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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

Tracking Information
First Submitted Date  ICMJE September 9, 2005
First Posted Date  ICMJE September 15, 2005
Last Update Posted Date February 28, 2012
Study Start Date  ICMJE May 2001
Actual Primary Completion Date January 2005   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 14, 2008)		 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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: September 9, 2005)		 Time to death, non-fatal myocardial infarction, acute coronary syndrome, cardiac intervention (PCI/CABG), stroke, leg amputation, revascularisation in the leg. Minimum 30 months follow up
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 14, 2008)
  • Time to All Cause Mortality. [ Time Frame: At occurrence ]
  • Time to Non-Fatal Myocardial Infarction. [ Time Frame: At occurrence ]
  • Time to Acute Coronary Syndrome. [ Time Frame: At occurrence ]
  • Time to Cardiac Intervention (including coronary artery bypass graft or percutaneous coronary intervention). [ Time Frame: At occurrence ]
  • Time to Stroke. [ Time Frame: At occurrence ]
  • Time to Major Leg Amputation (above the ankle). [ Time Frame: At occurrence ]
  • Time to Bypass Surgery [ Time Frame: At occurrence ]
  • Time to Revascularization of the Leg. [ Time Frame: At occurrence ]
  • Time to Cardiovascular Mortality. [ Time Frame: At occurrence ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 9, 2005)		 Adverse events
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy of Pioglitazone on Macrovascular Outcome in Patients With Type 2 Diabetes
Official Title  ICMJE 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
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Diabetes Mellitus
Intervention  ICMJE
  • Drug: Pioglitazone
    Pioglitazone 15 mg to 45 mg, tablets, orally, once daily for up to 48 months.
    Other Names:
    • Actos
    • AD4833
  • Drug: Placebo
    Pioglitazone placebo-matching tablets, orally, once daily for up to 48 months
Study Arms  ICMJE
  • Experimental: Pioglitazone QD
    Intervention: Drug: Pioglitazone
  • Placebo Comparator: Placebo QD
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 14, 2008)		 4373
Original Enrollment  ICMJE
 (submitted: September 9, 2005)		 5000
Actual Study Completion Date  ICMJE January 2005
Actual Primary Completion Date January 2005   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 35 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   Czech Republic,   Denmark,   Estonia,   Finland,   France,   Germany,   Hungary,   Italy,   Latvia,   Lithuania,   Netherlands,   Norway,   Poland,   Slovakia,   Sweden,   Switzerland,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00174993
Other Study ID Numbers  ICMJE AD4833/EC444
U1111-1114-2854 ( Registry Identifier: WHO )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Takeda
Original Responsible Party Not Provided
Current Study Sponsor  ICMJE Takeda
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Eli Lilly and Company
Investigators  ICMJE
Study Director: European Development Director Takeda
PRS Account Takeda
Verification Date February 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP