Simvastatin (Zocor) Therapy in Sickle Cell Disease

Study Overview
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Brief Summary
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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
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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: To obtain preliminary efficacy data on the effects of oral simvastatin on plasma biomarkers of endothelial injury in patients with SCD, and To assess the safety and tolerability of oral simvastatin in patients with SCD.

Official Title
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Phase I/II Study of Simvastatin (Zocor) Therapy in Sickle Cell Disease

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Simvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Established diagnosis of sickle cell disease (HbSS, SC or Sβ-thalassemia) Age greater than or equal to thirteen years Weight greater than or equal to 35 kg 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

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Simvastatin, Dose Escalation<br>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). | Drug: Simvastatin<br>* Comparison of 3 dosages of simvastatin given in a dose-escalating fashion. 20 mg, 40 mg, or 80 mg PO QD x 21 days followed by a drug taper x 4 days.<br>* Other names: Zocor;|

What is the study measuring?
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Primary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sickle cell disease, simvastatin, statin drugs, nitric oxide donors, vascular injury