The main aim of this study is to test whether reducing blood cholesterol with a combination tablet, containing both simvastatin and ezetimibe, can prevent heart disease and strokes in patients with kidney disease. Additionally, the trial will test the effect on blood cholesterol levels of combining ezetimibe with simvastatin, as compared with simvastatin alone. The trial will also be able to study a number of other potential effects of lowering cholesterol, including whether it can delay the need for dialysis in people who have kidney disease.

Condition	Intervention	Phase
Kidney Failure, Chronic	Drug: ezetimibe  Drug: simvastatin	Phase III

Further Study Details: 

Primary Outcomes: Major vascular events (defined as non-fatal myocardial infarction or cardiac death, non-fatal or fatal stroke, or revascularisation) at end of study
Secondary Outcomes: Major vascular events at end of study; Major cardiac events (non-fatal MI or cardiac death) at end of study; Stroke (fatal or non-fatal) at end of study; Coronary or non-coronary revascularisation at end of study; Mortality, both overall and within particular categories at end of study; Hospital admission for angina at end of study; End-stage renal disease (need for long-term dialysis or transplantation) at end of study; End-stage renal disease or death from any cause at end of study
Expected Total Enrollment:  9000

Among patients with pre-existing coronary heart disease, large-scale randomized trials have demonstrated that lowering LDL-cholesterol concentration by about 1 mmol/l for 4-5 years reduces the risk of coronary events and of strokes by about 25%. Patients with established chronic kidney disease (CKD) are at high risk of vascular disease, so the benefits of cholesterol-lowering therapy might be expected to be substantial in this population. But, patients with CKD have generally been excluded from previous trials, and there is currently no reliable randomized evidence that lowering LDL-cholesterol would be beneficial among them.

There are several reasons why the demonstrated benefits of lowering blood cholesterol in other populations might not translate to patients with CKD. First, observational studies among dialysis patients have reported a negative association between blood total cholesterol and mortality. Secondly, only about one quarter of cardiac mortality in such patients appears to be definitely attributable to acute myocardial infarction, and so potentially avoidable with cholesterol-lowering, while the other common causes (e.g. cardiac arrest, arrhythmia, and heart failure) may not be as dependent on cholesterol levels. Finally, the long-term safety of cholesterol reduction among patients with CKD remains unclear. Hence, there is an important need for reliable direct evidence on whether lowering cholesterol prevents a worthwhile proportion of vascular events, without unacceptable toxicity, among patients with chronic kidney disease.

Animal studies have suggested that glomerulosclerosis (a major mechanism leading to loss of renal function) shares many similarities with atherosclerosis, and may be promoted by certain blood lipid abnormalities. A meta-analysis of small-scale randomized trials among CKD patients has suggested that lowering LDL-cholesterol might reduce the rate of nephron loss among patients with progressive renal dysfunction. But, in order to confirm or refute this hypothesis properly, a large-scale trial of cholesterol-lowering therapy in such patients is now needed.

The Study of Heart and Renal Protection (SHARP) aims to assess the effects of cholesterol-lowering therapy with a combination of simvastatin and the cholesterol-absorption inhibitor ezetimibe among around 9,000 patients with CKD (around 6,000 of whom will be pre-dialysis and 3,000 on dialysis). Such large-scale recruitment will allow reliable assessment of the effects of lowering blood LDL-cholesterol on the risk of major vascular events and on the rate of loss of renal function in patients with various degrees of renal impairment. An international collaboration between nephrologists and clinical trialists, with an International Coordinating Centre and around 6 Regional Coordinating Centres, will conduct the trial in over 300 hospitals in about 20 countries. SHARP is “streamlined”: extra work for collaborating doctors and hospitals has been kept to a minimum, and essential data only will be collected electronically to help research staff record accurate information about participants.

Ages Eligible for Study:  40 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• History of Chronic Kidney Disease (CKD): either patients who are pre-dialysis (with a plasma or serum creatinine greater than or equal to 150 micromol/l [greater than or equal to 1.7 mg/dl] in men, or greater than or equal to 130 micromol/l [greater than or equal to 1.5 mg/dl] in women); or patients on dialysis (haemodialysis or peritoneal dialysis)
• Men or women aged greater than or equal to 40 years

Exclusion Criteria:

• Definite history of myocardial infarction or coronary revascularisation procedure
• Functioning renal transplant, or living donor-related transplant planned
• Less than 2 months since presentation as an acute uraemic emergency (but may be entered later, if appropriate);
• Definite history of chronic liver disease, or abnormal liver function (i.e. alanine aminotransferase (ALT) > 1.5 x upper limit of normal (ULN) or, if ALT not available, aspartate aminotransferase (AST) > 1.5 x ULN). (Note: Patients with a history of hepatitis are eligible provided these limits are not exceeded);
• Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or creatine kinase (CK) >3 x ULN;
• Definite previous adverse reaction to a statin or to ezetimibe
• Concurrent treatment with a contraindicated drug (Note: Patients who are temporarily taking such drugs may be re-screened for participation in the study when they discontinue them, if appropriate.) These contraindicated drugs include: HMG-CoA reductase inhibitor (“statin”; fibric acid derivative (“fibrate”); nicotinic acid; macrolide antibiotic (erythromycin, clarithromycin); systemic use of imidazole or triazole antifungals (e.g. itraconazole, ketoconazole); protease-inhibitors (e.g. antiretroviral drugs for HIV infection); nefazodone; ciclosporin
• Child-bearing potential (i.e. premenopausal woman who is not using a reliable method of contraception.)
• Known to be poorly compliant with clinic visits or prescribed medication
• Medical history that might limit the individual’s ability to take trial treatments for the duration of the study (e.g. severe respiratory disease, history of cancer other than non-melanoma skin cancer, or recent history of alcohol or substance misuse)

Please refer to this study by ClinicalTrials.gov identifier  NCT00125593

Colin N Baigent, BM BCh      +44 1865 743 866    colin.baigent@ctsu.ox.ac.uk
Martin J Landray, PhD MRCP      +44 1865 743 866    martin.landray@ctsu.ox.ac.uk

United Kingdom
      Clinical Trial Service Unit, University of Oxford, Oxford,  OX3 7LF,  United Kingdom; Recruiting

Study chairs or principal investigators

Colin N Baigent, BM BCh,  Study Director,  Clinical Trial Service Unit, University of Oxford   

Study ID Numbers:  CTSUSHARP1; ISRCTN54137607; EudraCT - 2004-001156-37
Last Updated:  August 1, 2005
Record first received:  July 29, 2005
ClinicalTrials.gov Identifier:  NCT00125593
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-08-02