Rosiglitazone for Clozapine Induced Glucose Metabolism Impairment
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 4

Summary: 
      We propose an eight-week, double-blind, placebo-controlled trial of rosiglitazone in
      schizophrenia subjects treated with clozapine using Bergman's Minimal Model (MINMOD)
      intravenous glucose tolerance test. Bergman's Minimal Model analysis with frequent sampled
      intravenous glucose tolerance test (FSIVGTT) provides a sensitive and reliable method to
      measure glucose effectiveness, insulin secretion and insulin sensitivity. The MINMOD
      determines the relationship between insulin sensitivity, insulin secretion and the degree of
      obesity and can be used to study drug effects upon these variables.
    

Detailed description: 
      This study is an eight-week, double-blind, placebo-controlled trial of rosiglitazone in
      schizophrenia subjects treated with clozapine using Bergman's Minimal Model Analysis (MINMOD)
      frequent sampled intravenous glucose tolerance test (FSIVGTT) for examination of glucose
      metabolism. Rosiglitazone, used for the treatment of type 2 diabetes, improves glycemic
      control by improving insulin sensitivity in target tissues while increase glucose uptake and
      improving signaling between insulin and glucose transporters. The MINMOD determines the
      relationship between insulin sensitivity, insulin secretion and the degree of obesity and can
      be used to study drug effects upon these variables. The computer program estimates glucose
      effectiveness (SG), insulin sensitivity (SI), and the acute insulin response to glucose
      (AIRG) from glucose and insulin values measured during the FSIVGTT.

      The site for subject enrollment, clinical assessment and collection of blood samples at weeks
      2, 4, and 6 will be at the Freedom Trail Clinic of the Erich Lindemann Mental Health Center.
      The FSIVGTT and blood samples at baseline and week 8 will be conducted at the Mallinckrodt
      General Clinical Research Center at Massachusetts General Hospital. Subjects will include 50
      clozapine treated patients with the diagnosis of schizophrenia or schizoaffective disorder.
      Subjects will be matched according to baseline fasting glucose.

      Subjects will be maintained on their pre-study medication. During the baseline assessment, a
      member of the research team will conduct the PANSS (Positive and Negative Symptom Subscale)
      and HAM-D (Hamilton Rating Scale for Depression) which will be repeated at weeks 4 and 8 to
      determine baseline and subsequent changes in psychopathology. The neuropsychological battery
      will be administered at baseline and week 8 and will consist of: North America Adult Reading
      Test, Trail Making, Degraded Stimulus Continuous Performance Test, California Verbal Learning
      Test, Faces and Family Picture subtests from WMS-III, Wisconsin Card Sorting Test, Letter and
      Category Fluency, Letter-Number Sequencing, and Grooved Peg Board. Baseline medical
      evaluation will include weight, height, vital signs, AIMS score, a 12-lead EKG and a physical
      examination.

      Subjects will be instructed to eat a diet high in carbohydrates for three days before the
      FSIVGTT. They are instructed to fast for 12 hours preceding the test. On the morning of the
      test, subjects will be admitted to the General Clinical Research Center at Massachusetts
      General Hospital. A nutritional assessment will be performed. Baseline blood samples for
      fasting glucose, basic chemistry profiles, liver enzymes, complete blood count (cbc),
      insulin, prolactin, lipid profile, glycohemoglobin, leptin, clozapine serum levels and
      cortisol will be drawn. Glucose 0.3 g/kg body weight will be infused. Approximately 35 2 cc
      blood samples will be withdrawn for measurement of glucose and insulin concentration. At
      minute 20, 0.05 units/kg of insulin will be administered as an intravenous bolus injection.

      Following baseline FSIVGTT, subjects will be randomized, double-blind, to either
      rosiglitazone or placebo. Subjects randomized to receive medication will receive
      rosiglitazone 4mg po qd for eight weeks or until study end. Subjects will be monitored for
      symptoms of diabetes at weeks 2, 4, and 8. Subjects will be evaluated at weeks 2, 4, and 8
      including measurements of blood pressure, pulse and weight. Adverse events will be monitored
      at weeks 2, 4, and 8 with the AMDP-5, a survey of side effects and somatic symptoms. The
      Medical Outcomes Study Short Form-12 (SF-12) will be used to measure general health status
      and function. The SF-12 will be performed at baseline, weeks 4, and 8 or study end.

      A cbc will be performed every two weeks, consistent with the requirements for treatment with
      clozapine. At week four, a fasting glucose, insulin level, and liver function tests will be
      performed. At the end of the eighth week, the FSIVGTT will be repeated and blood samples will
      be obtained for fasting glucose, basic chemistry profiles, liver enzymes, complete blood
      count (cbc), insulin, prolactin, lipid profile, glycohemoglobin, leptin, clozapine serum
      levels and cortisol. All other aspects of the subjects care will be treatment as usual.

      Potential risks associated with an intravenous line include bruising at the site, bleeding
      and the risk of infection. During the procedure patient may experience symptoms of low blood
      glucose including lightheadedness, dizziness, weakness, irritability, sweating, tremor,
      tachycardia, anxiety, and hunger. The amount of blood drawn with each FSIVGTT is
      approximately 150 cc. A low risk of anemia exists secondary to the FSIVGTT; anemia has also
      been a side effect of treatment with rosiglitazone. Treatment with rosiglitazone has been
      associated with side effects including accidental injury (cuts and abrasions), headache, back
      pain, anemia, edema, weight gain, decreased white blood cell count, increases in total
      cholesterol, LDL, and HDL and decreases in free fatty acids. Phlebotomy may produce
      discomfort, bruising, and rarely, infection. While the clinical assessment may be stressful,
      the questions contained in the SCID and PANSS do not differ from those asked in routine
      clinical evaluations.

      Potential benefits to the subject include a comprehensive diagnostic re-evaluation, screening
      blood tests, and estimation of risk of diabetes. The results of the tests will be shared with
      patients and clinicians and may contribute to medical management by helping the patient's
      physician in deciding if an intervention is required to reduce the risk of diabetes. An
      increased understanding of the process by which clozapine induces glucose intolerance and the
      awareness that diabetes and its complications can be prevented with concomitant treatment
      with an insulin sensitizer are potential benefits to this population.
    

Intervention name(s): rosiglitazone; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Rosiglitazone 4mg, one capsule per day for eight weeks; matched placebo for rosiglitazone 4mg/day
Intervention MeSH terms: Rosiglitazone
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Schizophrenia; Glucose Metabolism; Insulin Resistance