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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
Recruitment Status : Completed
First Posted : September 5, 2005
Last Update Posted : September 17, 2008
Sponsor:
Collaborators:
Institut de Recherches Internationales Servier
University of Sydney
National Health and Medical Research Council, Australia
Information provided by:
The George Institute

Tracking Information
First Submitted Date  ICMJE September 2, 2005
First Posted Date  ICMJE September 5, 2005
Last Update Posted Date September 17, 2008
Study Start Date  ICMJE June 2001
Actual Primary Completion Date March 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 19, 2007)
  • 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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: September 2, 2005)
  • 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.
Change History Complete list of historical versions of study NCT00145925 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 19, 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 2, 2005)
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.
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE Blood Pressure and Glucose Lowering for the Prevention of Vascular Disease in High Risk Patients With Type 2 Diabetes
Official Title  ICMJE ADVANCE - Action in Diabetes and Vascular Disease: Preterax and Diamicron - MR Controlled Evaluation
Brief 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.
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.

Study Type  ICMJE Interventional
Study Phase Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double
Primary Purpose: Prevention
Condition  ICMJE Diabetes Mellitus, Type 2
Intervention  ICMJE
  • Drug: Perindopril-indapamide
  • Drug: Gliclazide MR-based glucose lowering
Study Arms
  • Placebo Comparator: Blood pressure
    Perindopril indapamide vs placebo
    Intervention: Drug: Perindopril-indapamide
  • Glucose control
    Standard versus intensive glucose control
    Intervention: Drug: Gliclazide MR-based glucose lowering
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 19, 2007)
11140
Original Enrollment  ICMJE
 (submitted: September 2, 2005)
10000
Actual Study Completion Date March 2008
Actual Primary Completion Date March 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender
Sexes Eligible for Study: All
Ages 55 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   China,   Netherlands,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00145925
Other Study ID Numbers  ICMJE ADVANCE
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Not Provided
Study Sponsor  ICMJE The George Institute
Collaborators  ICMJE
  • Institut de Recherches Internationales Servier
  • University of Sydney
  • National Health and Medical Research Council, Australia
Investigators  ICMJE
Principal Investigator: John Chalmers, MB BS PhD The George Institute
Principal Investigator: Stephen W MacMahon, BSc PhD MPH The George Institute
PRS Account The George Institute
Verification Date September 2008

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP