Long-Acting Injectable Risperidone in the Treatment of Schizophrenia

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

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Schizoaffective Disorder
• Intervention / Treatment: Drug: IM risperidone; Drug: oral antipsychotic medication

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 382
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Tuscaloosa, Alabama, United States, 35404
      • VA Medical Center, Tuscaloosa
  • California
    • Long Beach, California, United States, 90822
      • VA Medical Center, Long Beach
    • Palo Alto, California, United States, 94304-1290
      • VA Palo Alto Health Care System
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • VA Connecticut Health Care System (West Haven)
  • Florida
    • Miami, Florida, United States, 33125
      • VA Medical Center, Miami
  • Georgia
    • Augusta, Georgia, United States, 30904
      • VA Medical Center, Augusta
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Jesse Brown VAMC (WestSide Division)
  • Massachusetts
    • Boston, Massachusetts, United States, 02130
      • VA Medical Center, Jamaica Plain Campus
  • Michigan
    • Detroit, Michigan, United States, 48201
      • John D. Dingell VA Medical Center, Detroit
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • VA Medical Center, Minneapolis
  • Missouri
    • Kansas City, Missouri, United States, 64128
      • VA Medical Center, Kansas City MO
  • Nebraska
    • Omaha, Nebraska, United States, 68105-1873
      • VA Medical Center, Omaha
  • New Mexico
    • Albuquerque, New Mexico, United States, 87108-5153
      • New Mexico VA Health Care System, Albuquerque
  • New York
    • New York, New York, United States, 10010
      • New York Harbor HCS
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • VA Medical Center, Cleveland
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • VA Medical Center, Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VA Medical Center (152)
    • Waco, Texas, United States, 76711
      • Central Texas Veterans Health Care System - Waco
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System, Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 years or older.
2. Diagnosed with schizophrenia or schizoaffective disorder by the Structured Clinical Interview for Diagnosis (SCID) (Spitzer and First et al., 1996).

3. Patients should

   1. have been hospitalized in the two years before study entry on a psychiatric inpatient unit, or
   2. 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.

4. .Adequate transportation is available and the participant lives within a travel time of less than 1.5 hours, allowing attendance at all scheduled visits.
5. Use of an acceptable method of birth control by female patients who have a possibility of becoming pregnant (safety concerns).
6. 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.
7. 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:

1. Physiologic substance dependence requiring detoxification (excluding nicotine) in the past 30 days (substance abuse is not an exclusion).
2. Intolerance of risperidone.
3. Intolerance of intramuscular injection.
4. Current treatment with depot antipsychotic medication.
5. Current treatment with oral clozapine or presence of refractory schizophrenia that, in the treating psychiatrist's opinion, requires clozapine.
6. Hepatic or renal problems AST or ALT (>2 times upper limit of normal);
7. Elevated bilirubin (>1.2), BUN (>24), creatinine (>1.7).
8. Unstable, serious medical condition or one requiring acute medical treatment, or anticipation of hospitalization for extended care.
9. Dementia, epilepsy, insulin-dependent diabetes, anticoagulation with coumadin.
10. Unstable living arrangements or not planning to remain in the area for the next year.
11. Legal entanglements or pending legal charges with potential of incarceration.
12. Assault or suicide gesture currently needing acute intervention.
13. Concurrent participation in another clinical trial with an investigational drug during the last 30 days.
14. Pregnant or lactating women or women planning to become pregnant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: US Department of Veterans Affairs
• Investigators: Study Chair: Robert A. Rosenheck, AB MD, VA Connecticut Health Care System (West Haven)

Publications and helpful links

General Publications

• Rosenheck RA, Krystal JH, Lew R, Barnett PG, Thwin SS, Fiore L, Valley D, Huang GD, Neal C, Vertrees JE, Liang MH; CSP 555 Research Group. Challenges in the design and conduct of controlled clinical effectiveness trials in schizophrenia. Clin Trials. 2011 Apr;8(2):196-204. doi: 10.1177/1740774510392931. Epub 2011 Jan 26.
• Rosenheck RA, Krystal JH, Lew R, Barnett PG, Fiore L, Valley D, Thwin SS, Vertrees JE, Liang MH; CSP555 Research Group. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N Engl J Med. 2011 Mar 3;364(9):842-51. doi: 10.1056/NEJMoa1005987. Erratum In: N Engl J Med. 2011 Mar 31;364(13):1281.
• Barnett PG, Scott JY, Rosenheck RA; CSP 555 Study Group. How do clinical trial participants compare to other patients with schizophrenia? Schizophr Res. 2011 Aug;130(1-3):34-9. doi: 10.1016/j.schres.2011.03.033. Epub 2011 Apr 22.
• Barnett PG, Scott JY, Krystal JH, Rosenheck RA; CSP 555 Research Group. Cost and cost-effectiveness in a randomized trial of long-acting risperidone for schizophrenia. J Clin Psychiatry. 2012 May;73(5):696-702. doi: 10.4088/JCP.11m07070.
• Thwin SS, Hermes E, Lew R, Barnett P, Liang M, Valley D, Rosenheck R. Assessment of the minimum clinically important difference in quality of life in schizophrenia measured by the Quality of Well-Being Scale and disease-specific measures. Psychiatry Res. 2013 Oct 30;209(3):291-6. doi: 10.1016/j.psychres.2013.01.016. Epub 2013 Mar 7.
• Hoblyn JC, Rosenheck RA, Leatherman S, Weil L, Lew R; CSP 555 Investigator Group. Veteran subjects willingness to participate in schizophrenia clinical trials. Psychiatr Q. 2013 Jun;84(2):209-18. doi: 10.1007/s11126-012-9240-4.

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): September 1, 2009

Study Registration Dates

• First Submitted: August 17, 2005
• First Submitted That Met QC Criteria: August 17, 2005
• First Posted (Estimate): August 19, 2005

Study Record Updates

• Last Update Posted (Estimate): December 20, 2013
• Last Update Submitted That Met QC Criteria: October 30, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin Antagonists; Dopamine Antagonists; Risperidone; Antipsychotic Agents
• Other Study ID Numbers: 555