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

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

ADVANCE - Action in Diabetes and Vascular Disease: Preterax and Diamicron - MR Controlled Evaluation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00145925
• Other study ID #: ADVANCE
• Status: Completed
• Phase: Phase 3
• First received: September 2, 2005
• Last updated: September 16, 2008
• Start date: June 2001
• Est. completion date: March 2008

Study information

• Verified date: September 2008
• Source: The George Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Department of Health and Ageing Therapeutic Goods AdministrationNew Zealand: Health Research CouncilPhilippines: Department of HealthMalaysia: Ministry of HealthIndia: Ministry of HealthChina: Food and Drug AdministrationCanada: Health CanadaUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyIreland: Irish Medicines BoardLithuania: State Medicine Control Agency - Ministry of HealthRussia: Pharmacological Committee, Ministry of HealthNetherlands: Medical Ethics Review Committee (METC)France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Italy: Ministry of HealthPoland: Ministry of HealthCzech Republic: State Institute for Drug ControlSlovakia: State Institute for Drug ControlGermany: Ethics CommissionHungary: National Institute of PharmacyEstonia: The State Agency of Medicine
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11140
• Est. completion date: March 2008
• Est. primary completion date: March 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 55 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double-Blind, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Vascular Diseases

Intervention

Drug:
• Perindopril-indapamide

• Gliclazide MR-based glucose lowering

Locations

Country	Name	City	State
Australia	The University of Melbourne	Melbourne	Victoria
Canada	University of Montreal	Montreal	Quebec
China	Cardiovascular Institute & Fu Wai Hospital	Xicheng District	Beijing
Netherlands	The Julius Center for Health Sciences and Primary Care	Utrecht
United Kingdom	Imperial College School of Medicine	London

Sponsors (4)

Lead Sponsor	Collaborator
The George Institute	Institut de Recherches Internationales Servier, National Health and Medical Research Council, Australia, University of Sydney

Countries where clinical trial is conducted

Australia,  Canada,  China,  Netherlands,  United Kingdom, 

References & Publications (3)

ADVANCE Collaborative Group. ADVANCE--Action in Diabetes and Vascular Disease: patient recruitment and characteristics of the study population at baseline. Diabet Med. 2005 Jul;22(7):882-8. — View Citation

ADVANCE Management Committee. Study rationale and design of ADVANCE: action in diabetes and vascular disease--preterax and diamicron MR controlled evaluation. Diabetologia. 2001 Sep;44(9):1118-20. — View Citation

Rationale and design of the ADVANCE study: a randomised trial of blood pressure lowering and intensive glucose control in high-risk individuals with type 2 diabetes mellitus. Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation. J Hypertens Suppl. 2001 Nov;19(4):S21-8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of non-fatal stroke, non-fatal myocardial infarction or death from any cardiovascular cause		July 2001 - December 2007
Primary	Composite of new or substantially worsening nephropathy or microvascular eye disease.		July 2001 - December 2007
Secondary	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.		July 2001 - December 2007

External Links

•   Sponsor's web page
•   Study web page