Clinical trial NCT00391222: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bipolar Disorder
Keywords: Bipolar I Disorder
Intramuscular injection
prevention of mood episodes
long acting injectable
risperidone
Lead sponsor: Janssen Pharmaceutica N.V., Belgium
Sponsor class: INDUSTRY
First posted: 2006-10-23
Enrollment: 585
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to Recurrence of a Mood Episode (Risperidone LAI Versus Placebo)
timeFrame: 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 outcomes:
measure: Time to Recurrence of an Elevated Mood (Hypomanic, Manic, or Mixed) Episode
timeFrame: 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)
measure: Time to Recurrence of a Depressive Episode
timeFrame: 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)
measure: Time to Early Study Discontinuation for Any Reason
timeFrame: 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)
measure: Change From Double-blind Baseline to Endpoint in Young Mania Rating Scale (YMRS)
timeFrame: 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)
measure: Change From Double-blind Baseline to Endpoint in Montgomery Åsberg Depression Rating Scale (MADRS)
timeFrame: 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)
measure: Time to Recurrence of a Mood Episode (Exploratory/Olanzapine)
timeFrame: 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)
Other outcomes:
Locations:
city: Baoding
country: China
city: Beijing
country: China
city: Guangzhou
country: China
city: Nanjing
country: China
city: Shanghai
country: China
city: Suozhou
country: China
city: Wuhan
country: China
city: Barranquilla Atlantico
country: Colombia
city: Bello Antioquia
country: Colombia
city: Bogota
country: Colombia
city: Bogotá S/N
country: Colombia
city: Medellin Antioquia
country: Colombia
city: Pereira Risaralda
country: Colombia
city: Freiburg
country: Germany
city: Hildesheim
country: Germany
city: Oranienburg
country: Germany
city: Athens
country: Greece
city: Ahmedabad
country: India
city: Bangalore
country: India
city: Chennai
country: India
city: Hyderabad
country: India
city: Ludhiana
country: India
city: Mangalore
country: India
city: Mumbai
country: India
city: New Delhi
country: India
city: Pune
country: India
city: Varanasi
country: India
city: Jakarta
country: Indonesia
city: Amman
country: Jordan
city: Beirut
country: Lebanon
city: Johor Bahru
country: Malaysia
city: Kuala Lumpur
country: Malaysia
city: Ciudad De Mexico
country: Mexico
city: Merida
country: Mexico
city: Monterrey
country: Mexico
city: Puebla
country: Mexico
city: Tabasco
country: Mexico
city: Tampico
country: Mexico
city: Zapopan
country: Mexico
city: Lima Lima
country: Peru
city: Lima
country: Peru
city: Iloilo
country: Philippines
city: Mandaluyong
country: Philippines
city: Mandaue
country: Philippines
city: Arkhangelsky District
country: Russian Federation
city: Chelyabinsk
country: Russian Federation
city: Izhevsk
country: Russian Federation
city: Kazan N/A
country: Russian Federation
city: Moscow Region
country: Russian Federation
city: Moscow
country: Russian Federation
city: Nizny Novgorod
country: Russian Federation
city: Orenburg
country: Russian Federation
city: Saratov N/A
country: Russian Federation
city: St Petersburg N/A
country: Russian Federation
city: St-Petersburg
country: Russian Federation
city: Stavropol Na
country: Russian Federation
city: Tomsk Na
country: Russian Federation
city: Voronezh
country: Russian Federation
city: Bloemfontein
country: South Africa
city: Cape Town
country: South Africa
city: Durban
country: South Africa
city: Pretoria
country: South Africa
city: Tainan
country: Taiwan
city: Taipei
country: Taiwan
Study officials:
affiliation: Janssen Pharmaceutica N.V.
name: Janssen Pharmaceutica N.V. Clinical Trial
role: STUDY_DIRECTOR
References: