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

February 27, 2012 updated by: Takeda

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

4373

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

35 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo QD
Drug: Placebo
Pioglitazone placebo-matching tablets, orally, once daily for up to 48 months
Experimental: Pioglitazone QD
Drug: Pioglitazone
Pioglitazone 15 mg to 45 mg, tablets, orally, once daily for up to 48 months.
Other Names:
  • Actos
  • AD4833

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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.
Time Frame: At First Occurrence
At First Occurrence

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Takeda

Collaborators

Eli Lilly and Company

Investigators

  • Study Director: European Development Director, Takeda

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2001

Primary Completion (Actual)

January 1, 2005

Study Completion (Actual)

January 1, 2005

Study Registration Dates

First Submitted

September 9, 2005

First Submitted That Met QC Criteria

September 9, 2005

First Posted (Estimate)

September 15, 2005

Study Record Updates

Last Update Posted (Estimate)

February 28, 2012

Last Update Submitted That Met QC Criteria

February 27, 2012

Last Verified

February 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AD4833/EC444
  • U1111-1114-2854 (Registry Identifier: WHO)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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