Diabetes, Myocardial Infarction, Stroke
Conditions
Keywords
stroke, heart attack, diabetes, pioglitazone, insulin resistance
Brief summary
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
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.
Interventions
DRUGpioglitazone
a thiazolidinedione drug
DRUGplacebo
an inactive substance
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Takeda Pharmaceuticals North America, Inc.
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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
.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Recurrent Fatal or Non-fatal Stroke, or Fatal or Non-fatal Myocardial Infarction | Up to 5 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Coronary Syndrome | 5 years | Fatal or non-fatal acute myocardial infarction or unstable angina |
| Development of Overt Diabetes | 5 years | — |
| Fatal or Non-fatal Stroke Alone | 5 years | — |
| Decline in Cognitive Status | Annual measures from baseline to exit (up to 5 years) | 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. |
| Composite Outcome of Fatal or Non-fatal Stroke, Fatal or Non-fatal MI or Episode of Serious Congestive Heart Failure | 5 years | — |
| All Cause Mortality | 5 years | — |
Countries
Australia, Canada, Germany, Israel, Italy, Puerto Rico, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone pioglitazone: a thiazolidinedione drug | 1,939 |
| Placebo placebo: an inactive substance | 1,937 |
| Total | 3,876 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 58 | 41 |
| Overall Study | Withdrawal by Subject | 117 | 110 |
Baseline characteristics
| Characteristic | Placebo | Total | Pioglitazone |
|---|---|---|---|
| Age, Continuous | 63.5 Years STANDARD_DEVIATION 10.6 | 63.5 Years STANDARD_DEVIATION 10.7 | 63.5 Years STANDARD_DEVIATION 10.7 |
| Region of Enrollment Australia | 55 participants | 108 participants | 53 participants |
| Region of Enrollment Canada | 271 participants | 543 participants | 272 participants |
| Region of Enrollment Germany | 77 participants | 151 participants | 74 participants |
| Region of Enrollment Israel | 88 participants | 178 participants | 90 participants |
| Region of Enrollment Italy | 26 participants | 48 participants | 22 participants |
| Region of Enrollment Puerto Rico | 11 participants | 20 participants | 9 participants |
| Region of Enrollment United Kingdom | 133 participants | 256 participants | 123 participants |
| Region of Enrollment United States | 1276 participants | 2572 participants | 1296 participants |
| Sex: Female, Male Female | 692 Participants | 1338 Participants | 646 Participants |
| Sex: Female, Male Male | 1245 Participants | 2538 Participants | 1293 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,007 / 1,939 | 724 / 1,937 |
| serious Total, serious adverse events | 950 / 1,939 | 987 / 1,937 |
Outcome results
Primary
Recurrent Fatal or Non-fatal Stroke, or Fatal or Non-fatal Myocardial Infarction
Time frame: Up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Recurrent Fatal or Non-fatal Stroke, or Fatal or Non-fatal Myocardial Infarction | 175 participants |
| Placebo | Recurrent Fatal or Non-fatal Stroke, or Fatal or Non-fatal Myocardial Infarction | 228 participants |
p-value: 0.006795% CI: [0.62, 0.93]Regression, Cox
Secondary
Acute Coronary Syndrome
Fatal or non-fatal acute myocardial infarction or unstable angina
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Acute Coronary Syndrome | 206 participants |
| Placebo | Acute Coronary Syndrome | 249 participants |
p-value: 0.1195% CI: [0.52, 1.07]Regression, Cox
Secondary
All Cause Mortality
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | All Cause Mortality | 136 participants |
| Placebo | All Cause Mortality | 146 participants |
p-value: 0.5295% CI: [0.73, 1.17]Regression, Cox
Secondary
Composite Outcome of Fatal or Non-fatal Stroke, Fatal or Non-fatal MI or Episode of Serious Congestive Heart Failure
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Composite Outcome of Fatal or Non-fatal Stroke, Fatal or Non-fatal MI or Episode of Serious Congestive Heart Failure | 206 participants |
| Placebo | Composite Outcome of Fatal or Non-fatal Stroke, Fatal or Non-fatal MI or Episode of Serious Congestive Heart Failure | 249 participants |
p-value: 0.1195% CI: [0.65, 1.05]Regression, Cox
Secondary
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.
Time frame: Annual measures from baseline to exit (up to 5 years)
Population: Participants with baseline and at least 1 follow-up modified mini-mental examination score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Decline in Cognitive Status | 0.27 units on a scale | Standard Error 0.13 |
| Placebo | Decline in Cognitive Status | 0.29 units on a scale | Standard Error 0.13 |
Comparison: Changes in modified mini-mental examination (3MS) score from baseline (to annual scores) were analyzed using a longitudinal repeated measures mixed effects model.p-value: 0.8895% CI: [-0.326, 0.28]Mixed Models Analysis
Secondary
Development of Overt Diabetes
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Development of Overt Diabetes | 73 participants |
| Placebo | Development of Overt Diabetes | 149 participants |
Secondary
Fatal or Non-fatal Stroke Alone
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Fatal or Non-fatal Stroke Alone | 127 participants |
| Placebo | Fatal or Non-fatal Stroke Alone | 154 participants |
p-value: 0.1995% CI: [0.61, 1.1]Regression, Cox