The purpose of IRIS is to determine the effectiveness of pioglitazone, compared with placebo, for prevention of recurrent stroke and heart attack among non-diabetic men and women with a recent ischemic stroke or transient ischemic attack (TIA) and insulin resistance.
Potential participants for IRIS will be screened for insulin resistance by means of a blood test at over 100 research centers throughout the world. Those with insulin resistance will be randomly assigned to receive pioglitazone or placebo for an average duration of 4 years. During the trial, IRIS researchers will stay in close contact with participants to monitor progress, ask about recurrent stroke or heart attacks, and encourage health behaviors that will reduce stroke risk. Researchers will telephone participants or visit them in person every 4 months (more frequently as needed). Neither IRIS participants nor the study researchers will know if a participant is taking pioglitazone or placebo until the end of the research. Blood will be drawn before a patient enters the IRIS trial and every year from the date of study entry. This blood will be tested to determine the effectiveness of pioglitazone in reducing insulin resistance, detect side effects, screen for new diabetes, and monitor stroke risk factors.
The IRIS Trial is funded by the National Institute of Neurological Disorders and Stroke, a division of the United States National Institutes of Heath. Study pills are provided by the manufacturer of pioglitazone, Takeda Pharmaceuticals North America.
Men and women with an ischemic-type stroke or TIA within the past 6 months may participate if they are:
- Age 40 years or older
- Able to stand, communicate, and participate in follow-up
- Insulin resistant as determined by a special blood test
Persons with any of the following conditions will be excluded from participation in IRIS:
- Heart failure
- Marked swelling of the feet and legs (edema)
- Active liver disease, severe anemia, or other medical condition that will severely limit life expectancy
- Use of steroids or birth control pills
- Pregnancy or intention to get pregnant
The following table describes the basic activities for IRIS participants in the order they occur.
|Sign an Informed Consent Document||Soon after the stroke/TIA.||For persons who may want to participate in IRIS, a researcher will explain the study in detail. The potential participant will then sign one or more document(s) that will allow researchers to do further test to confirm their eligibility and possibly enter them into the IRIS trial.|
|Screening Blood Test||At least 2 weeks after the stroke/TIA, but no more than 6 months.||Persons who may be eligible for IRIS first undergo a blood test to determine if they have insulin resistance or any illnesses that might make them ineligible. Those illnesses include unrecognized diabetes, anemia, or liver disease. Blood is drawn after a standard overnight fast of 10 hours. Patients may drink water and take all of their usual medications during this fast, but they may not drink other liquid or food. Results are available in about a week.|
|Treatment Assignment||About one week after the blood tests.||Patients who are eligible for participation based on the blood testing undergo a final interview and brief physical examination. A computer program is used to randomly assign them to receive either pioglitazone or placebo (an inactive look-alike pill).|
|Dose Escalation||During the first 2 months after the study drug is started.||Participants begin taking one pill daily for a month, then two pills daily for a month, then three pills daily for a month. These initial pills contain pioglitazone 15 mg or placebo. IRIS research staff will call participants every two weeks during this initial part of the study to answer questions, ask about side effects, and remind them to increase their dose. After the third month, participants receive a single 45 mg pioglitazone pill or placebo.|
Insulin resistance is a common condition that affects about one out of every four adults. It is particularly common among persons who are older, inactive, or overweight. Insulin resistance is important because it can lead to diabetes and vascular disease that can cause heart attack and stroke.
Insulin is a hormone (a chemical signal) that enters the bloodstream after a meal. The insulin travels to muscle and other cells, opening "doors" to let in sugar from the meal. Under normal circumstances, insulin assures that the concentration of sugar in the blood stream stays within a narrow, safe range. Under circumstances of insulin resistance, however, the doors on cells do not open properly in response to insulin and sugar cannot get in. As a consequence, the body makes more insulin to overcome the resistance and force open the doors. If the body cannot make enough insulin, sugar builds up in the bloodstream and diabetes develops. However, most people with insulin resistance do not have diabetes - they are able to make enough insulin to keep blood sugar in a reasonable range.
In addition to causing high insulin and blood sugar, insulin resistance is linked to atherosclerosis, the vascular disease that causes most strokes and heart attacks. Recent research shows that persons with insulin resistance are more likely to have strokes and heart attacks compared to persons without insulin resistance. As a result of this research, scientists are interested in knowing if treatment of insulin resistance can prevent these vascular events.
