Blood Pressure and Glucose Lowering for the Prevention of Vascular Disease in High Risk Patients With Type 2 Diabetes
Information source: The George Institute
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Diabetes Mellitus, Type 2
Intervention: Perindopril-indapamide (Drug); Gliclazide MR-based glucose lowering (Drug)
Phase: Phase 3
Status: Completed
Sponsored by: The George Institute Official(s) and/or principal investigator(s): John Chalmers, MB BS PhD, Principal Investigator, Affiliation: The George Institute Stephen W MacMahon, BSc PhD MPH, Principal Investigator, Affiliation: The George Institute
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.
Clinical Details
Official title: ADVANCE - Action in Diabetes and Vascular Disease: Preterax and Diamicron - MR Controlled Evaluation
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double-Blind, Primary Purpose: Prevention
Primary outcome: Composite of non-fatal stroke, non-fatal myocardial infarction or death from any cardiovascular causeComposite of new or substantially worsening nephropathy or microvascular eye disease.
Secondary outcome: 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.
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
Minimum age: 55 Years.
Maximum age: N/A.
Gender(s): 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.
Locations and Contacts
The Julius Center for Health Sciences and Primary Care, Utrecht 3508 BA, Netherlands
Imperial College School of Medicine, London W2 1PG, United Kingdom
Cardiovascular Institute & Fu Wai Hospital, Xicheng District, Beijing 100037, China
University of Montreal, Montreal, Quebec H26 1X2, Canada
The University of Melbourne, Melbourne, Victoria 3010, Australia
Additional Information
Study web page Sponsor's web page
Related publications: 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. 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. 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.
Starting date: June 2001
Last updated: September 16, 2008
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