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

NCT00174993 | Completed Phase 3

• 2 other identifiers: AD4833/EC444U1111-1114-2854
• Study Type: interventional
• Target: 4,373
• Locations: 19 countries
• Sites: 19

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.

Conditions

Diabetes Mellitus

Keywords

Glucose Metabolism Disorder; Dysmetabolic Syndrome; Type II Diabetes; Diabetes Mellitus; Lipoatrophic; Dyslipidemia; Drug Therapy

Outcome Measures

Primary Outcomes (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.

  At First Occurrence

Secondary Outcomes (9)

• 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

Study Arms (2)

Pioglitazone QD

EXPERIMENTAL

Drug: Pioglitazone

Placebo QD

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Pioglitazone DRUG

Pioglitazone 15 mg to 45 mg, tablets, orally, once daily for up to 48 months.

Also known as: Actos, AD4833

Pioglitazone QD

Placebo DRUG

Pioglitazone placebo-matching tablets, orally, once daily for up to 48 months

Placebo QD

Eligibility Criteria

• Age: 35 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Takeda: lead
• Eli Lilly and Company: collaborator

Study Sites (19)

Unknown Facility

Multiple Cities, Austria

Location

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Multiple Cities, Belgium

Location

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Multiple Cities, Czechia

Location

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Multiple Cities, Denmark

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Multiple Cities, Estonia

Location

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Multiple Cities, Finland

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Multiple Cities, France

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Multiple Cities, Germany

Location

Unknown Facility

Multiple Cities, Hungary

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Multiple Cities, Italy

Location

Unknown Facility

Multiple Cities, Latvia

Location

Unknown Facility

Multiple Cities, Lithuania

Location

Unknown Facility

Multiple Cities, Netherlands

Location

Unknown Facility

Multiple Cities, Norway

Location

Unknown Facility

Multiple Cities, Poland

Location

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Multiple Cities, Slovakia

Location

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Multiple Cities, Sweden

Location

Unknown Facility

Multiple Cities, Switzerland

Location

Unknown Facility

Multiple Cities, United Kingdom

Location

Related Publications (30)

• 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

  BACKGROUND

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

  BACKGROUND

• Brandle 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: 10.4414/smw.2009.12381.

  PMID: 19330561 BACKGROUND

• 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.

  PMID: 18375395 BACKGROUND

• 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.

  PMID: 19416529 BACKGROUND

• 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. No abstract available.

  PMID: 20101019 BACKGROUND

• Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J; PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005 Oct 8;366(9493):1279-89. doi: 10.1016/S0140-6736(05)67528-9.

  PMID: 16214598 RESULT

• 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. doi: 10.1681/ASN.2007060678. Epub 2007 Dec 5.

  PMID: 18057215 RESULT

• Ryden L, Thrainsdottir I, Swedberg K. Adjudication of serious heart failure in patients from PROactive. Lancet. 2007 Jan 20;369(9557):189-90. doi: 10.1016/S0140-6736(07)60106-8. No abstract available.

  PMID: 17240282 RESULT

• 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.

  PMID: 17969365 RESULT

• 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

  RESULT

• 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 the PROactive (PROactive 05) Study. J Am Coll Cardiol. 2007 May 1;49(17):1772-80. doi: 10.1016/j.jacc.2006.12.048. Epub 2007 Apr 16.

  PMID: 17466227 RESULT

• Valentine WJ, Bottomley JM, Palmer AJ, Brandle 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):982-1002. doi: 10.1111/j.1464-5491.2007.02188.x. Epub 2007 Jun 25.

  PMID: 17593245 RESULT

• 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 Clinical Trial In macroVascular Events 04). Stroke. 2007 Mar;38(3):865-73. doi: 10.1161/01.STR.0000257974.06317.49. Epub 2007 Feb 8.

  PMID: 17290029 RESULT

• 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 from the PROactive study (PROactive 08). Diabetes Care. 2007 Nov;30(11):2773-8. doi: 10.2337/dc07-0717. Epub 2007 Jul 31.

