Effect of Simvastatin Treatment on Vaso-occlusive Pain in Sickle Cell Disease

Sickle cell disease (SCD) is characterized by recurrent vaso-occlusive episodes and a
chronic inflammatory state leading to progressive multi-organ injury. The pathophysiology of
SCD is related to endothelial dysfunction driven largely by impaired nitric oxide (NO)
homeostasis and chronic inflammation. Through multiple mechanisms, including upregulation of
NO, statins have been shown to confer protection from endothelial injury, independent of
their cholesterol-lowering properties.

By inhibiting inflammation and several common pathways leading to vascular
damage,simvastatin may help prevent the acute and chronic complications of SCD. The
objective of this study is to determine whether our preliminary results showing
simvastatin-associated reductions in plasma markers of vascular injury will translate into a
reduction in vaso-occlusive pain episodes in patients with SCD. A web-based,
smartphone-accessible electronic pain diary will be used to monitor frequency and intensity
of vaso-occlusive pain in SCD patients treated with a single daily dose of simvastatin.

Inclusion Criteria:

- Sickle cell disease (HbSS or S/β0 thalassemia)

- ≥ 3 vaso-occlusive pain episodes in the year prior to enrollment

- Age ≥ 10 years

- Weight > 30 kg

Exclusion Criteria:

- Creatine kinase (CK) >1X UNL

- Total cholesterol < 90 mg/dL, or TG <30mg/dL

- Renal dysfunction (Creatinine > 1.5X UNL)

- Hepatic dysfunction (ALT > 2X UNL)

- Treatment with drugs having known metabolic interactions with statins (e.g.cytochrome
P450 3A4 metabolism or amiodarone) within the past 30 days

- Vaso-occlusive pain requiring hospitalization within past 30 days

- RBC transfusion within the past 30 days

- Pregnancy/lactation

- Musculoskeletal disorder associated with an elevated CK level

- Past or present history of substance abuse (alcohol, cocaine, amphetamines, heroin,
PCP)

- Chronic pain caused by avascular necrosis of the bone (AVN) or leg ulcers, and pain
due to trauma or causes other than SCD.

- Major cognitive or neurological impairments that may hamper the ability to use the
smartphone or complete the eDiary in this study