Simvastatin (Zocor) Therapy in Sickle Cell Disease

Sickle Cell Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00508027
• Other study ID #: 1R01FD003080-01A1
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: July 26, 2007
• Last updated: August 20, 2013
• Start date: June 2007
• Est. completion date: December 2011

Study information

• Verified date: August 2013
• Source: Children's Hospital & Research Center Oakland
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: December 2011
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 13 Years and older

Eligibility

Inclusion Criteria:

• Established diagnosis of sickle cell disease (HbSS, SC or Sß-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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Simvastatin
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.

Locations

Country	Name	City	State
United States	Children's Hospital and Research Center Oakland	Oakland	California

Sponsors (3)

Lead Sponsor	Collaborator
Children's Hospital & Research Center Oakland	Department of Health and Human Services, FDA Office of Orphan Products Development

Country where clinical trial is conducted

United States, 

References & Publications (18)

Belcher JD, Marker PH, Weber JP, Hebbel RP, Vercellotti GM. Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood. 2000 Oct 1;96(7):2451-9. — View Citation

Brown MD, Wick TM, Eckman JR. Activation of vascular endothelial cell adhesion molecule expression by sickle blood cells. Pediatr Pathol Mol Med. 2001 Jan-Feb;20(1):47-72. — View Citation

Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther. 1999 Dec;84(3):413-28. Review. Erratum in: Pharmacol Ther 2000 May;86(2):199. — View Citation

Gladwin MT, Crawford JH, Patel RP. The biochemistry of nitric oxide, nitrite, and hemoglobin: role in blood flow regulation. Free Radic Biol Med. 2004 Mar 15;36(6):707-17. Review. — View Citation

Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyörälä K. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med. 1999 Dec 13-27;159(22):2661-7. — View Citation

Hebbel RP, Vercellotti GM. The endothelial biology of sickle cell disease. J Lab Clin Med. 1997 Mar;129(3):288-93. Review. — View Citation

Hebbel RP. Extracorpuscular factors in the pathogenesis of sickle cell disease. Am J Pediatr Hematol Oncol. 1982 Fall;4(3):316-9. — View Citation

Hebbel RP. Perspectives series: cell adhesion in vascular biology. Adhesive interactions of sickle erythrocytes with endothelium. J Clin Invest. 1997 Jun 1;99(11):2561-4. Review. — View Citation

Hebbel RP. Special issue of Microcirculation: examination of the vascular pathobiology of sickle cell anemia. Foreword. Microcirculation. 2004 Mar;11(2):99-100. — View Citation

Hoppe C, Kuypers F, Larkin S, Hagar W, Vichinsky E, Styles L. A pilot study of the short-term use of simvastatin in sickle cell disease: effects on markers of vascular dysfunction. Br J Haematol. 2011 Jun;153(5):655-63. doi: 10.1111/j.1365-2141.2010.08480 — View Citation

Kaul DK, Liu XD, Choong S, Belcher JD, Vercellotti GM, Hebbel RP. Anti-inflammatory therapy ameliorates leukocyte adhesion and microvascular flow abnormalities in transgenic sickle mice. Am J Physiol Heart Circ Physiol. 2004 Jul;287(1):H293-301. Epub 2004 Mar 4. — View Citation

Laufs U, Wassmann S, Hilgers S, Ribaudo N, Böhm M, Nickenig G. Rapid effects on vascular function after initiation and withdrawal of atorvastatin in healthy, normocholesterolemic men. Am J Cardiol. 2001 Dec 1;88(11):1306-7. — View Citation

Platt OS. Sickle cell anemia as an inflammatory disease. J Clin Invest. 2000 Aug;106(3):337-8. — View Citation

Reiter CD, Gladwin MT. An emerging role for nitric oxide in sickle cell disease vascular homeostasis and therapy. Curr Opin Hematol. 2003 Mar;10(2):99-107. Review. — View Citation

Solovey A, Gui L, Key NS, Hebbel RP. Tissue factor expression by endothelial cells in sickle cell anemia. J Clin Invest. 1998 May 1;101(9):1899-904. — View Citation

Solovey A, Lin Y, Browne P, Choong S, Wayner E, Hebbel RP. Circulating activated endothelial cells in sickle cell anemia. N Engl J Med. 1997 Nov 27;337(22):1584-90. — View Citation

Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001 Nov;21(11):1712-9. Review. — View Citation

Wood KC, Hebbel RP, Granger DN. Endothelial cell P-selectin mediates a proinflammatory and prothrombogenic phenotype in cerebral venules of sickle cell transgenic mice. Am J Physiol Heart Circ Physiol. 2004 May;286(5):H1608-14. Epub 2004 Jan 2. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in Plasma NOx Levels	Measurements of the levels of plasma nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), tissue factor (TF) and vascular endothelial growth factor (VEGF)were performed before and after simvastatin treatment. Changes in mean plasma biomarker levels were assessed for each dose level; however, dose level 3 results were not analyzed, as only 2 subjects were enrolled in this dose group.	Baseline, 21 days	No
Other	Change in Plasma Hs-CRP Levels	Change in plasma high sensitivity C-reactive protein levels in subjects treated with simvastatin	Baseline, 21 days	No
Other	Change in Plasma IL-6 Levels	Change in plasma IL-6 level after treatment with simvastatin	Baseline, 21 days	No
Other	Change in Plasma VEGF Levels	Change in plasma vascular endothelial adhesion molecule-1 levels after treatment with simvastatin	Baseline, 21 days	No
Other	Change in Plasma VCAM1 Levels	Change in plasma vascular cellular adhesion molecule-1 levels after treatment with simvastatin	Baseline, 21 days	No
Other	Change in Plasma TF Levels	Change in plasma tissue factor (TF) levels after treatment with simvastatin	Baseline, 21 days	No
Primary	Change in Total Cholesterol Level	Change in serum total cholesterol level after treatment with simvastatin	Baseline, 21 days	Yes
Primary	Change in Hemoglobin Level	Change in plasma hemoglobin (Hb) level after treatment with simvastatin	Baseline, 21 days	Yes
Primary	Change in Serum Creatine Kinase Levels	Change in serum creatine kinase (CK) levels after treatment with simvastatin	Baseline, 21 days	Yes
Primary	Change in Serum Alanine Transaminase (ALT) Levels	Change in serum alanine transaminase (ALT) after treatment with simvastatin	Baseline, 21 days	Yes
Primary	Change in Serum Creatinine Levels	Change in serum creatinine (Cr) levels after treatment with simvastatin	Baseline, 21 days	Yes

External Links

•   Children's Hospital and Research Center Oakland Official Website
•   CHO Sickle Cell Program: National Center for Sickle Cell Disease
•   Medline Plus: Sickle Cell Anemia
•   NHLBI Website - Sickle Cell Disease