 25 mg every 14 days
      in patients entering Period II. If judged clinically appropriate, patients may start with
      37.5 mg every 14 days. Dosage can only be increased (up to a maximum dose of 50 mg every 14
      days) if the Clinical Global Impression - Severity (CGI-S) score has increased by => 1 over 2
      consecutive assessments at least 2 weeks apart and if there is symptom exacerbation that
      cannot be treated adequately with short-term (14 days) benzodiazepine medication. If an
      increase in risperidone LAI dosage is necessary, oral risperidone (1 to 2 mg/day) needs to be
      added for 3 weeks after the first injection of the higher dosage. Washout of all
      psychotropics other than risperidone long acting must be completed by the end of the first
      week. Non-acute patients on an antipsychotic or mood stabilizer for at least 4 weeks will
      continue their previous treatment for the first 3 weeks. No changes will be made in the
      regimens of non-acute patients receiving an antipsychotic or mood stabilizer unless there is
      concern about efficacy or safety.Patients experiencing an acute manic or mixed episode will
      additionally be treated with oral risperidone at whole-milligram dosages between 1 and 6
      mg/day as needed to treat the symptoms of the acute episode for the first 3 weeks, in order
      to cover the 3 weeks lag period of Risperidone long acting. Patients experiencing an acute
      episode who do not respond to treatment within 4 weeks will be discontinued from the study.
      Patients who do not show a response (acute patients at baseline) or do not maintain the
      efficacy (non-acute patients at baseline and acute patients after initial response) during
      the 12-week (3 month) open-label risperidone LAI stabilization period (Period II), will be
      discontinued from the study as soon as any one of the following criteria is met: The patient
      meets Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, text revised
      (DSM-IV-TR) criteria for a hypomanic, manic, mixed, or depressive episode; the patient needs
      treatment intervention with any mood stabilizer, antipsychotic medication (other than study
      drug), benzodiazepine (beyond the dosage allowed), or antidepressant medication; the patient
      requires hospitalization for any bipolar mood episode; the patient either has a Young Mania
      Rating Scale (YMRS) score >12 in combination with CGI-S score =>4 or a Montgomery-Åsberg
      Depression Rating Scale (MADRS) score >12 in combination with a CGI-S score =>4. (If either
      of these criteria is fulfilled at an assessment but if the investigator assumes that this is
      only a temporary state that requires no action, the investigator is allowed to postpone the
      decision about maintenance or response by a maximum of 4 days. If after 4 days, the criteria
      are still met, the patient must be withdrawn from Period II.) Patients who show initial and
      maintained response (acute patients at baseline) or who maintain the efficacy (non-acute
      patients at baseline) during the 12-week (3-month) open-label risperidone LAI stabilization
      period (Period II), will be eligible for entering the double-blind treatment period (Period
      III). Patients who enter Period III will be randomized to receive intramuscular injections of
      risperidone LAI every 14 days (at the dosage achieved at the end of Period II) and oral
      placebo daily, or placebo injections every 14 days and oral placebo daily, or placebo
      injections every 14 days and oral olanzapine 10 mg/day. No supplementation with oral
      risperidone and no dosage titration will be allowed during this period of the study. Using
      the double-dummy design, all patients will receive an intramuscular injection every 14 days
      and will take oral medication every day. Patients who present with a recurrence during Period
      III, will be considered as meeting the end point of the study. Patients will remain in the
      double-blind treatment period until they meet recurrence criteria, until they withdraw
      consent, or are lost to follow-up, until the last patient completed at least 9 months without
      a mood episode in Period III, or until the study ends. The study will end when 158 patients
      have presented with a mood episode in Period III, or if the study is terminated based on the
      decision of the sponsor. Approximately 860 patients meeting the inclusion and exclusion
      criteria will be enrolled in this study, with the goal of observing at least 158 recurrence
      events in Period III. Safety evaluations will include adverse events, clinical laboratory
      tests - including blood glucose/lipid profile (fasting), prolactin, TSH, and urinalysis -
      vital signs (pulse and blood pressure) and ECG, physical examination, body weight and height,
      the Extrapyramidal Symptom Rating Scale, pregnancy testing, and urine drug screen. The
      patients will receive risperidone LAI (25, 37.5 or 50 mg (period II)) every 14 days during
      the 12 week long open-label period (Period II). Patients who enter the double-blind period
      (Period III) will be randomized to receive intramuscular injections of risperidone LAI every
      14 days and oral placebo daily, or placebo injections every 14 days and oral placebo daily,
      or placebo injections every 14 days and oral olanzapine 10 mg/day.
    

Intervention name(s): Olanzapine; Placebo; Risperidone Long Acting Injectable (LAI)
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Intramuscular injections of placebo every 2 weeks and oral olanzapine 10 mg daily; Intramuscular injections of placebo every 2 weeks and oral placebo daily; Intramuscular injections of risperidone LAI (25, 37.5, or 50 mg) every 2 weeks and oral placebo daily
Intervention MeSH terms: Olanzapine; Risperidone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Bipolar I Disorder; Intramuscular injection; prevention of mood episodes; long acting injectable; risperidone