Ziprasidone for Clozapine- or Olanzapine-Associated Diabetes Mellitus
Condition: Schizophrenia
MeSH terms: Diabetes Mellitus; Schizophrenia
Study type: Interventional
Phase: Phase 4

Summary: 
      This study is a six-week, open label trial of the novel antipsychotic agent, ziprasidone,
      added to a stable dose of clozapine or olanzapine in 40 diabetes mellitus patients, patients
      with an impaired fasting glucose or insulin resistance with schizophrenia or schizoaffective
      disorder. The first two weeks will be a fixed-dose of ziprasidone 40 mg twice a day. During
      weeks 2-6, the ziprasidone dose may be increased up to 80 mg twice a day.
    

Detailed description: 
      Specific Aims:

      This study is a six-week, open label trial of the novel antipsychotic agent, ziprasidone,
      added to a stable dose of clozapine or olanzapine in 40 diabetes mellitus patients, patients
      with an impaired fasting glucose or insulin resistance with schizophrenia or schizoaffective
      disorder.

      STUDY PROCEDURES:

      We have designed this trial to examine effects upon weight, lipids and glucose metabolism
      along with positive symptoms, negative symptoms, and depressive symptoms during a six-week
      open label study.

      Location:

      This study will be performed at the Freedom Trail Clinic by faculty of the Schizophrenia
      Program of the Massachusetts General Hospital and staff of the Freedom Trail Clinic.

      Subjects:

      Subjects will include 40 outpatients with schizophrenia or schizoaffective disorder treated
      with clozapine or olanzapine for at least one year. Twenty clozapine-treated subjects and
      twenty olanzapine-treated subjects with type 2 diabetes mellitus, impaired fasting glucose,
      or insulin resistance will be recruited. Patients will be excluded for significant medical
      illness, seizure disorder, substance abuse, or inability to provide informed consent.

      Methods:

      Medication Trial:

      Patients will be treated with open label ziprasidone 40 mg 2x/day for the first 2 weeks.
      After 2 weeks the study drug may be increased up to ziprasidone 80 mg 2x/day. The clozapine
      or olanzapine dose will be unchanged during the trial. Patients will be given a two-week
      supply of medication at baseline and weeks 2 and 4 with additional capsules for study drug
      compliance and accountability. Following completion of the trial patients will have the
      option of continuing the ziprasidone. Subjects will return 4 weeks following study completion
      to examine whether any observed changes are persistent. Additionally, patients will be
      assessed at a 3 month follow-up post their 10 week assessment for metabolic changes.

      Screening Visit The diagnosis of schizophrenia or schizoaffective disorder will be confirmed
      by a research psychiatrist using DSM IV criteria. A physical examination will be performed
      and medical history, vital signs, weight, waist/hip circumference, EKG and demographic
      information will be obtained. Demographic information will also include the date of onset or
      the duration of diabetes mellitus. Laboratory measures will include a CBC, fasting glucose,
      insulin, cholesterol (total, HDL and LDL), triglycerides, hemoglobin A1C and leptin. Plasma
      will also be obtained for assay of clozapine, norclozapine, or olanzapine concentrations at
      the screening visit.

      Baseline Assessment:

      The following scales will be completed at baseline and will comprise the treatment efficacy
      battery: Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative
      Symptoms (SANS), Clinical Global Impression Scale (CGI), Hamilton Depression Rating Scale
      (HAM-D), Global Assessment Scale (GAS), Fatigue Scale Inventory (FSI) and the Quality of Life
      Scale (QOL).

      Safety Assessments:

      Vital signs, weight, and waist/hip circumference will be performed at each visit (weeks 0, 2,
      4, 6 and 10 and at the 3 month follow-up). Side effects will be monitored at baseline and
      weeks 2, 4, 6 and 10 using the SAFTEE (Levine and Schooler 1986). EPS will be evaluated at
      baseline and weeks 2, 4, 6 and 4 week follow-up using the Simpson-Angus Scale, Barnes
      Akathisia Scale, and the Abnormal Involuntary Movement Scale (AIMS). EKG will be performed at
      baseline, weeks 2, 4, 6, and 10. A patient will be discontinued from the study if their QTc
      interval is greater than 450. Changes in medication will be recorded throughout the study
      including changes to diabetes medication (weeks 0, 2, 4, 6 and 10 and at the 3-month
      follow-up).