  PMID: 17666462 RESULT

• 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-Feb;12(1):1-9. doi: 10.1111/j.1524-4733.2008.00403.x. Epub 2008 Jul 24.

  PMID: 18657104 RESULT

• 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 (PROactive 10). Am Heart J. 2008 Apr;155(4):712-7. doi: 10.1016/j.ahj.2007.11.029. Epub 2008 Feb 21.

  PMID: 18371481 RESULT

• 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 characteristics of 5238 patients. Diabetes Care. 2004 Jul;27(7):1647-53. doi: 10.2337/diacare.27.7.1647.

  PMID: 15220241 RESULT

• 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. 2009 Jul 15;104(2):234-9. doi: 10.1016/j.amjcard.2009.03.023. Epub 2009 Jun 3.

  PMID: 19576353 RESULT

• 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: 10.1111/j.1464-5491.2009.02816.x.

  PMID: 19900236 RESULT

• 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). Diabet Med. 2009 Dec;26(12):1242-9. doi: 10.1111/j.1464-5491.2009.02857.x.

  PMID: 20002476 RESULT

• 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.atherosclerosis.2008.03.002. Epub 2008 Mar 18.

  PMID: 18538774 RESULT

• 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.

  RESULT

• 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: 10.2165/00002018-200932030-00002.

  PMID: 19338377 RESULT

• 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.

  PMID: 19744248 RESULT

• 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 from the PROactive study (PROactive 20). J Diabetes. 2010 Sep;2(3):212-20. doi: 10.1111/j.1753-0407.2010.00082.x.

  PMID: 20923486 RESULT

• 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 Aug;13(8):759-64. doi: 10.1111/j.1463-1326.2011.01404.x.

  PMID: 21457426 RESULT

• Doehner W, Erdmann E, Cairns R, Clark AL, Dormandy JA, Ferrannini E, Anker SD. Inverse relation of body weight and weight change with mortality and morbidity in patients with type 2 diabetes and cardiovascular co-morbidity: an analysis of the PROactive study population. Int J Cardiol. 2012 Dec 15;162(1):20-6. doi: 10.1016/j.ijcard.2011.09.039. Epub 2011 Oct 29.

  PMID: 22037349 DERIVED

• Pfister R, Cairns R, Erdmann E, Schneider CA; PROactive investigators. Prognostic impact of electrocardiographic signs in patients with Type 2 diabetes and cardiovascular disease: results from the PROactive study. Diabet Med. 2011 Oct;28(10):1206-12. doi: 10.1111/j.1464-5491.2011.03281.x.

  PMID: 21388447 DERIVED

• Charbonnel B, DeFronzo R, Davidson J, Schmitz O, Birkeland K, Pirags V, Scheen A; PROactive investigators. Pioglitazone use in combination with insulin in the prospective pioglitazone clinical trial in macrovascular events study (PROactive19). J Clin Endocrinol Metab. 2010 May;95(5):2163-71. doi: 10.1210/jc.2009-1974. Epub 2010 Mar 17.

  PMID: 20237169 DERIVED

Related Links

• ACTOS Package Insert

MeSH Terms

Conditions

Diabetes Mellitus; Glucose Metabolism Disorders; Diabetes Mellitus, Type 2; Dyslipidemias

Interventions

Pioglitazone

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Lipid Metabolism Disorders

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• European Development Director

  Takeda

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 9, 2005
• First Posted: September 15, 2005
• Study Start: May 1, 2001
• Primary Completion: January 1, 2005
• Study Completion: January 1, 2005
• Last Updated: February 28, 2012

Record last verified: 2012-02

Locations

PL (1); SL (1); BE (1); CZ (1); DE (1); ES (1); GB (1); DK (1); FI (1); FR (1); AU (1); HU (1); SE (1); CH (1); NO (1); LI (1); IT (1); LA (1); NL (1)