Long-Acting Injectable Risperidone in the Treatment of Schizophrenia

Study Overview
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Brief Summary
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In the proposed study 450 veterans with a primary diagnosis of schizophrenia who had at least one psychiatric hospitalization for schizophrenia in the previous 2 years would be randomly assigned at 16 VA medical centers to long-acting injectable risperidone or doctor's choice of oral antipsychotic medication (i.e., excluding other long-acting injectable medications, but not specifying any particular oral agents or dosages). Recruitment would take 27 months to complete, and the study would continue for a third year to allow 9 months of follow-up for the last patient recruited. All patients would be treated from the time of entry up to the end of the three-year study period. Follow-up assessments would continue quarterly. Treatments would not be blinded since giving placebo injections to the comparison group would interfere with the goal of comparing the acceptability of two different methods of medication administration. However, end points will be blindly rated.

Detailed Description
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The purpose of the study is to assess the effectiveness of long-acting injectable risperidone on psychiatric inpatient hospitalization, schizophrenia symptoms, quality of life, medication adherence, side effects, and health care costs. Objectives: Primary: To evaluate the impact of long-acting intramuscular (IM) risperidone on risk of inpatient psychiatric hospitalization in comparison to standard oral antipsychotic treatment in a randomized controlled trial to be conducted with 450 veterans diagnosed with schizophrenia or schizoaffective disorder at 16 VA medical centers over three years. Secondary: To evaluate adherence, health benefits, and costs of long-acting IM risperidone as compared to standard oral antipsychotic treatment as measured by: a) symptom reduction over 12 months, b) time to all-cause medication discontinuation, c) quality of life, d) VA and non-VA health service use and related costs, e) medication side effects, f) violent behavior, g) use of concomitant medication, and h) the incremental cost-effectiveness ratio.

Official Title
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CSP #555 - Long-Acting Injectable Risperidone in the Treatment of Schizophrenia

Conditions
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Schizoaffective Disorder, Schizophrenia

Intervention / Treatment
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* Drug: IM risperidone
* Drug: oral antipsychotic medication


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older. Diagnosed with schizophrenia or schizoaffective disorder by the Structured Clinical Interview for Diagnosis (SCID) (Spitzer and First et al., 1996). Patients should have been hospitalized in the two years before study entry on a psychiatric inpatient unit, or document explicit current evidence of increased use of outpatient services such as additional visits, day treatment or non-hospital residential treatment, increased dosage of medications or addition of concomitant psychotropic medications. The b criterion will promptly be adjudicated by the study chairmen on a case-by case basis to insure credibility. .Adequate transportation is available and the participant lives within a travel time of less than 1.5 hours, allowing attendance at all scheduled visits. Use of an acceptable method of birth control by female patients who have a possibility of becoming pregnant (safety concerns). Able to demonstrate decisional capacity in order to give informed consent as assessed by the MacArthur Competence Assessment Tool (MacCAT) (Appelbaum and Grisso, 1996). Guardian consent is acceptable where applicable. Dually diagnosed patients with both schizophrenia and addictive disorders would be included in this study but should not be in need of acute detoxification for physiologic substance dependence (excluding nicotine) in the past 30 days. Exclusion Criteria: Physiologic substance dependence requiring detoxification (excluding nicotine) in the past 30 days (substance abuse is not an exclusion). Intolerance of risperidone. Intolerance of intramuscular injection. Current treatment with depot antipsychotic medication. Current treatment with oral clozapine or presence of refractory schizophrenia that, in the treating psychiatrist's opinion, requires clozapine. Hepatic or renal problems AST or ALT (>2 times upper limit of normal); Elevated bilirubin (>1.2), BUN (>24), creatinine (>1.7). Unstable, serious medical condition or one requiring acute medical treatment, or anticipation of hospitalization for extended care. Dementia, epilepsy, insulin-dependent diabetes, anticoagulation with coumadin. Unstable living arrangements or not planning to remain in the area for the next year. Legal entanglements or pending legal charges with potential of incarceration. Assault or suicide gesture currently needing acute intervention. Concurrent participation in another clinical trial with an investigational drug during the last 30 days. Pregnant or lactating women or women planning to become pregnant.

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>long-acting injectable risperidone | Drug: IM risperidone<br>* long-acting injectable risperidone<br>|
| Active Comparator: Arm 2<br>oral antipsychotic medication | Drug: oral antipsychotic medication<br>* doctor's choice (excluding other long-acting injectable medications but not specifying any particular oral agents or dosages)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospitalization-free Survival - Time to Event | A hospitalization-free survival was defined as the time from the date of randomization to the time of a psychiatric hospitalization (in both VA and non-VA hospitals) or, in the case of patients who were hospitalized at randomization, the time from the date of discharge from the initial stay to subsequent hospitalization. Patients without an event were censored at 24 months after the date of randomization. | From randomization until date of first re-hospitalization, assessed up to 24 months | 
| Hazard Ratio for Hospitalization | Hazard ratio of LAI versus Oral for psychiatric hospitalization (in both VA and non-VA hospitals), after randomization up to 24 months, obtained from a Cox proportional hazards model. | 24 months |