Clinical trial NCT00508027: Simvastatin (Zocor) Therapy in Sickle Cell Disease
Official title: Phase I/II Study of Simvastatin (Zocor) Therapy in Sickle Cell Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Sickle Cell Disease
Keywords: sickle cell disease
simvastatin
statin drugs
nitric oxide donors
vascular injury
Lead sponsor: UCSF Benioff Children's Hospital Oakland
Sponsor class: OTHER
Collaborators: name: Department of Health and Human Services
name: FDA Office of Orphan Products Development
First posted: 2007-07-27
Enrollment: 42
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Total Cholesterol Level
timeFrame: Baseline, 21 days
measure: Change in Hemoglobin Level
timeFrame: Baseline, 21 days
measure: Change in Serum Creatine Kinase Levels
timeFrame: Baseline, 21 days
measure: Change in Serum Alanine Transaminase (ALT) Levels
timeFrame: Baseline, 21 days
measure: Change in Serum Creatinine Levels
timeFrame: Baseline, 21 days
Secondary outcomes:
Other outcomes:
measure: Change in Plasma NOx Levels
timeFrame: Baseline, 21 days
measure: Change in Plasma Hs-CRP Levels
timeFrame: Baseline, 21 days
measure: Change in Plasma IL-6 Levels
timeFrame: Baseline, 21 days
measure: Change in Plasma VEGF Levels
timeFrame: Baseline, 21 days
measure: Change in Plasma VCAM1 Levels
timeFrame: Baseline, 21 days
measure: Change in Plasma TF Levels
timeFrame: Baseline, 21 days
Locations:
city: Oakland
country: United States
facility: Children's Hospital and Research Center Oakland
state: California
Study officials:
affiliation: UCSF Benioff Children's Hospital Oakland
name: Carolyn C Hoppe, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hebbel RP. Extracorpuscular factors in the pathogenesis of sickle cell disease. Am J Pediatr Hematol Oncol. 1982 Fall;4(3):316-9.
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. doi: 10.1172/JCI119442. No abstract available.
citation: Hebbel RP. Special issue of Microcirculation: examination of the vascular pathobiology of sickle cell anemia. Foreword. Microcirculation. 2004 Mar;11(2):99-100. No abstract available.
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. doi: 10.1152/ajpheart.01150.2003. Epub 2004 Mar 4.
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. doi: 10.1152/ajpheart.01056.2003. Epub 2004 Jan 2.
citation: 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.
citation: Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala 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. doi: 10.1001/archinte.159.22.2661.
citation: Laufs U, Wassmann S, Hilgers S, Ribaudo N, Bohm 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. doi: 10.1016/s0002-9149(01)02095-1. No abstract available.
citation: Hebbel RP, Vercellotti GM. The endothelial biology of sickle cell disease. J Lab Clin Med. 1997 Mar;129(3):288-93. doi: 10.1016/s0022-2143(97)90176-1. No abstract available.
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. doi: 10.1056/NEJM199711273372203.
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. doi: 10.1172/JCI1932.
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. doi: 10.1097/00062752-200303000-00001.
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. doi: 10.1016/j.freeradbiomed.2003.11.032.
citation: Platt OS. Sickle cell anemia as an inflammatory disease. J Clin Invest. 2000 Aug;106(3):337-8. doi: 10.1172/JCI10726. No abstract available.
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.
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. doi: 10.1161/hq1101.098486.
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. doi: 10.1016/s0163-7258(99)00045-5.
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.x. Epub 2011 Apr 8.