Insulin Resistance Intervention After Stroke Trial

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 drugs (called "TZDs") 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 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.

Inclusion Criteria

1. Ages 40 years or greater at the time of randomization.

2. Ischemic stroke or TIA no less than 14 days and no more than 6 months before
randomization

3. Documentation of insulin resistance as defined by a value over 3.0 on the Homeostasis
Model Assessment of insulin sensitivity (HOMA).

4. Both ability and willingness to provide informed consent.

5. Presence of none of the exclusion criteria.

Exclusion Criteria

Permanent Exclusions

1. Severely disabling stroke as indicated by an inability to participate in scheduled
follow-up activities.

2. Persons whose ischemic stroke or TIA was related to structural cardiac lesion,
significant head trauma, proximal arterial dissection or medical instrumentation.

3. 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.

4. HgbA1c > 7.0%.

5. 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).

6. History of intolerance to any thiazolidinedione.

7. Pregnancy or desire to become pregnant.

8. Oral contraceptive use.

9. Ongoing use of oral corticosteroids.

10. History of heart failure

11. 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.

12. History of bladder cancer.

13. 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.

1. ALT >2.5 times the upper limit of normal.

2. Hemoglobin <8.5 g/dl.

3. Moderate or severe pitting edema of the feet or legs (IRIS grade 3 or 4).

4. Carotid surgery or carotid stenting procedure scheduled (delay randomization until 2
weeks following procedure).