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

Diabetes Mellitus Clinical Trial

— PROactive  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00174993
• Other study ID #: AD4833/EC444
• Secondary ID: U1111-1114-2854
• Status: Completed
• Phase: Phase 3
• First received: September 9, 2005
• Last updated: February 27, 2012
• Start date: May 2001
• Est. completion date: January 2005

Study information

• Verified date: February 2012
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesItaly: The Italian Medicines AgencyAustria: Federal Ministry for Health and WomenSwitzerland: SwissmedicBelgium: The Federal Public Service (FPS) Health, Food Chain Safety and EnvironmentDenmark: Danish Medicines AgencySweden: Medical Products AgencyFinland: Finnish Medicines AgencyNorway: Norwegian Medicines AgencyNetherlands: Medicines Evaluation Board (MEB)Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsHungary: National Institute of PharmacySlovakia: State Institute for Drug ControlCzech Republic: State Institute for Drug ControlLatvia: State Agency of MedicinesLithuania: State Medicine Control Agency - Ministry of HealthEstonia: The State Agency of Medicine
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4373
• Est. completion date: January 2005
• Est. primary completion date: January 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 35 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus

Intervention

Drug:
• Pioglitazone
Pioglitazone 15 mg to 45 mg, tablets, orally, once daily for up to 48 months.
• Placebo
Pioglitazone placebo-matching tablets, orally, once daily for up to 48 months

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Takeda	Eli Lilly and Company

Countries where clinical trial is conducted

Austria,  Belgium,  Czech Republic,  Denmark,  Estonia,  Finland,  France,  Germany,  Hungary,  Italy,  Latvia,  Lithuania,  Netherlands,  Norway,  Poland,  Slovakia,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (27)

Betteridge DJ, DeFronzo RA, Chilton RJ. PROactive: time for a critical appraisal. Eur Heart J. 2008 Apr;29(8):969-83. doi: 10.1093/eurheartj/ehn114. Epub 2008 Mar 28. Review. — View Citation

Betteridge DJ. CHICAGO, PERISCOPE and PROactive: CV risk modification in diabetes with pioglitazone. Fundam Clin Pharmacol. 2009 Dec;23(6):675-9. doi: 10.1111/j.1472-8206.2009.00741.x. Epub 2009 Sep 10. Review. — View Citation

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

Brändle M, Goodall G, Erny-Albrecht KM, Erdmann E, Valentine WJ. Cost-effectiveness of pioglitazone in patients with type 2 diabetes and a history of macrovascular disease in a Swiss setting. Swiss Med Wkly. 2009 Mar 21;139(11-12):173-84. doi: smw-12381. — View Citation

Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A; PROactive Study Group. The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline c — View Citation

Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR; PROactive investigators. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf. 2009;32(3):187-202. doi: 10.2165/00002018- — View Citation

Dormandy JA, Betteridge DJ, Schernthaner G, Pirags V, Norgren L; PROactive investigators. Impact of peripheral arterial disease in patients with diabetes--results from PROactive (PROactive 11). Atherosclerosis. 2009 Jan;202(1):272-81. doi: 10.1016/j.ather — View Citation

Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefèbvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Korányi L, Laakso M, Mokán M, Norkus A, Pirags V, Po — View Citation

Erdmann E, Charbonnel B, Wilcox RG, Skene AM, Massi-Benedetti M, Yates J, Tan M, Spanheimer R, Standl E, Dormandy JA; PROactive Investigators. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data — View Citation

Erdmann E, Dormandy J, Wilcox R, Massi-Benedetti M, Charbonnel B. PROactive 07: pioglitazone in the treatment of type 2 diabetes: results of the PROactive study. Vasc Health Risk Manag. 2007;3(4):355-70. Review. — View Citation

Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM; PROactive Investigators. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from th — View Citation

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

Erdmann E, Spanheimer R, Charbonnel B; PROactive Study Investigators. Pioglitazone and the risk of cardiovascular events in patients with Type 2 diabetes receiving concomitant treatment with nitrates, renin-angiotensin system blockers, or insulin: results — View Citation

Ferrannini E, Betteridge DJ, Dormandy JA, Charbonnel B, Wilcox RG, Spanheimer R, Erdmann E, Defronzo RA, Laakso M. High-density lipoprotein-cholesterol and not HbA1c was directly related to cardiovascular outcome in PROactive. Diabetes Obes Metab. 2011 Au — View Citation

Kirby,M, Heart Disease Prevention - What Place for the Glitazones. Br J Cardiol 2006;13:(1):66-70.

Rydén L, Thráinsdóttir I, Swedberg K. Adjudication of serious heart failure in patients from PROactive. Lancet. 2007 Jan 20;369(9557):189-90. — View Citation

Scheen AJ, Tan MH, Betteridge DJ, Birkeland K, Schmitz O, Charbonnel B; PROactive investigators. Long-term glycaemic control with metformin-sulphonylurea-pioglitazone triple therapy in PROactive (PROactive 17). Diabet Med. 2009 Oct;26(10):1033-9. doi: 10. — View Citation

Scheen AJ, Tan MH, Betteridge DJ, Birkeland K, Schmitz O, Charbonnel B; PROactive investigators. Long-term glycaemic effects of pioglitazone compared with placebo as add-on treatment to metformin or sulphonylurea monotherapy in PROactive (PROactive 18). D — View Citation

Scherbaum WA, Goodall G, Erny-Albrecht KM, Massi-Benedetti M, Erdmann E, Valentine WJ. Cost-effectiveness of pioglitazone in type 2 diabetes patients with a history of macrovascular disease: a German perspective. Cost Eff Resour Alloc. 2009 May 5;7:9. doi: 10.1186/1478-7547-7-9. — View Citation

Schneider CA, Ferrannini E, Defronzo R, Schernthaner G, Yates J, Erdmann E. Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease. J Am Soc Nephrol. 2008 Jan;19(1):182-7. Epub 2007 Dec 5. — View Citation

Spanheimer R, Betteridge DJ, Tan MH, Ferrannini E, Charbonnel B; PROactive Investigators. Long-term lipid effects of pioglitazone by baseline anti-hyperglycemia medication therapy and statin use from the PROactive experience (PROactive 14). Am J Cardiol. — View Citation

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.

Valentine WJ, Bottomley JM, Palmer AJ, Brändle M, Foos V, Williams R, Dormandy JA, Yates J, Tan MH, Massi-Benedetti M; PROactive Study Group. PROactive 06: cost-effectiveness of pioglitazone in Type 2 diabetes in the UK. Diabet Med. 2007 Sep;24(9):982-100 — View Citation

Valentine WJ, Tucker D, Palmer AJ, Minshall ME, Foos V, Silberman C; PROactive Study Group. Long-term cost-effectiveness of pioglitazone versus placebo in addition to existing diabetes treatment: a US analysis based on PROactive. Value Health. 2009 Jan-Fe — View Citation

van Troostenburg de Bruyn AR, Dormandy J. Risk of thiazolidinedione-associated fracture should be appropriately assessed. Arch Intern Med. 2010 Jan 25;170(2):209-10. doi: 10.1001/archinternmed.2009.487. — View Citation

Wilcox R, Bousser MG, Betteridge DJ, Schernthaner G, Pirags V, Kupfer S, Dormandy J; PROactive Investigators. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinic — View Citation

Wilcox R, Kupfer S, Erdmann E; PROactive Study investigators. Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROacti — View Citation

* Note: There are 27 references in all — Click here to view all references

Outcome

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

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