Cardio Risk of Acute Schizophrenia Olanzapine Duke (CRASOD)
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ClinicalTrials.gov Identifier: NCT00672464 |
Recruitment Status
:
Withdrawn
(lack of funding)
First Posted
: May 6, 2008
Last Update Posted
: July 31, 2014
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Primary Objective: To compare added metformin and/or added simvastatin versus no intervention in reducing or eliminating increased cardiovascular risk (as estimated by elevation in non-HDL cholesterol levels) during the treatment of schizophrenia with olanzapine.
Secondary Objective(s): To compare added metformin and/or added simvastatin versus no intervention in reducing or eliminating increased cardiovascular risk (as estimated by elevation in triglyceride levels) during the treatment of schizophrenia with olanzapine. To compare added metformin and/or added simvastatin versus no intervention in reducing or eliminating increased cardiovascular risk (as estimated by C-reactive protein levels) during the treatment of schizophrenia with olanzapine
Condition or disease | Intervention/treatment | Phase |
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Schizophrenia Schizoaffective Disorder | Drug: Olanzapine Drug: Metformin Drug: Simvastatin | Phase 4 |
Olanzapine offers greater therapeutic antipsychotic benefit than the other non-clozapine antipsychotic medications available in the U.S., making it a desirable choice for the long-term maintenance treatment of patients with schizophrenia (Lieberman et al, 2005). Long-term compliance with an efficacious antipsychotic medication is fundamental to optimal therapeutic outcomes. Toward this goal, a long-acting injectable preparation of olanzapine will soon be available.
However, the long-term use of olanzapine has been limited by its substantial, un-wanted effects on metabolism that result in weight gain, increases in insulin resistance, increases in non-HDL-cholesterol, and increases in C-reactive protein (Lieberman et al, 2005; McEvoy et al, 2005;Meyer et al, 2008; McEvoy et al, in submission). Over the long term, insulin resistance contributes to the accelerated incidence of diabetes mellitus that has been observed among patients with schizophrenia since the availability of the atypical antipsychotic medication (Basu A, 2006). Over the long term, elevated non-HDL-cholesterol and increased inflammation contribute independently to the accelerated cardiovascular mortality that has been observed among patients with schizophrenia since the availability of the atypical antipsychotic medications (Saha et al, 2007, Capasso et al, 2007). Inflammation, as measured by C-reactive protein, provides added, independent predictive value of cardiovascular risk beyond that of measures of insulin resistance and elevated non-HDL-cholesterol.
Established strategies exist that may attenuate these unwanted effects of olanzapine on metabolism and inflammation. Metformin has been shown to reduce weight gain and insulin resistance in pre-diabetic, obese individuals without mental problems (Salpeper et al, 2008) and in patients treated with atypical antipsychotic medications (Wu et al, 2008). Statins have been shown to reduce non-HDL-cholesterol and cardiovascular morbidity and mortality (Lee et al, 2007). Both metformin and statins have been shown to reduce C-reactive protein (Bulcau et al, 2007).
We propose to implement a pilot study to estimate the effects sizes (for change in triglycerides, change in non-HDL-cholesterol, and change in CRP) of added metformin, added simvastatin, or added metformin and simvastatin, versus added no intervention in 120 newly-admitted, acutely psychotic, recently un-medicated patients with schizophrenia over 4 weeks of prospective treatment with olanzapine. We will also compare these patients (baseline values, in the not recently medicated state) to 40 age, race, and gender matched control subjects on fasting triglycerides, non-HDL-cholesterol, and CRP levels.
We will recruit newly admitted patients experiencing an acute psychotic relapse of schizophrenia (related to failure to take their prescribed antipsychotic medication). After baseline assessments and samplings have been completed, all patient will be treated with olanzapine zydis 15 mg QHS for 28 days. All patients will be randomized 1:1:1:1 to added metformin, added simvastatin, added metformin and simvastatin, or no intervention. All treatments will be open label. Repeated assessments of weight, non-HDL-cholesterol, triglycerides and C-reactive protein will be obtained. Subjects will remain as inpatients at JUH for the duration of the study.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 0 participants |
Allocation: | Randomized |
Intervention Model: | Factorial Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Prevention |
Official Title: | Combined Treatment of Cardiovascular Risk Factors In Newly Admitted Patients With Schizophrenia or Schizoaffective Disorder Who Are Receiving Olanzapine And Matched Controls |
Study Start Date : | April 2008 |
Estimated Primary Completion Date : | December 2009 |
Estimated Study Completion Date : | February 2010 |

