search
Back to results

Simvastatin (Zocor) Therapy in Sickle Cell Disease

Primary Purpose

Sickle Cell Disease

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Simvastatin
Sponsored by
UCSF Benioff Children's Hospital Oakland
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease focused on measuring sickle cell disease, simvastatin, statin drugs, nitric oxide donors, vascular injury

Eligibility Criteria

13 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Hospital and Research Center Oakland

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Simvastatin, Dose Escalation

Arm Description

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).

Outcomes

Primary Outcome Measures

Change in Total Cholesterol Level
Change in serum total cholesterol level after treatment with simvastatin
Change in Hemoglobin Level
Change in plasma hemoglobin (Hb) level after treatment with simvastatin
Change in Serum Creatine Kinase Levels
Change in serum creatine kinase (CK) levels after treatment with simvastatin
Change in Serum Alanine Transaminase (ALT) Levels
Change in serum alanine transaminase (ALT) after treatment with simvastatin
Change in Serum Creatinine Levels
Change in serum creatinine (Cr) levels after treatment with simvastatin

Secondary Outcome Measures

Full Information

First Posted
July 26, 2007
Last Updated
August 20, 2013
Sponsor
UCSF Benioff Children's Hospital Oakland
Collaborators
Department of Health and Human Services, FDA Office of Orphan Products Development
search

1. Study Identification

Unique Protocol Identification Number
NCT00508027
Brief Title
Simvastatin (Zocor) Therapy in Sickle Cell Disease
Official Title
Phase I/II Study of Simvastatin (Zocor) Therapy in Sickle Cell Disease
Study Type
Interventional

2. Study Status

Record Verification Date
August 2013
Overall Recruitment Status
Completed
Study Start Date
June 2007 (undefined)
Primary Completion Date
December 2011 (Actual)
Study Completion Date
December 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
UCSF Benioff Children's Hospital Oakland
Collaborators
Department of Health and Human Services, FDA Office of Orphan Products Development

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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: 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease
Keywords
sickle cell disease, simvastatin, statin drugs, nitric oxide donors, vascular injury

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
42 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Simvastatin, Dose Escalation
Arm Type
Other
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Simvastatin
Other Intervention Name(s)
Zocor
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in Total Cholesterol Level
Description
Change in serum total cholesterol level after treatment with simvastatin
Time Frame
Baseline, 21 days
Title
Change in Hemoglobin Level
Description
Change in plasma hemoglobin (Hb) level after treatment with simvastatin
Time Frame
Baseline, 21 days
Title
Change in Serum Creatine Kinase Levels
Description
Change in serum creatine kinase (CK) levels after treatment with simvastatin
Time Frame
Baseline, 21 days
Title
Change in Serum Alanine Transaminase (ALT) Levels
Description
Change in serum alanine transaminase (ALT) after treatment with simvastatin
Time Frame
Baseline, 21 days
Title
Change in Serum Creatinine Levels
Description
Change in serum creatinine (Cr) levels after treatment with simvastatin
Time Frame
Baseline, 21 days
Other Pre-specified Outcome Measures:
Title
Change in Plasma NOx Levels
Description
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.
Time Frame
Baseline, 21 days
Title
Change in Plasma Hs-CRP Levels
Description
Change in plasma high sensitivity C-reactive protein levels in subjects treated with simvastatin
Time Frame
Baseline, 21 days
Title
Change in Plasma IL-6 Levels
Description
Change in plasma IL-6 level after treatment with simvastatin
Time Frame
Baseline, 21 days
Title
Change in Plasma VEGF Levels
Description
Change in plasma vascular endothelial adhesion molecule-1 levels after treatment with simvastatin
Time Frame
Baseline, 21 days
Title
Change in Plasma VCAM1 Levels
Description
Change in plasma vascular cellular adhesion molecule-1 levels after treatment with simvastatin
Time Frame
Baseline, 21 days
Title
Change in Plasma TF Levels
Description
Change in plasma tissue factor (TF) levels after treatment with simvastatin
Time Frame
Baseline, 21 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
13 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carolyn C Hoppe, M.D.
Organizational Affiliation
UCSF Benioff Children's Hospital Oakland
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital and Research Center Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
7149170
Citation
Hebbel RP. Extracorpuscular factors in the pathogenesis of sickle cell disease. Am J Pediatr Hematol Oncol. 1982 Fall;4(3):316-9.
Results Reference
background
PubMed Identifier
9169483
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.
Results Reference
background
PubMed Identifier
15280085
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.
Results Reference
background
PubMed Identifier
15001449
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.
Results Reference
background
PubMed Identifier
14704223
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.
Results Reference
background
PubMed Identifier
11001897
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.
Results Reference
background
PubMed Identifier
10597756
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.
Results Reference
background
PubMed Identifier
11728362
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.
Results Reference
background
PubMed Identifier
9042813
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.
Results Reference
background
PubMed Identifier
9371854
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.
Results Reference
background
PubMed Identifier
9576754
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.
Results Reference
background
PubMed Identifier
12579034
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.
Results Reference
background
PubMed Identifier
14990351
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.
Results Reference
background
PubMed Identifier
10930436
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.
Results Reference
background
PubMed Identifier
12673844
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.
Results Reference
background
PubMed Identifier
11701455
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.
Results Reference
background
PubMed Identifier
10665838
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. Erratum In: Pharmacol Ther 2000 May;86(2):199.
Results Reference
background
PubMed Identifier
21477202
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.
Results Reference
result
Links:
URL
http://www.childrenshospitaloakland.org
Description
Children's Hospital and Research Center Oakland Official Website
URL
http://www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_WhatIs.html
Description
NHLBI Website - Sickle Cell Disease
URL
http://www.nlm.nih.gov/medlineplus/ency/article/000527.htm
Description
Medline Plus: Sickle Cell Anemia
URL
http://www.childrenshospitaloakland.org/healthcare/health_library.asp
Description
CHO Library: Sickle Cell Disease Information
URL
http://www.childrenshospitaloakland.org/healthcare/depts/sickle_cell_center.asp
Description
CHO Sickle Cell Program: National Center for Sickle Cell Disease

Learn more about this trial

Simvastatin (Zocor) Therapy in Sickle Cell Disease

We'll reach out to this number within 24 hrs