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

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ClinicalTrials.gov Identifier: NCT00174993
Recruitment Status : Completed
First Posted : September 15, 2005
Last Update Posted : February 28, 2012
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Takeda

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus Drug: Pioglitazone Drug: Placebo Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4373 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : May 2001
Actual Primary Completion Date : January 2005
Actual Study Completion Date : January 2005

Resource links provided by the National Library of Medicine


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


Outcome Measures
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Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. Time to All Cause Mortality. [ Time Frame: At occurrence ]
  2. Time to Non-Fatal Myocardial Infarction. [ Time Frame: At occurrence ]
  3. Time to Acute Coronary Syndrome. [ Time Frame: At occurrence ]
  4. Time to Cardiac Intervention (including coronary artery bypass graft or percutaneous coronary intervention). [ Time Frame: At occurrence ]
  5. Time to Stroke. [ Time Frame: At occurrence ]
  6. Time to Major Leg Amputation (above the ankle). [ Time Frame: At occurrence ]
  7. Time to Bypass Surgery [ Time Frame: At occurrence ]
  8. Time to Revascularization of the Leg. [ Time Frame: At occurrence ]
  9. Time to Cardiovascular Mortality. [ Time Frame: At occurrence ]

Eligibility Criteria
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Ages Eligible for Study:   35 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00174993


  Show 19 Study Locations
Sponsors and Collaborators
Takeda
Eli Lilly and Company
Investigators
Study Director: European Development Director Takeda
More Information
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Additional Information:
ACTOS Package Insert  This link exits the ClinicalTrials.gov site
FDA Safety Alerts and Recalls  This link exits the ClinicalTrials.gov site

Publications of Results:
Erdmann E, Dormandy JA. The Effect of Pioglitazone on Recurrent Myocardial Infarction in 2445 Patients with Type 2 Diabetes and Preexisting Myocardial Infarction - Data from the PROactive Study. Circulation 2005;112:(21):3364-3364
Spanheimer,RG, Ferrannini,E, Long term effects of pioglitazone on diabetic dyslipidemia independent of baseline statin use and antihyperglycemic medication: a review from PROactive. Asia Pac J Cardiol 2009;1:(1):75-81.

Other Publications:
Bottomley JM, Palmer AJ, Williams R, Dormandy JA, Massi-Benedetti M. PROactive 03: Pioglitazone, type 2 diabetes and reducing macrovascular events - economic implications?. Br J Diabetes Vasc Dis 2006;6(Pt 2):64-69
Kirby,M, Heart Disease Prevention - What Place for the Glitazones. Br J Cardiol 2006;13:(1):66-70.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00174993     History of Changes
Other Study ID Numbers: AD4833/EC444
U1111-1114-2854 ( Registry Identifier: WHO )
First Posted: September 15, 2005    Key Record Dates
Last Update Posted: February 28, 2012
Last Verified: February 2012

Keywords provided by Takeda:
Glucose Metabolism Disorder
Dysmetabolic Syndrome
Type II Diabetes; Diabetes Mellitus
 Lipoatrophic
Dyslipidemia
Drug Therapy

Additional relevant MeSH terms:
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
 Pioglitazone
Hypoglycemic Agents
Physiological Effects of Drugs