Insulin Resistance Intervention After Stroke Trial

Study Overview
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Brief Summary
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The purpose of this study is to determine if pioglitazone is effective in preventing future strokes or heart attacks among non-diabetic persons who have had a recent ischemic stroke.

Detailed Description
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Among patients throughout the world who experience a transient ischemic attack (TIA)or ischemic stroke, subsequent stroke and heart attack are major causes of death and disability. Within 4 years of the initial TIA or ischemic stroke, 16 percent of patients will have a recurrent stroke and 9 percent will have a heart attack. Prevention of further vascular events, therefore, is critically important to the health of patients with stroke. The IRIS trial will test a new treatment strategy based on evidence linking insulin resistance to increased risk for stroke and other vascular diseases. Insulin resistance is a condition in which insulin, a normal human hormone, does not work effectively because the body is resistant to its effects. This condition can lead to diabetes and is thought to cause blood vessel disease, including stroke and heart attack, in patients with and without diabetes. Insulin resistance affects up to 50% of stroke patients and is effectively modified with thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In addition to reducing insulin resistance, these drugs have other favorable effects on blood vessels, reduce blood vessel inflammation, and potentially prevent atherosclerosis. Currently marketed TZDs include rosiglitazone and pioglitazone. The IRIS is a clinical trial that will enroll 3936 subjects at approximately 170 hospitals in Australia, Canada, Germany, Israel, Italy, the United Kingdom (UK) and the US. After an initial screening blood test, each participant will be randomly assigned to take either pioglitazone or placebo tablets. Recruitment will be completed during 2005-2012, and all participants will be followed for a minimum of 3 years.

Official Title
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Insulin Resistance Intervention After Stroke (IRIS) Trial

Conditions
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Stroke, Myocardial Infarction, Diabetes

Intervention / Treatment
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* Drug: pioglitazone
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Ages 40 years or greater at the time of randomization. Ischemic stroke or TIA no less than 14 days and no more than 6 months before randomization Documentation of insulin resistance as defined by a value over 3.0 on the Homeostasis Model Assessment of insulin sensitivity (HOMA). Both ability and willingness to provide informed consent. Presence of none of the exclusion criteria. Exclusion Criteria Permanent Exclusions Severely disabling stroke as indicated by an inability to participate in scheduled follow-up activities. Persons whose ischemic stroke or TIA was related to structural cardiac lesion, significant head trauma, proximal arterial dissection or medical instrumentation. Diabetes mellitus as defined by recent use of medication for diabetes as an out-patient (*see note below) or two fasting plasma blood sugars > 126 mg/dL. HgbA1c > 7.0%. Irreversible medical conditions likely to affect short-term survival or ability to participate in the study protocol. These include: Cancer or other chronic disease with poor prognosis (predicted survival of less than four years). Severe neurologic or psychiatric disease that would complicate the evaluation of study outcomes (e.g., dementia or schizophrenia). History of intolerance to any thiazolidinedione. Pregnancy or desire to become pregnant. Oral contraceptive use. Ongoing use of oral corticosteroids. History of heart failure Active liver disease as defined by known liver disease accompanied by cirrhosis, significant cholestasis, portal hypertension, hepatic encephalopathy, hepatic synthetic dysfunction, or expected significant loss of liver function over the course of the study. History of bladder cancer. Current participation in a conflicting clinical trial. A conflicting clinical trial is defined as a trial with any of following: Intervention that is known to affect the incidence of stroke or myocardial infarction. Intervention that is an experimental drug. Outcome that includes stroke or myocardial infarction. Exclusion for participation in another trial. Temporary Exclusions Persons with temporary exclusions may be enrolled as soon as the exclusion has resolved. Alanine aminotransferase (ALT) >2.5 times the upper limit of normal. Hemoglobin <8.5 g/dl. Moderate or severe pitting edema of the feet or legs (IRIS grade 3 or 4). Carotid surgery or carotid stenting procedure scheduled (delay randomization until 2 weeks following procedure).

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pioglitazone<br>pioglitazone | Drug: pioglitazone<br>* a thiazolidinedione drug<br>|
| Placebo Comparator: Placebo<br>inactive substance | Drug: placebo<br>* an inactive substance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrent Fatal or Non-fatal Stroke, or Fatal or Non-fatal Myocardial Infarction |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fatal or Non-fatal Stroke Alone |  | 5 years | 
| Acute Coronary Syndrome | Fatal or non-fatal acute myocardial infarction or unstable angina | 5 years | 
| Development of Overt Diabetes |  | 5 years | 
| All Cause Mortality |  | 5 years | 
| Decline in Cognitive Status | Change in modified mental status examination (3MS) score from baseline to exit. Theoretical range of 3MS scores is 0-100. Baseline scores ranged from 22-100. | Annual measures from baseline to exit (up to 5 years) | 
| Composite Outcome of Fatal or Non-fatal Stroke, Fatal or Non-fatal MI or Episode of Serious Congestive Heart Failure |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, heart attack, diabetes, pioglitazone, insulin resistance