      Energy Expenditure and Dietary Assessment:

      Patients will be asked to wear an accelerometer (Actigraph model 7164) to obtain an objective
      measure of physical activity. This is single channel accelerometer which measures and records
      vertical accelerations ranging from 0.05 to 2 G's with a frequency response of 0.25 to 2.50
      hertz. These parameters detect normal body motion and filter out high frequency movement such
      as vibrations. The accelerometer is positioned at the waist and worn for four consecutive
      days except during sleep or while in water (i.e. swimming or taking a shower). The raw data
      is then read and processed by a custom data processing program to estimate energy
      expenditure. Patients will be instructed to complete a four-day food record to assess dietary
      intake. Food records will be reviewed for completeness and analyzed using Nutrition Data
      System (NDS). Energy expenditure and dietary intake will be assessed at baseline, weeks 4 and
      6 and at the 3 month follow-up.

      Subject Recruitment:

      The Freedom Trail Clinic has well established procedures for identifying, referring and
      recruiting subjects for research. Each week clinicians and research staff meet to discuss the
      research projects that are currently being conducted and open to enrollment. Using this
      information, clinicians approach their patients they deem to be appropriate for research and
      that meet inclusion criteria. If a patient expresses interest in participating in research,
      the clinician completes a Clinician Referral Form and refers the patient to the appropriate
      research assistant for additional information regarding the study. A member of the research
      team will meet with the subject and explain the study protocol, including a review of risks
      and potential benefits.

      Patients who express interest after this first meeting will be evaluated for competency to
      provide informed consent by a physician who is not a member of the research team. Competence
      to provide consent is assessed by a research psychiatrist using the Assessment of Capacity to
      Participate in Clinical Research form. Patients who are judged to be competent will then be
      asked to meet with the principal investigator who will review the study protocol and consent
      form with the patient and obtain informed consent. A copy of the study consent form will be
      provided to the patient at this time.

      In addition, the prospective subject must ultimately score a 100% correct score on a
      True/False quiz about informed consent and the study they are interested in participating in.

      Potential Risks:

      Ziprasidone did not produce any serious adverse effects in animal and human safety studies.
      No consistent abnormality of vital signs, laboratory, or EEG has emerged. Prolongation of the
      QTC on EKG has been observed with ziprasidone treatment. In clinical trials, no side effects
      occurred at rates greater than 2x placebo. Nausea, vomiting, anxiety, headache, dyspepsia,
      somnolence, orthostatic hypotension, tachycardia, insomnia, akathisia, and EPS may be
      potential side effects.

      Benefits:

      It is not known if ziprasidone added to clozapine or olanzapine will help a subject's mood,
      motivation, hallucinations, and unusual experiences. Other patients may benefit if this study
      finds that ziprasidone added to clozapine or olanzapine is useful for treating symptoms of
      schizophrenia.

      Protection of Human Subjects:

      Principal members of our research team have all completed certification for protection of
      human subjects in clinical trials. The clinical protocol will be submitted for approval by
      the institutional review boards of the Massachusetts Department of Mental Health. Potential
      subjects will be referred by their clinicians. Clinicians will be asked to sign a statement
      that verifies that the patient is interested in participating, understands that participation
      is voluntary, and understands that declining participation will not affect treatment at the
      facility. A member of the research team will meet with the patient and explain the study
      protocol, including a review of risks and potential benefits. A copy of the study consent
      form will be provided to the patient at that time to share with family members or residential
      staff. Patients who continue to express interest after this first meeting will be evaluated
      by a physician for capacity to provide informed consent. Patients who are judged to be
      competent will then be asked to meet with the principal investigator or co-investigator who
      will review the study protocol and consent form with the patient and obtain informed consent.

      Each subject that enrolls in the study is asked to sign an authorization to release
      information to their clinician. Upon consent, a letter is sent to the clinician with
      notification of study enrollment, the duration of the study and the dose and duration of any
      study medications.

      All laboratory work and physical assessments performed during the study are either conducted
      or reviewed by a research physician. Side effects and vital signs are monitored routinely by
      the research assistants. Should any abnormal lab values or adverse events occur during the
      course of the subject's participation, the research physician would be notified immediately
      of these values and consulted on how to proceed with patient care. Furthermore, the subject's
      clinician would also be informed of the results.
    

Intervention name(s): Ziprasidone
Intervention type(s): Drug
Intervention MeSH terms: Ziprasidone
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Schizophrenia; Ziprasidone; Diabetes; Insulin Resistance