A Placebo-Controlled, Cross-Over Trial of Aripiprazole
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 4

Summary: 
      This study is a ten-week, placebo-controlled, double-blind, cross-over, randomized trial of
      the novel antipsychotic agent, aripiprazole, added to 20 obese stable olanzapine-treated
      patients with schizophrenia or schizoaffective disorder. The advantage of the crossover
      design is that each subject will act as their own control and fewer subjects will be required
      than a between-group design.
    

Detailed description: 
      Specific Aims:

      This study is a ten-week, placebo-controlled, double-blind, cross-over, randomized trial of
      the novel antipsychotic agent, aripiprazole, added to 20 obese stable olanzapine-treated
      patients with schizophrenia or schizoaffective disorder. The advantage of the crossover
      design is that each subject will act as their own control and fewer subjects will be
      required.

      Study Procedures:

      We have designed this trial to examine effects upon weight, lipids, glucose metabolism,
      positive symptoms, negative symptoms, and depressive symptoms. This project, examining the
      usefulness of combination therapy, may offer a possible intervention for patients who are
      obese and treated with olanzapine, but otherwise experiencing a good clinical response. Many
      patients, despite the medical problems that may occur, are reluctant to switch their
      antipsychotic agent.

      Location:

      This study will be performed at the Freedom Trail Clinic of the Erich Lindemann Mental Health
      Center by faculty of the Schizophrenia Program of the Massachusetts General Hospital and
      staff of the Freedom Trail Clinic.

      Subjects:

      Subjects will include 20 stable outpatients with schizophrenia or schizoaffective disorder
      treated with olanzapine for at least one year. Prior to enrollment, we will determine that
      the clinician has optimized the dose of the antipsychotic and maintained the medication at a
      stable dose for at least 1 month. Patients will be excluded for significant medical illness,
      substance abuse, or inability to provide informed consent.

      Safety Assessments:

      Medication Trial:

      Patients will have a baseline assessment performed and then randomized to placebo or
      aripiprazole 15 mg/day for 4 weeks. After the initial 4 weeks of medication patients will be
      reassessed, have a 2-week washout period and then crossover to the other treatment for
      another 4 weeks. The olanzapine dose will be unchanged during the trial. Patients will be
      given a two-week supply of medication at baseline and week 2 and then again at weeks 6 and 8.

      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, height, waist/hip circumference, skin-fold
      measurements, 12-lead EKG and demographic information will be obtained. Laboratory measures
      will include olanzapine blood levels, fasting glucose, insulin, basic chemistry profiles,
      liver enzymes, CBC, lipid profile, leptin, LDL- particle size, PAI-1, C-reactive protein,
      sICAM, vWF and a DNA sample will be drawn at screening for future analysis of the 5-HT-2C and
      H1 receptor genes.

      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 Impressions scale (CGI), Hamilton Depression Rating Scale
      (HAM-D), Global Assessment Scale (GAS), Fatigue Scale Inventory (FSI) Trauma History
      Questionnaire (THQ) and the Quality of Life Scale (QOL). A single rater will perform all
      assessments. If it is necessary to use a second rater, inter-rater reliability will be
      established before the addition of the second rater and will be repeated every three months
      by use of videotaped interviews. The treatment efficacy battery will be repeated at week 4, 6
      and 10 except for the THQ, which will only be administered at the beginning of the study.

      Safety and Monitoring Assessments:

      Blood pressure, heart rate, temperature, weight, waist/hip circumference will be performed at
      each visit (baseline, weeks 2, 4, 6, 8 and 10). Side effects will be monitored at baseline
      and weeks 2, 4, 6, 8, and 10 using the Systematic Assessment for Treatment Emergent Events
      (SAFTEE). Body fat composition will be measured by skin-fold calipers at baseline, week 4, 6
      and 10. EPS will be evaluated at baseline and weeks 2, 4, 6, 8 and 10 using the Simpson-Angus
      Scale, Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale (AIMS).

      Measure of Energy Expenditure and Dietary Assessment:

      Patients will be asked to wear an accelerometer for four consecutive days to obtain an
      objective measure of physical activity. During the same four days the patients will maintain
      a four-day food record of all food and beverages consumed. This will provide a means of
      assessing energy intake verses energy output. Patients will also complete the Modifiable
      Activity Questionnaire (MAQ). Energy expenditure and dietary intake will be assessed at
      baseline, weeks 4, 6 and 10.

      Randomization:

      The double-blind, placebo-controlled, crossover study will consist of two random order 4-week
      treatment arms (aripiprazole 15 mg or placebo) separated by a 2-week adjuvant treatment
      washout. Following baseline, subjects will be randomized, double-blind, to either
      aripiprazole or placebo for 4 weeks. After the initial 4 weeks of medication patients will be
      reassessed, have a 2-week washout period and then crossover to the other treatment for
      another 4 weeks.

      Subject Recruitment:

      Potential subjects will be identified by their clinicians at the Freedom Trail Clinic.
      Patients will give their physician verbal permission to be contacted for research purposes. A
      member of the research team will meet with the subject 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 this time. 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. 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. The human rights officer of the North Suffolk Mental
      Health Association will be asked to participate in this meeting unless the patient declines.
      Family and residential staff will also be invited to participate if the patient agrees.

      Potential Risks:

      Aripiprazole did not produce any serious adverse effects in animal and human safety studies.
      No consistent abnormality of vital signs, laboratory, EKG or EEG has emerged. In clinical
      trials, no side effects occurred at rates greater than 2x placebo. Nausea, vomiting, anxiety,
      headache, dyspepsia, somnolence, orthostatic hypotension, tachycardia, insomnia, akathisia,
      EPS, and weight gain may be potential side effects.

      Benefits:

      It is not known if aripiprazole added to olanzapine will help a subject's mood, motivation,
      hallucinations, and unusual experiences. Other patients may benefit if this study finds that
      aripiprazole added to olanzapine is useful for treating symptoms of schizophrenia.

      Data Management and Statistical Analysis:

      Data management and statistical analysis will be provided by Dr. David Schoenfeld from the
      Massachusetts General Hospital, Biostatistics Center.

      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 who is not a member of the research team 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.
    

Intervention name(s): Aripiprazole; placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Aripiprazole
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Schizophrenia; Diabetes; Obesity; Olanzapine; Insulin Resistance