Simvastatin (Zocor) Therapy in Sickle Cell Disease

Phase 1

Completed

Brief Summary: Recent clinical and experimental data indicate that statins have effects beyond cholesterol lowering that may be beneficial in sickle cell disease by protecting the vascular endothelium. Statins have been shown to attenuate endothelial dysfunction through their anti-inflammatory, anti-oxidant and anti-thrombotic properties. This phase I/II dose-escalating trial is designed to assess the safety and potential clinical efficacy of oral simvastatin (Zocor)in adolescents and adults with sickle cell disease (SCD).

Detailed Description: Although statins have been used extensively for their cholesterol-lowering effects, recent clinical and experimental data indicate that statins regulate yet other processes, many of which play a major role in sickle cell disease (SCD). Independent of their cholesterol-lowering effects, statins have been shown to prevent damage to blood vessels in several ways, through upregulation of endothelial nitric oxide (NO)and decreased inflammation. Numerous studies documenting the protective effects of statins, together with data showing the therapeutic role of NO in SCD, provide the basis for investigating the potential clinical benefit of simvastatin in SCD.

Data supporting the safety and tolerability of simvastatin in patients with SCD are now needed. For this phase I/II dose-escalation study of oral simvastatin in SCD, we propose the following specific aims:

1. To obtain preliminary efficacy data on the effects of oral simvastatin on plasma biomarkers of endothelial injury in patients with SCD, and

2. To assess the safety and tolerability of oral simvastatin in patients with SCD.

Recruitment & Eligibility

Inclusion Criteria

Exclusion Criteria

Renal dysfunction (Serum Creatinine > 1.5 UNL)
Hepatic dysfunction (ALT > 2X UNL)
Pretreatment total cholesterol < 100 mg/dL or triglycerides < 30 mg/dL
Pretreatment baseline creatine kinase >1X UNL (215 U/L)
Pregnancy/lactation
RBC transfusion in the last 30 days
Vaso-Occlusive Event needing hospitalization in the past 30 days
Treatment with any statin drugs within the past 30 days
Treatment with drugs having known metabolic interactions with statin drugs (e.g. cytochrome P450 3A4 metabolism), including ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, azithromycin, niacin (nicotinic acid), digoxin, coumadin, sildenafil or amiodarone within the past 30 days
Treatment (past or present) with amiodarone
Musculoskeletal disorder associated with an elevated creatine kinase level
Past or present history of substance abuse (alcohol, cocaine, amphetamines, heroin, PCP)
Allergy to statins

Arm && Interventions

Group	Intervention	Description
Simvastatin, Dose Escalation	Simvastatin	There are no arms in this study. Simvastatin will be given in a dose-escalating fashion to 3 sequential dosage groups (20 mg/day, 40 mg/day, 80 mg/day).

Primary Outcome Measures

Name	Time	Method
Change in Hemoglobin Level	Baseline, 21 days	Change in plasma hemoglobin (Hb) level after treatment with simvastatin
Change in Serum Creatine Kinase Levels	Baseline, 21 days	Change in serum creatine kinase (CK) levels after treatment with simvastatin
Change in Total Cholesterol Level	Baseline, 21 days	Change in serum total cholesterol level after treatment with simvastatin
Change in Serum Alanine Transaminase (ALT) Levels	Baseline, 21 days	Change in serum alanine transaminase (ALT) after treatment with simvastatin
Change in Serum Creatinine Levels	Baseline, 21 days	Change in serum creatinine (Cr) levels after treatment with simvastatin