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

This study has been completed.
Sponsor:
Collaborators:
Institut de Recherches Internationales Servier
University of Sydney
National Health and Medical Research Council, Australia
Information provided by:
The George Institute
ClinicalTrials.gov Identifier:
NCT00145925
First received: September 2, 2005
Last updated: September 16, 2008
Last verified: September 2008
  Purpose

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 Intervention Phase
Diabetes Mellitus, Type 2
Drug: Perindopril-indapamide
Drug: Gliclazide MR-based glucose lowering
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double-Blind
Primary Purpose: Prevention
Official Title: ADVANCE - Action in Diabetes and Vascular Disease: Preterax and Diamicron - MR Controlled Evaluation

Resource links provided by NLM:


Further study details as provided by The George Institute:

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

Secondary Outcome Measures:
  • 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 ]

Enrollment: 11140
Study Start Date: June 2001
Study Completion Date: March 2008
Primary Completion Date: March 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Blood pressure
Perindopril indapamide vs placebo
Drug: Perindopril-indapamide
Glucose control
Standard versus intensive glucose control
Drug: Gliclazide MR-based glucose lowering

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.

  Eligibility

Ages Eligible for Study:   55 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00145925

Locations
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
Netherlands
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
Investigators
Principal Investigator: John Chalmers, MB BS PhD The George Institute
Principal Investigator: Stephen W MacMahon, BSc PhD MPH The George Institute
  More Information

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

ClinicalTrials.gov Identifier: NCT00145925     History of Changes
Other Study ID Numbers: ADVANCE
Study First Received: September 2, 2005
Last Updated: September 16, 2008
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
New Zealand: Health Research Council
Philippines: Department of Health
Malaysia: Ministry of Health
India: Ministry of Health
China: Food and Drug Administration
Canada: Health Canada
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Ireland: Irish Medicines Board
Lithuania: State Medicine Control Agency - Ministry of Health
Russia: Pharmacological Committee, Ministry of Health
Netherlands: Medical Ethics Review Committee (METC)
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Italy: Ministry of Health
Poland: Ministry of Health
Czech Republic: State Institute for Drug Control
Slovakia: State Institute for Drug Control
Germany: Ethics Commission
Hungary: National Institute of Pharmacy
Estonia: The State Agency of Medicine

Keywords provided by The George Institute:
Diabetes Mellitus, Type 2
Blood Pressure
Stroke
MI

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Vascular Diseases
Cardiovascular Diseases
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Indapamide
Indapamide, perindopril drug combination
Perindopril
Angiotensin-Converting Enzyme Inhibitors
Antihypertensive Agents
Cardiovascular Agents
Diuretics
Enzyme Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Protease Inhibitors
Sodium Chloride Symporter Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014