IRIS

Overview

Status: Active, not recruiting
Keywords: Ischemic Stroke , Insulin Resistnace , Thiazolidinedione , placebo
IRB Number: 00014093
Specialty: Neurology
Sub Specialties: Stroke

Brief Summary

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. 3936 participants will be randomly assigned to pioglitazone, a thiazolidinedione (TZD), or
placebo. The specific aims are:
Primary Aim:
1. 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 non-diabetics 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 all-cause 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.

Principal Investigator: Jennifer Majersik
Department: Neurology
Co Investigator: Michael Wilder
Co Investigator: Dana DeWitt
Co Investigator: Jana Wold

Contact Information

Name:Suyi Niu
Phone: 801-587-8046
Email: suyi.niu@hsc.utah.edu

Inclusion Criteria

a. Ages 40 years or greater at the time of randomization.
b. Ischemic stroke or TIA no less than 14 days and no more than 6 months before randomization
c. Documentation of insulin resistance as defined by a value over 3.0 on the Homeostasis Model
Assessment of insulin sensitivity (HOMA).
d. Both ability and willingness to provide informed consent.
e. Presence of none of the exclusion criteria.

Exclusion Criteria

Permanent Exclusions
a. Severely disabling stroke as indicated by an inability to participate in scheduled follow-up
activities.
b. Persons whose ischemic stroke or TIA was related to structural cardiac lesion, significant
head trauma, proximal arterial dissection or medical instrumentation.
c. 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.
d. HgbA1c > 7.0%.
e. Irreversible medical conditions likely to affect short-term survival or ability to participate in the
study protocol. These include:
1. Cancer or other chronic disease with poor prognosis (predicted survival of less than four
years).
2. Severe neurologic or psychiatric disease that would complicate the evaluation of study
outcomes (e.g., dementia or schizophrenia).
f. History of intolerance to any thiazolidinedione.
g. Pregnancy, desire to become pregnant, or currently breastfeeding.
h. Oral or estrogen patch contraceptive use.
i. Ongoing use of oral corticosteroids.
j. History of heart failure (includes patients with current or previous NYHA class 1-4 heart
failure).
k. 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.
l. History of bladder cancer.
m. High risk for bladder cancer (i.e., current uninvestigated macroscopic hematuria, history of
cyclophosphamide exposure, or history of irradiation of the pelvic region).
n. Current participation in a conflicting clinical trial. A conflicting clinical trial is defined as a trial
with any of following:
1. Intervention that is known to affect the incidence of stroke or myocardial infarction.
2. Intervention that is an experimental drug.
3. Outcome that includes stroke or myocardial infarction.
4. Exclusion for participation in another trial.

Temporary Exclusions
Persons with temporary exclusions may be enrolled as soon as the exclusion has resolved.
a. ALT >2.5 times the upper limit of normal.
b. Hemoglobin <8.5 g/dl.
c. Moderate or severe pitting edema of the feet or legs (IRIS grade 3 or 4).
d. 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.