Simvastatin (Zocor) Therapy in Sickle Cell Disease

NCT00508027 | Completed Phase 1 Results DMC

• 1 other identifier: 1R01FD003080-01A1
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

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).

Conditions

Sickle Cell Disease

Keywords

sickle cell disease; simvastatin; statin drugs; nitric oxide donors; vascular injury

Outcome Measures

Primary Outcomes (5)

• 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

Other Outcomes (6)

• Change in Plasma NOx Levels

  Baseline, 21 days

• Change in Plasma Hs-CRP Levels

  Baseline, 21 days

• Change in Plasma IL-6 Levels

  Baseline, 21 days

Study Arms (1)

Simvastatin, Dose Escalation

OTHER

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

Interventions

Simvastatin DRUG

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.

Also known as: Zocor

Simvastatin, Dose Escalation

Eligibility Criteria

• Age: 13 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• UCSF Benioff Children's Hospital Oakland: lead
• Department of Health and Human Services: collaborator
• FDA Office of Orphan Products Development: collaborator

Study Sites (1)

Children's Hospital and Research Center Oakland

Oakland, California, 94609, United States

Location

Related Publications (18)

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

  PMID: 7149170 BACKGROUND

• 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.

  PMID: 9169483 BACKGROUND

• 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.

  PMID: 15280085 BACKGROUND

• 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.

  PMID: 15001449 BACKGROUND

• 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.

  PMID: 14704223 BACKGROUND

• 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.

  PMID: 11001897 BACKGROUND

• 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.

  PMID: 10597756 BACKGROUND

• 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.

  PMID: 11728362 BACKGROUND

• 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.

  PMID: 9042813 BACKGROUND

• 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.

  PMID: 9371854 BACKGROUND

• 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.

  PMID: 9576754 BACKGROUND

• 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.

  PMID: 12579034 BACKGROUND

• 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.

  PMID: 14990351 BACKGROUND

• 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.

  PMID: 10930436 BACKGROUND

• 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.

  PMID: 12673844 BACKGROUND

• 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.

  PMID: 11701455 BACKGROUND

• 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.

  PMID: 10665838 BACKGROUND

• 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.

  PMID: 21477202 RESULT

Related Links

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

MeSH Terms

Conditions

Anemia, Sickle Cell; Vascular System Injuries

Interventions

Simvastatin

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Vascular Diseases; Cardiovascular Diseases; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Carolyn Hoppe, Principal Investigator
• Organization: Children's Hospital & Research Center Oakland

choppe@mail.cho.org

(510)428-3193

Study Officials

• Carolyn C Hoppe, M.D.

  UCSF Benioff Children's Hospital Oakland

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Hematologist

Study Record Dates

• First Submitted: July 26, 2007
• First Posted: July 27, 2007
• Study Start: June 1, 2007
• Primary Completion: December 1, 2011
• Study Completion: December 1, 2011
• Last Updated: September 17, 2013
• Results First Posted: August 16, 2013

Record last verified: 2013-08

Locations

US (1)