CARE Study: Improving Treatment for the Most Severely Ill With Schizophrenia

International Study of Improving Treatment for the Most Severely Ill With Schizophrenia

This is a 9 week, multicentre, randomized, double-blind, placebo-controlled trial with two parallel groups. There is also an open-label extension phase of 18 weeks. Both medications to be used in the study, clozapine and risperidone, are fully approved for the treatment of schizophrenia.

Subjects may be inpatients or outpatients. All subjects will be treated throughout the study with clozapine, at a dose of 400 mg or more, unless limited by side effects. After screening, subjects will be augmented with placebo for 7 days. Any subject with a reduction in PANSS total score of 20% or greater will be discontinued from the study. Beginning on day 8, subjects will be randomized to continued augmentation of clozapine with placebo, or to augmentation with risperidone. The initial daily dose of risperidone will be 1.0 mg, increased in 1.0 mg increments to a total of 3.0 mg/day over a two week period. Subjects unable to tolerate at least one tablet of study medication will be dropped from the study. At the end of 8 weeks following randomization, at the choice of the investigator, open-label risperidone augmentation can be started.

The primary outcome measure is the PANSS total score at week 9. Subjects will be classified as responders if the improvement in PANSS total score is 20% or greater, and the proportion of responders in each group will be determined. Complementary outcome measures will be the CGI severity score, CGI improvement score, and SOFAS score. Safety and tolerance will be assessed by reports of adverse events and clinically significant changes in vital signs, weight, waist circumference, extrapyramidal side effects, metabolic and hematological measures.

Inclusion Criteria:

• Subjects treated with clozapine for the indication of poor response to other antipsychotic medications.
• Treatment with clozapine is at a stable dose for at least 12 weeks. Dose must be 400 mg/day or more, unless side effects limited increase of dose.

Exclusion Criteria:

• Subjects with significant alcohol or substance abuse in the past 3 months.
• Subjects with a previous trial of risperidone augmentation of clozapine
• Subjects who are pregnant, breast-feeding, or women of child-bearing potential not using adequate contraception
• Subjects requiring treatment with anticonvulsants.
• Subjects with known hypersensitivity or allergy to risperidone.
• Subjects with hematological or other contraindications to continued clozapine treatment.