Blood Pressure and Glucose Lowering for the Prevention of Vascular Disease in High Risk Patients With Type 2 Diabetes
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| ClinicalTrials.gov Identifier: NCT00145925 |
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Recruitment Status :
Completed
First Posted : September 5, 2005
Last Update Posted : September 17, 2008
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Diabetes Mellitus, Type 2 | Drug: Perindopril-indapamide Drug: Gliclazide MR-based glucose lowering | Phase 3 |
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.
| 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 |
| Arm | Intervention/treatment |
|---|---|
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Placebo Comparator: Blood pressure
Perindopril indapamide vs placebo
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Drug: Perindopril-indapamide |
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Glucose control
Standard versus intensive glucose control
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Drug: Gliclazide MR-based glucose lowering |
- 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 ]
- 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 ]
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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:
- A diagnosis of type 2 diabetes mellitus first made at age 30 years or older
- Age 55 years or older at entry
- Ability to provide informed consent
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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:
- A definite contraindication to treatment with an ACE inhibitor or a thiazide-like diuretic
- 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
- A definite and specific indication for treatment with gliclazide or a haemoglobin A1c control target of 6.5% or less
- A definite contra-indication to treatment with gliclazide or a haemoglobin A1c control target of 6.5% or less
- A definite indication for long-term full-dose or bed-time insulin therapy
- 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.
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 ClinicalTrials.gov identifier (NCT number): NCT00145925
| 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 | |
| Principal Investigator: | John Chalmers, MB BS PhD | The George Institute | |
| Principal Investigator: | Stephen W MacMahon, BSc PhD MPH | The George Institute |
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| ClinicalTrials.gov 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 |
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Diabetes Mellitus, Type 2 Blood Pressure Stroke MI |
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Vascular Diseases Diabetes Mellitus Diabetes Mellitus, Type 2 Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Cardiovascular Diseases Gliclazide Perindopril Indapamide 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 Diuretics Natriuretic Agents Sodium Chloride Symporter Inhibitors Membrane Transport Modulators |