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 (double-blind placebo conrolled)  Procedure: Gliclazide MR-based glucose lowering (PROBE design)	Phase III

Further Study Details: 

Primary Outcomes: 1. Composite of non-fatal stroke, non-fatal myocardial infarction or death from any cardiovascular cause; 2. Composite of new or substantially worsening nephropathy or microvascular eye disease.
Secondary Outcomes: 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.
Expected Total Enrollment:  10000

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. The original scheduled average duration of treatment and follow-up was 4.5 years. However active consideration is being given to extending this period by at least 12 to 18 months. 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.

Ages Eligible for Study:  55 Years and above,  Genders Eligible for Study:  Both

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.

Australia, Victoria
      The University of Melbourne, Melbourne,  Victoria,  3010,  Australia
Canada, Quebec
      University of Montreal, Montreal,  Quebec,  H26 1X2,  Canada
China, Beijing
      Cardiovascular Institute & Fu Wai Hospital, Xicheng District,  Beijing,  100037,  China
Netherlands
      The Julius Center for Health Sciences and Primary Care, Utrecht,  3508 BA,  Netherlands
United Kingdom
      Imperial College School of Medicine, London,  W2 1PG,  United Kingdom

Study chairs or principal investigators

John Chalmers, MB BS PhD,  Principal Investigator,  The George Institute   
Stephen W MacMahon, BSc PhD MPH,  Principal Investigator,  The George Institute   

Study ID Numbers:  ADVANCE
Last Updated:  September 2, 2005
Record first received:  September 2, 2005
ClinicalTrials.gov Identifier:  NCT00145925
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: India''''s Drug Controller General, a division of the Ministry of Health; China: State 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 - French Health Products Safety Agency; 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
ClinicalTrials.gov processed this record on 2005-09-13