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Blood Pressure and Glucose Lowering for the Prevention of Vascular Disease in High Risk Patients With Type 2 Diabetes

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. Identifier: NCT00145925
Recruitment Status : Completed
First Posted : September 5, 2005
Last Update Posted : September 17, 2008
Institut de Recherches Internationales Servier
University of Sydney
National Health and Medical Research Council, Australia
Information provided by:
The George Institute

Brief Summary:
The purpose of this study is to provide information on the risks and benefits of routine blood pressure lowering (regardless of blood pressure level), and intensive lowering of blood glucose levels, in patients with Type 2 diabetes at high risk of cardiovascular events. The major outcomes of the study will be cardiovascular events (heart attack, stroke or dying as a result of cardiovascular disease), as well as new or worsening diabetic eye and kidney disease.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Drug: Perindopril-indapamide Drug: Gliclazide MR-based glucose lowering Phase 3

Detailed Description:

Patients with type 2 diabetes are at increased risks of macrovascular and microvascular disease, both of which are reduced by control of raised blood pressure in hypertensive individuals. Intensive glycaemic control has also been shown to reduce microvascular disease, but the effects on macrovascular disease remain uncertain. This study will examine the hypotheses that blood pressure lowering (with an ACE inhibitor-diuretic combination) and intensive glycaemic control (with a sulphonylurea-based regimen) in high-risk individuals with type 2 diabetes (including hypertensive and non-hypertensive subjects) reduces the incidence of both macrovascular and microvascular disease.

The study is a 2 x 2 factorial randomised controlled trial that includes 11,140 adults with type 2 diabetes at elevated risk of vascular disease. Following 6 weeks on open label perindopril-indapamide combination, eligible individuals were randomised to continued perindopril-indapamide or matching placebo, and to an intensive gliclazide MR-based glucose control regimen (aiming for HbA1c of 6.5% or lower) or usual guidelines-based therapy. Primary outcomes are, first, the composite of non-fatal stroke, non-fatal myocardial infarction or cardiovascular death and, second, the composite of new or worsening nephropathy or diabetic eye disease. These primary outcomes will be analysed jointly and separately. The average duration of treatment and follow-up is 5.5 to 6 years. The study is being conducted in 214 centres in Australasia, Asia, Europe and North America.

ADVANCE is designed to provide reliable evidence about the balance of benefits and risks conferred by blood pressure lowering therapy and intensive glucose control therapy in high-risk diabetic patients, irrespective of initial blood pressure or glucose levels.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11140 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double
Primary Purpose: Prevention
Official Title: ADVANCE - Action in Diabetes and Vascular Disease: Preterax and Diamicron - MR Controlled Evaluation
Study Start Date : June 2001
Actual Primary Completion Date : March 2008
Actual Study Completion Date : March 2008

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Placebo Comparator: Blood pressure
Perindopril indapamide vs placebo
Drug: Perindopril-indapamide
Glucose control
Standard versus intensive glucose control
Drug: Gliclazide MR-based glucose lowering

Primary Outcome Measures :
  1. Composite of non-fatal stroke, non-fatal myocardial infarction or death from any cardiovascular cause [ Time Frame: July 2001 - December 2007 ]
  2. Composite of new or substantially worsening nephropathy or microvascular eye disease. [ Time Frame: July 2001 - December 2007 ]

Secondary Outcome Measures :
  1. Includes cerebrovascular disease, coronary heart disease, heart failure, peripheral vascular disease, cardiovascular and all-cause mortality, microalbuminuria, visual deterioration, new or worsening nephropathy, cognitive function, and dementia. [ Time Frame: July 2001 - December 2007 ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   55 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. A diagnosis of type 2 diabetes mellitus first made at age 30 years or older
  2. Age 55 years or older at entry
  3. Ability to provide informed consent
  4. A substantially elevated risk of cardiovascular disease, indicated by:

    • A history of major macrovascular disease defined as any one of: stroke, myocardial infarction, hospital admission for transient ischaemic attack, hospital admission for unstable angina, coronary artery bypass graft, percutaneous transluminal coronary angioplasty (with or without stenting), peripheral revascularisation (angioplasty or surgery) or amputation secondary to vascular disease or
    • A history of major microvascular disease defined as any one of nephropathy (albumin:creatinine ratio >300ug/mg), retinal photocoagulation therapy, proliferative retinopathy (new blood vessels on the disc or elsewhere, vitreous haemorrhage, pre-retinal haemorrhage, or fibrous proliferations on the disc or elsewhere), macular oedema (retinal thickening within one disc diameter of the macular centre) or blindness in either eye (corrected visual acuity 6/60 or worse, persisting for three months or more) not known to be due to non-diabetic causes or
    • A first diagnosis of type 2 diabetes made 10 or more years prior to entry or
    • Another major risk factor for vascular disease defined as any one of: current daily cigarette smoking, total cholesterol greater than 6.0 mmol/l (with or without cholesterol lowering treatment), HDL cholesterol <1.0 mmol/l, microalbuminuria (albumin:creatinine ratio 30-300ug/mg) or
    • Age 65 years or over

Exclusion Criteria:

  1. A definite contraindication to treatment with an ACE inhibitor or a thiazide-like diuretic
  2. A specific indication for treatment with an ACE inhibitor other than perindopril 2-4 mg daily (see also section 5.2.3) or a thiazide-like diuretic
  3. A definite and specific indication for treatment with gliclazide or a haemoglobin A1c control target of 6.5% or less
  4. A definite contra-indication to treatment with gliclazide or a haemoglobin A1c control target of 6.5% or less
  5. A definite indication for long-term full-dose or bed-time insulin therapy
  6. Participation in a trial within the month prior to the Registration Visit or current participation in another trial

Other potential reasons for ineligibility include:

  • High probability of non-adherence to study treatment or follow-up
  • Current clinical instability (e.g. a major cerebral or coronary event or sight-threatening retinopathy or macular oedema within the previous few weeks)
  • Life threatening non-vascular disease other than diabetes and its complications
  • Moderate or severe dementia
  • Major disability that is likely to prevent regular attendance at study clinics

Final decisions about eligibility were made at the discretion of the study investigator and the potential study participant, in the light of any requirements or guidance from local ethics committees and other regulatory bodies.

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 identifier (NCT number): NCT00145925

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Australia, Victoria
The University of Melbourne
Melbourne, Victoria, Australia, 3010
Canada, Quebec
University of Montreal
Montreal, Quebec, Canada, H26 1X2
China, Beijing
Cardiovascular Institute & Fu Wai Hospital
Xicheng District, Beijing, China, 100037
The Julius Center for Health Sciences and Primary Care
Utrecht, Netherlands, 3508 BA
United Kingdom
Imperial College School of Medicine
London, United Kingdom, W2 1PG
Sponsors and Collaborators
The George Institute
Institut de Recherches Internationales Servier
University of Sydney
National Health and Medical Research Council, Australia
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Principal Investigator: John Chalmers, MB BS PhD The George Institute
Principal Investigator: Stephen W MacMahon, BSc PhD MPH The George Institute
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):

Layout table for additonal information Identifier: NCT00145925    
Other Study ID Numbers: ADVANCE
First Posted: September 5, 2005    Key Record Dates
Last Update Posted: September 17, 2008
Last Verified: September 2008
Keywords provided by The George Institute:
Diabetes Mellitus, Type 2
Blood Pressure
Additional relevant MeSH terms:
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Vascular Diseases
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Cardiovascular Diseases
Indapamide, perindopril drug combination
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Hypoglycemic Agents
Physiological Effects of Drugs
Natriuretic Agents
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators