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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, Double Blind, Placebo and Active Controlled Parallel Group Study to Evaluate the Efficacy and Safety of Risperidone Long-acting Injectable (LAI) for the Prevention of Mood Episodes in the Treatment of Subjects With Bipolar I Disorder

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Olanzapine
* Drug: Placebo
* Drug: Risperidone Long Acting Injectable (LAI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of bipolar I disorder as defined by DSM-IV-TR criteria. All diagnoses will be confirmed by the Mini International Neuropsychiatric Interview (M.I.N.I.). Patients who present with additional signs or symptoms compatible with Axis I diagnoses of social anxiety disorder or generalized anxiety disorder are acceptable. All other comorbid or active Axis I diagnoses are excluded. Personality disorders as defined by DSM IV TR criteria are acceptable, with the exception of antisocial and borderline personality disorders Must be currently experiencing a manic or mixed episode (acute YMRS >20 and CGI-S =>4 [moderate]) or must be between mood episodes (non-acute YMRS <12 and CGI-S=<3 [mild]) Must have had at least 2 bipolar mood (manic, mixed manic, or depressed) episodes, exclusive of the current episode (if applicable), during the last year. For non-acute subjects (YMRS <12 and CGI-S=<3 [mild]), one manic episode must have occurred within 4 months of enrollment Patients who are non-acute (YMRS <12 and CGI-S =<3 [mild]) and are currently receiving an antipsychotic other than risperidone or a mood stabilizer must have received this other medication at the same dosage for a minimum of 4 weeks and must be either experiencing problems of safety or tolerability with the antipsychotic or mood stabilizer or request a change of medication Exclusion Criteria: No history of more than 4 mood episodes each year (rapid cycling) during the last 2 years prior to screening No history of ADHD, anxiety disorder, or panic disorder as the primary diagnosis Not meeting DSM-IV-TR criteria for a hypomanic or depressive episode Not meeting DSM-IV-TR criteria for any comorbid or active Axis I disorder other than those specifically allowed in the Inclusion Criteria Not meeting DSM-IV-TR criteria for antisocial or borderline personality disorder Not having a chronic or serious general medical illness, including hepatic, renal, respiratory, cardiovascular, endocrine, neurologic (including seizure disorder), or hematologic disease as determined by the clinical judgment of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 001<br>Risperidone Long Acting Injectable (LAI) Intramuscular injections of risperidone LAI (25 37.5 or 50 mg) every 2 weeks and oral placebo daily | Drug: Risperidone Long Acting Injectable (LAI)<br>* Intramuscular injections of risperidone LAI (25, 37.5, or 50 mg) every 2 weeks and oral placebo daily<br>|
| Placebo Comparator: 002<br>Placebo Intramuscular injections of placebo every 2 weeks and oral placebo daily | Drug: Placebo<br>* Intramuscular injections of placebo every 2 weeks and oral placebo daily<br>|
| Active Comparator: 003<br>Olanzapine Intramuscular injections of placebo every 2 weeks and oral olanzapine 10 mg daily | Drug: Olanzapine<br>* Intramuscular injections of placebo every 2 weeks and oral olanzapine 10 mg daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Recurrence of a Mood Episode (Risperidone LAI Versus Placebo) | Recurrence was estimated using the Kaplan-Meier method and defined as meeting any of the following: DSM-IV-TR criteria for a hypomanic, manic, mixed, or depressive episode; in need of mood stabilizer, antipsychotic medication, benzodiazepine or antidepressant; requiring hospitalization for mood episode; either Young Mania Rating Scale (YMRS) >12 or Montgomery-Åsberg Depression Rating Scale (MADRS) >12 combined with Clinical Global Impression - Severity (CGI-S) >=4; in need of increase in study medication dose or supplementation with oral risperidone or another antipsychotic or mood stabilizer. | Assessed at every visit from the moment of randomization to a treatment arm (baseline Period III) until the end of treatment (Month 21 or earlier) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Recurrence of an Elevated Mood (Hypomanic, Manic, or Mixed) Episode | Recurrences were classified as elevated mood or depressive by the investigator based on the patient's data at the time of the event. Time to recurrence of an elevated mood episode was estimated by means of the same survival analysis method as for the primary outcome. | Assessed at every visit from the moment of randomization to a treatment arm (baseline Period III) until the end of treatment (Month 21 or earlier) | 
| Time to Recurrence of a Depressive Episode | Recurrences were classified as elevated mood or depressive by the investigator based on the patient's data at the time of the event. Time to recurrence of a depressive episode was estimated by means of the same survival analysis method as for the primary outcome. | Assessed at every visit from the moment of randomization to a treatment arm (baseline Period III) until the end of treatment (Month 21 or earlier) | 
| Time to Early Study Discontinuation for Any Reason | The robustness of the primary outcome analysis was tested by means of a sensitivity analysis: patients who discontinued the study during Period III for any reason were analyzed as having a recurrence of a mood episode at the time of their study discontinuation. The same survival analysis method as for the primary outcome was applied. | Assessed at every visit from the moment of randomization to a treatment arm (baseline Period III) until the end of treatment (Month 21 or earlier) | 
| Change From Double-blind Baseline to Endpoint in Young Mania Rating Scale (YMRS) | The 11-item YMRS was administered by an adequately trained clinician who did not provide psychotherapy or psycho-education to the patient. A severity rating was assigned to each of the items, based on the patient's subjective report of his or her condition over the previous 7 days or since the last visit (whichever was shorter) and the clinician's behavioral observations during the interview, with emphasis on the latter. The total YMRS score included the score of all 11 items ranging from 0 to 60, a higher score indicating a more severe condition. | Assessed at every visit from the moment of randomization to a treatment arm (baseline Period III) until the end of treatment (Month 21 or earlier) | 
| Change From Double-blind Baseline to Endpoint in Montgomery Åsberg Depression Rating Scale (MADRS) | The MADRS was assessed by an adequately trained clinician who did not provide psychotherapy or psycho-education to the patient. The scale consists of 10 items that cover all of the core depressive symptoms. Each item is scored from 0 to 6 and a total score is calculated by adding the scores of all 10 items. For each individual item as well as for the total score, a higher score represents a more severe condition. | Assessed at every visit from the moment of randomization to a treatment arm (baseline Period III) until the end of treatment (Month 21 or earlier) | 
| Time to Recurrence of a Mood Episode (Exploratory/Olanzapine) | Recurrence was defined as for the risperidone LAI and placebo arms (meeting any of 5 criteria). Since the study was designed to compare the efficacy of risperidone LAI versus placebo, this olanzapine analysis was exploratory in nature. | Assessed at every visit from the moment of randomization to a treatment arm (baseline Period III) until the end of treatment (Month 21 or earlier) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar I Disorder, Intramuscular injection, prevention of mood episodes, long acting injectable, risperidone