Efficacy of Pioglitazone on Macrovascular Outcome in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to determine whether pioglitazone, once daily (QD), can delay the time to death, heart attack, acute coronary syndrome, heart bypass surgery, stroke, leg bypass surgery or amputation in patients with type 2 diabetes.

Detailed Description
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Diabetes mellitus is one of the most common non-communicable diseases worldwide. More than 22 million persons have been diagnosed with diabetes in the European region of the International Diabetes Federation. Complications of diabetes involving both microvascular and macrovascular systems contribute to increased disability and reduced life expectancy. Damage to the coronary, cerebral (brain), and peripheral vascular beds as a consequence of diabetes is responsible for the increased macrovascular illness and death associated with the disease. Insulin resistance is common to the genesis of both atherosclerosis and type 2 diabetes mellitus. In diabetes, insulin resistance is coupled to receptor dysfunction. In atherosclerosis, insulin resistance may have both direct effects on the cardiovascular system as well as indirect effects provoked by imbalances in blood glucose, lipids, clotting factors, endothelial function, and other factors. Considerable indirect evidence suggests that peroxisome proliferator-activated receptor agonists may favorably influence macrovascular outcome, either through modification of risk factors (such as blood lipids) or through effects on the vessel wall. Pioglitazone, a thiazolidinedione compound discovered by Takeda Pharmaceutical Company, Ltd, functions as a peroxisome proliferator-activated receptor agonist as its mode of action. This study is designed to assess whether pioglitazone in combination with other medications administered for glycemic management of type 2 diabetes might reduce the incidence of macrovascular events associated with this disease compared with placebo. Individuals who participate in this study will provide written informed consent and will be required to commit to screening and randomization visits and approximately 17 additional visits (1 every 2 months for the first year and every 3 months thereafter) at the study center. Study participation is anticipated to be about 40 months (or approximately 3 years and 4 months). Multiple procedures will occur at each visit which may include fasting, blood collection, physical examinations and electrocardiograms.

Official Title
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PROspective PioglitAzone Clinical Trial In MacroVascular Events: A Macrovascular Outcome Study in Type 2 Diabetic Patients Comparing Pioglitazone With Placebo in Addition to Existing Therapy

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: Pioglitazone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Type 2 diabetes mellitus Glycosylated hemoglobin above the upper limit of normal (ie, the local equivalent of 6.5% for) Established history of macrovascular disease, defined as 1 or more of: Myocardial infarction at least 6 months before entry into the study. Stroke at least 6 months before entry into the study Percutaneous coronary intervention or coronary artery bypass graft at least 6 months before entry into the study. Acute coronary syndrome at least 3 months before entry into the study. Objective evidence of coronary artery disease. Peripheral arterial obstructive disease Exclusion Criteria Signs of type 1 diabetes. Patients prescribed insulin as sole therapy for glycemic control of diabetes for 2 weeks or more at any time in the previous 3 months. Myocardial infarction, stroke, coronary artery bypass graft, or percutaneous cardiac intervention in the 6 months prior to enrolment. Acute coronary syndrome in the 3 months prior to enrolment. Heart failure at entry defined as patient having a New York Heart Association functional score of II or above. Had an appointment for a coronary angiogram or endovascular or surgical intervention. Leg ulcers, gangrene, or ischemic rest pain. Had an appointment for an angiogram or endovascular or surgical intervention for leg ischemia. Had undergone a major operation (defined as a surgical procedure lasting for more than 30 minutes) at any time in the previous 4 weeks. Significantly impaired hepatic function, defined as alanine aminotransferase greater than 2.5 times the upper limit of normal. Familial polyposis coli. Required dialysis. History of alcohol or drug abuse. Any other intercurrent disease believed to be likely to have a significant impact on the patient's life expectancy during the course of the study (eg, cancer). Patient was undergoing follow-up as part of another clinical trial or less than 3 months had elapsed since the last dose of an investigational drug or procedure. Hypersensitivity to pioglitazone or other TZD. Current use of pioglitazone or other TZD. Patient was known to be infected with human immunodeficiency virus or was known to have viral hepatitis. Women who were any of the following: pregnant, breast feeding, wished to become pregnant during the course of the study or of childbearing potential and not planning to use a reliable method of contraception throughout the study.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pioglitazone QD<br> | Drug: Pioglitazone<br>* Pioglitazone 15 mg to 45 mg, tablets, orally, once daily for up to 48 months.<br>* Other names: AD4833;|
| Placebo Comparator: Placebo QD<br> | Drug: Placebo<br>* Pioglitazone placebo-matching tablets, orally, once daily for up to 48 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the Composite of All Cause Mortality, Non-Fatal Myocardial Infarction, Stroke, Acute Coronary Syndrome, Major Leg Amputation, Cardiac Intervention, Bypass Surgery or Leg Revascularization. |  | At First Occurrence | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to All Cause Mortality. |  | At occurrence | 
| Time to Non-Fatal Myocardial Infarction. |  | At occurrence | 
| Time to Acute Coronary Syndrome. |  | At occurrence | 
| Time to Cardiac Intervention (including coronary artery bypass graft or percutaneous coronary intervention). |  | At occurrence | 
| Time to Stroke. |  | At occurrence | 
| Time to Major Leg Amputation (above the ankle). |  | At occurrence | 
| Time to Bypass Surgery |  | At occurrence | 
| Time to Revascularization of the Leg. |  | At occurrence | 
| Time to Cardiovascular Mortality. |  | At occurrence | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucose Metabolism Disorder, Dysmetabolic Syndrome, Type II Diabetes; Diabetes Mellitus, Lipoatrophic, Dyslipidemia, Drug Therapy