Pioglitazone (pronounced "Pie-Oh-Glit-Ah-Zone") is a medication that is commonly used to treat patients with Type 2 (or Adult-Onset) diabetes. It is also known by its trade-name, ACTOSTM. Pioglitazone works by reducing insulin resistance. When diabetic patients take pioglitazone, the body's response to insulin improves and blood sugar levels return toward normal. Pioglitazone never causes the blood sugar to fall below normal unless a patient is also taking insulin or other diabetes medications.
Pioglitazone has been used in the United States since 1999, and several million patients with diabetes have used it throughout the world. IRIS participants will start by taking one pill daily that contains 15 mg of pioglitazone or placebo. The dose will be gradually increased to three pills daily over two months to a final dose of 45 mg daily of pioglitazone or placebo. Pioglitazone can be taken with or without food, and with or without other medications.
Most patients do well on pioglitazone with no significant side effects. As with any medication, however, side effects may occur in some patients. The most common are weight gain and swelling of the feet and legs (edema).
In people without diabetes, such as those in IRIS, pioglitazone can lead to weight gain of about 3-4 pounds. For persons who gain weight, cutting down on food intake and getting more physical exercise to burn calories will help. Of course, as with any drug, side effects are variable. Some patients gain no weight and others gain more weight than usual.
Swelling of the Feet or Legs
Pioglitazone may cause swelling in the feet or legs in about 1 in 20 patients. The first sign is usually puffy feet or ankles, especially toward the end of the day. If this is mild, nothing needs to be done. Edema is a relatively common condition with many causes, including high salt intake, immobility, varicose veins, and heart disease. If swelling becomes severe or uncomfortable and no other cause is found, it can be relieved by reducing the dose.
Heart Failure Symptoms
Heart failure is a condition associated with shortness of breath during exertion or, sometimes, at rest. It occurs when the pumping action of the heart is not adequate to move blood through the body. This problem may happen, for example, when the heart muscle is damaged by a heart attack or years of high blood pressure. Heart failure can cause fluid to build up in the legs and lungs. This may result in leg swelling or shortness of breath. Heart failure is treated with medications like diuretics (water pills).
Pioglitazone does not harm the heart, but it can cause fluid retention. As a result, there is a very small chance that pioglitazone might worsen leg swelling or shortness of breath in patients with existing heart failure. There is also an extremely low risk that pioglitazone might cause swelling or shortness of breath in patients who are not known to have heart failure (because of unrecognized heart disease). Prior studies have found that about 1 in 100 patients treated with pioglitazone developed new or worsening symptoms of heart failure.
To reduce the chance of significant heart failure symptoms, IRIS patients with heart failure will not be enrolled. All IRIS participants will be monitored for shortness of breath and other symptoms that may indicate fluid retention, such as swollen ankles or excessive weight gain. If these symptoms develop, participants will be referred to their personal doctor or an IRIS clinician for evaluation. Often, these symptoms are not due to heart failure and other causes are found. However, if heart failure is confirmed as the cause of the symptoms, the dose of the IRIS study medication may be reduced or stopped. We don't expect worsening heart failure symptoms to occur often among IRIS participants, but we will monitor participants carefully to ensure their safety.
An older drug related to pioglitazone, troglitazone, was removed from the market in 1999 because of rare instances of liver failure. Although the two medications are chemically different, doctors were originally asked to check blood tests every 2 months to screen for liver disease. Fortunately, no evidence emerged to suggest that pioglitazone caused serious liver disease. As a result, in early 2004 the FDA changed its recommendations, and now persons have a liver blood test before starting the drug, and periodically during treatment. To ensure safety, we will measure liver blood tests in IRIS participants before entry and annually from the date of entry.
Anemia (low blood count)
Pioglitazone may be associated with a small decline in the blood hemoglobin concentration, a measure of anemia. This decline is probably caused by an increase in the volume of fluid in the blood stream, diluting the hemoglobin slightly. The effect typically produces no more than a 1-2% fall in hemoglobin (for example, from 14 g/dl to 13.7 g/dl). The FDA does not recommend routine monitoring of the hemoglobin during pioglitazone therapy for diabetic patients. However, we will check hemoglobin at study entry.