IRIS: The Insulin Resistance Intervention after Stroke Trial
Objectives (Aims): The Insulin Resistance Intervention after Stroke Trial (IRIS) is a
randomized, double-blind, placebo-controlled trial that will test the hypothesis that
reducing insulin resistance and its sequelae with thiazolidinedione therapy will prevent
stroke and myocardial infarction (MI) among patients with a recent ischemic stroke or
transient ischemic attack (TIA). Eligible participants are men and women 40 years or
older without diabetes mellitus who have insulin resistance and a recent non-disabling
ischemic stroke or TIA. 3136 participants will be randomly assigned to pioglitazone, a
thiazolidinedione (TZD), or placebo. The specific aims are:
Primary Aim:
To determine if pioglitazone, compared to placebo, will reduce the overall risk for fatal
or non-fatal stroke or fatal or non-fatal MI among non-diabetic men and women 40
years or older with insulin resistance and a recent ischemic stroke or TIA. Among nondiabetics with insulin resistance, we hypothesize that pioglitazone will reduce the
occurrence of any primary endpoint (fatal or non-fatal stroke or MI) within four years
from 27% to 22%.
Secondary Aims:
1. To determine if pioglitazone, compared to placebo, will reduce the risk for
stroke. We hypothesize that pioglitazone will reduce the occurrence of fatal or
non-fatal stroke as a discrete outcome.
2. To determine if pioglitazone, compared to placebo, will reduce the risk for
acute coronary syndromes (acute MI or unstable angina). Unstable angina is an
important clinical event because it identifies individuals at high risk for MI who
need urgent diagnostic and therapeutic intervention. We hypothesize that
pioglitazone will reduce the overall occurrence of acute coronary syndromes.
3. To determine if pioglitazone, compared to placebo, is effective in preventing
progression to overt diabetes. Insulin resistance is the principal risk factor for type
II diabetes. We hypothesize that pioglitazone, by sensitizing cells to insulin’s
action, will prevent progression to diabetes.
4. To determine if pioglitazone, compared to placebo, will reduce the risk for allcause mortality. We hypothesize that pioglitazone will reduce all-cause mortality
because of its potent vasoprotective effects.
5. To determine if pioglitazone, compared to placebo, will reduce the risk for
cognitive decline. We hypothesize that pioglitazone will reduce the risk for
cognitive decline by reducing the incidence of clinically apparent and unapparent
stroke.
6. To determine if pioglitazone, compared to placebo, will reduce the overall risk for
fatal or non-fatal stroke or fatal or non-fatal MI or episodes of congestive heart
failure.
Number of Subjects: There will be 3136 participants.
Inclusion/Exclusion Criteria
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 outpatient (*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).
*Patients who have taken a medication to treat diabetes in the prior 3 months as an
out-patient will not be eligible for participation. However, a patient who has recently
taken a diabetes medication while hospitalized or for a reason other than diabetes (e.g.,
for impaired glucose tolerance), may be tested for eligibility after at least 7 days off the
medication.