Arm | Intervention/treatment |
---|---|
Active Comparator: Olanzapine only
Newly Admitted Patients with Schizophrenia or Schizoaffective Disorder Who Are Receiving Olanzapine
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Drug: Olanzapine
Olanzapine zydis 15 mg QHS for 28 days
|
Experimental: Added Metformin
Newly Admitted Patients with Schizophrenia or Schizoaffective Disorder Who Are Receiving Olanzapine with Added Metformin
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Drug: Olanzapine
Olanzapine zydis 15 mg QHS for 28 days
Drug: Metformin
Metformin capsules will be started at 500 mg twice a day (before breakfast and before dinner) for days 1-3, then 500 mg before breakfast and 1000 mg before dinner for days 4-7, and then 1000 mg twice a day thereafter.
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Experimental: Added Simvastatin
Newly Admitted Patients with Schizophrenia or Schizoaffective Disorder Who Are Receiving Olanzapine with Added Simvastatin
|
Drug: Olanzapine
Olanzapine zydis 15 mg QHS for 28 days
Drug: Simvastatin
Simvastatin will be started at 10 mg at bed time for the first week and 20 mg at bedtime thereafter.
|
Experimental: Added Metf. + Simv.
Newly Admitted Patients with Schizophrenia or Schizoaffective Disorder Who Are Receiving Olanzapine with Added Metformin and Simvastatin
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Drug: Olanzapine
Olanzapine zydis 15 mg QHS for 28 days
Drug: Metformin
Metformin capsules will be started at 500 mg twice a day (before breakfast and before dinner) for days 1-3, then 500 mg before breakfast and 1000 mg before dinner for days 4-7, and then 1000 mg twice a day thereafter.
Drug: Simvastatin
Simvastatin will be started at 10 mg at bed time for the first week and 20 mg at bedtime thereafter.
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No Intervention: Matched Controls
Matched Control Subjects by age, race, and gender
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- To compare added metformin and/or added simvastatin versus no intervention in reducing or eliminating increased cardiovascular risk (as estimated by elevation in non-HDL cholesterol levels) during the treatment of schizophrenia with olanzapine. [ Time Frame: 28 days ]
- To compare added metformin and/or added simvastatin versus no intervention in reducing or eliminating increased cardiovascular risk during the treatment of schizophrenia with olanzapine. [ Time Frame: 28 days ]

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Ages Eligible for Study: | 18 Years to 60 Years (Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
- We will include patients who come to us free of antipsychotic medication, i.e., patients with chronic schizophrenia (with at least one prior psychiatric hospitalization) who have been off antipsychotic medication for at least 3 weeks and who are newly hospitalized for treatment of an acute psychotic relapse; these patients will be male or female, 18-60 years of age, meet DSM-IV criteria for schizophrenia, and have scores >=4 on at least two of the PANSS Positive subscale items.
Exclusion Criteria:
- We will exclude patients whose psychoses are predominantly affective in nature or explainable on the basis of substance abuse or a co-morbid medical condition, patients with diabetes mellitus, epilepsy, mental retardation, or organic mental syndromes, and patients currently taking metformin or a statin.

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00672464
United States, North Carolina | |
John Umstead Hospital | |
Butner, North Carolina, United States, 27509 | |
Duke University Medical Center | |
Durham, North Carolina, United States, 27705 |
Principal Investigator: | Joseph P McEvoy, MD | Duke University Medical Center, Dep't. Psychiatry |
Responsible Party: | Duke University |
ClinicalTrials.gov Identifier: | NCT00672464 History of Changes |
Other Study ID Numbers: |
Pro00006916 None (investigator sponsored) |
First Posted: | May 6, 2008 Key Record Dates |
Last Update Posted: | July 31, 2014 |
Last Verified: | July 2014 |
Keywords provided by Duke University:
Schizophrenia Schizoaffective Cardiovascular |
Olanzapine Metformin Simvastatin |
Additional relevant MeSH terms:
Schizophrenia Psychotic Disorders Schizophrenia Spectrum and Other Psychotic Disorders Mental Disorders Metformin Simvastatin Olanzapine Hypoglycemic Agents Physiological Effects of Drugs Anticholesteremic Agents Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors |
Enzyme Inhibitors Antiemetics Autonomic Agents Peripheral Nervous System Agents Gastrointestinal Agents Antipsychotic Agents Tranquilizing Agents Central Nervous System Depressants Psychotropic Drugs Serotonin Uptake Inhibitors Neurotransmitter Uptake Inhibitors Membrane Transport Modulators Neurotransmitter Agents Serotonin Agents |