SHARP: Study of Heart and Renal Protection - Full Text View

Sponsor:	University of Oxford
Collaborator:	Merck Schering-Plough
Information provided by:	University of Oxford
ClinicalTrials.gov Identifier:	NCT00125593

Purpose

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: Simvastatin/ezetimibe Drug: Simvastatin Drug: Placebo	Phase III

Study Type:	Interventional
Study Design:	Prevention, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	International Study of Ezetimibe/Simvastatin Cholesterol Lowering and Major Vascular Events in Chronic Kidney Disease

Resource links provided by NLM:

MedlinePlus related topics: Cholesterol Kidney Failure

Drug Information available for: Simvastatin Ezetimibe

U.S. FDA Resources

Further study details as provided by University of Oxford:

Primary Outcome Measures:

Major vascular events (defined as non-fatal myocardial infarction [MI] or cardiac death, non-fatal or fatal stroke, or revascularisation) at end of study [ Time Frame: Duration of study follow-up ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Major vascular events at end of study [ Time Frame: Duration of study follow-up ] [ Designated as safety issue: No ]
Major cardiac events (non-fatal MI or cardiac death) at end of study [ Time Frame: Duration of study follow-up ] [ Designated as safety issue: No ]
Stroke (fatal or non-fatal) at end of study [ Time Frame: Duration of study follow-up ] [ Designated as safety issue: No ]
Coronary or non-coronary revascularisation at end of study [ Time Frame: Duration of study follow-up ] [ Designated as safety issue: No ]
Mortality, both overall and within particular categories at end of study [ Time Frame: Duration of study follow-up ] [ Designated as safety issue: No ]
Hospital admission for angina at end of study [ Time Frame: Duration of study follow-up ] [ Designated as safety issue: No ]
End-stage renal disease (need for long-term dialysis or transplantation) at end of study [ Time Frame: Duration of study follow-up ] [ Designated as safety issue: No ]
End-stage renal disease or death from any cause at end of study [ Time Frame: Duration of study follow-up ] [ Designated as safety issue: No ]

Enrollment:	9438
Study Start Date:	June 2003
Estimated Study Completion Date:	November 2010
Estimated Primary Completion Date:	August 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Simvastatin 20 mg: Active Comparator The study has a double blind, double-dummy design. During the first year after randomization, the 3 study arms are as follows: placebo-combination and placebo-simvastatin (Arm 1); ezetimibe/simvastatin and placebo-simvastatin (Arm 2); or placebo-combination and simvastatin (Arm 3). At the end of the first year, patients in Arm 3 will be randomized to placebo-combination (Arm 3a) or ezetimibe/simvastatin (Arm 3b), and patients in Arms 1 and 2 will discontinue placebo-simvastatin. Thus, from the start of the second year all patients will be on either placebo-combination (in Arms 1 and 3a) or ezetimibe/simvastatin (in Arms 2 and 3b).	Drug: Simvastatin Arm 3: Simvastatin 20mg once daily tablet.
Placebo: Placebo Comparator The study has a double blind, double-dummy design. During the first year after randomization, the 3 study arms are as follows: placebo-combination and placebo-simvastatin (Arm 1); ezetimibe/simvastatin and placebo-simvastatin (Arm 2); or placebo-combination and simvastatin (Arm 3). At the end of the first year, patients in Arm 3 will be randomized to placebo-combination (Arm 3a) or ezetimibe/simvastatin (Arm 3b), and patients in Arms 1 and 2 will discontinue placebo-simvastatin. Thus, from the start of the second year all patients will be on either placebo-combination (in Arms 1 and 3a) or ezetimibe/simvastatin (in Arms 2 and 3b).	Drug: Placebo Arm 1: Placebo once daily tablet.
Simvastatin 20mg/Ezetimibe 10mg: Active Comparator The study has a double blind, double-dummy design. During the first year after randomization, the 3 study arms are as follows: placebo-combination and placebo-simvastatin (Arm 1); ezetimibe/simvastatin and placebo-simvastatin (Arm 2); or placebo-combination and simvastatin (Arm 3). At the end of the first year, patients in Arm 3 will be randomized to placebo-combination (Arm 3a) or ezetimibe/simvastatin (Arm 3b), and patients in Arms 1 and 2 will discontinue placebo-simvastatin. Thus, from the start of the second year all patients will be on either placebo-combination (in Arms 1 and 3a) or ezetimibe/simvastatin (in Arms 2 and 3b).	Drug: Simvastatin/ezetimibe Arm 2: Simvastatin 20mg/ezetimibe 10mg once daily tablet.

Detailed Description:

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.

Eligibility

Ages Eligible for Study:	40 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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 creatinine 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)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00125593

Locations

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

Sponsors and Collaborators

University of Oxford

Merck Schering-Plough

Investigators

Study Director:

Colin N Baigent, BM BCh

Clinical Trial Service Unit, University of Oxford

More Information

No publications provided

Responsible Party:	CTSU, University of Oxford ( Professor Colin Baigent )
Study ID Numbers:	CTSUSHARP1, ISRCTN54137607, EudraCT - 2004-001156-37
Study First Received:	July 29, 2005
Last Updated:	December 7, 2009
ClinicalTrials.gov Identifier:	NCT00125593 History of Changes
Health Authority:	United States: Food and Drug Administration; United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University of Oxford:

Kidney Failure, Chronic
cholesterol
simvastatin
ezetimibe
cardiovascular diseases

Additional relevant MeSH terms:

Antimetabolites
Renal Insufficiency
Molecular Mechanisms of Pharmacological Action
Simvastatin
Antilipemic Agents
Kidney Failure, Chronic
Enzyme Inhibitors
Ezetimibe

Anticholesteremic Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Pharmacologic Actions
Urologic Diseases
Renal Insufficiency, Chronic
Therapeutic Uses
Kidney Diseases
Kidney Failure

ClinicalTrials.gov processed this record on February 08, 2010