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Simvastatin (Zocor) Therapy in Sickle Cell Disease

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00508027
First Posted: July 27, 2007
Last Update Posted: September 17, 2013
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Department of Health and Human Services
FDA Office of Orphan Products Development
Information provided by (Responsible Party):
Carolyn Hoppe, Children's Hospital & Research Center Oakland
  Purpose
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).

Condition Intervention Phase
Sickle Cell Disease Drug: Simvastatin Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of Simvastatin (Zocor) Therapy in Sickle Cell Disease

Resource links provided by NLM:


Further study details as provided by Carolyn Hoppe, Children's Hospital & Research Center Oakland:

Primary Outcome Measures:
  • Change in Total Cholesterol Level [ Time Frame: Baseline, 21 days ]
    Change in serum total cholesterol level after treatment with simvastatin

  • Change in Hemoglobin Level [ Time Frame: Baseline, 21 days ]
    Change in plasma hemoglobin (Hb) level after treatment with simvastatin

  • Change in Serum Creatine Kinase Levels [ Time Frame: Baseline, 21 days ]
    Change in serum creatine kinase (CK) levels after treatment with simvastatin

  • Change in Serum Alanine Transaminase (ALT) Levels [ Time Frame: Baseline, 21 days ]
    Change in serum alanine transaminase (ALT) after treatment with simvastatin

  • Change in Serum Creatinine Levels [ Time Frame: Baseline, 21 days ]
    Change in serum creatinine (Cr) levels after treatment with simvastatin


Other Outcome Measures:
  • Change in Plasma NOx Levels [ Time Frame: Baseline, 21 days ]
    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.

  • Change in Plasma Hs-CRP Levels [ Time Frame: Baseline, 21 days ]
    Change in plasma high sensitivity C-reactive protein levels in subjects treated with simvastatin

  • Change in Plasma IL-6 Levels [ Time Frame: Baseline, 21 days ]
    Change in plasma IL-6 level after treatment with simvastatin

  • Change in Plasma VEGF Levels [ Time Frame: Baseline, 21 days ]
    Change in plasma vascular endothelial adhesion molecule-1 levels after treatment with simvastatin

  • Change in Plasma VCAM1 Levels [ Time Frame: Baseline, 21 days ]
    Change in plasma vascular cellular adhesion molecule-1 levels after treatment with simvastatin

  • Change in Plasma TF Levels [ Time Frame: Baseline, 21 days ]
    Change in plasma tissue factor (TF) levels after treatment with simvastatin


Enrollment: 42
Study Start Date: June 2007
Study Completion Date: December 2011
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Simvastatin, Dose Escalation
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
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.
Other Name: Zocor

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

Information from the National Library of Medicine

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Ages Eligible for Study:   13 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00508027


Locations
United States, California
Children's Hospital and Research Center Oakland
Oakland, California, United States, 94609
Sponsors and Collaborators
Children's Hospital & Research Center Oakland
Department of Health and Human Services
FDA Office of Orphan Products Development
Investigators
Principal Investigator: Carolyn C Hoppe, M.D. Children's Hospital & Research Center Oakland
  More Information

Additional Information:
Publications:

Responsible Party: Carolyn Hoppe, Associate Hematologist, Children's Hospital & Research Center Oakland
ClinicalTrials.gov Identifier: NCT00508027     History of Changes
Other Study ID Numbers: 1R01FD003080-01A1 ( U.S. FDA Grant/Contract )
First Submitted: July 26, 2007
First Posted: July 27, 2007
Results First Submitted: February 11, 2013
Results First Posted: August 16, 2013
Last Update Posted: September 17, 2013
Last Verified: August 2013

Keywords provided by Carolyn Hoppe, Children's Hospital & Research Center Oakland:
sickle cell disease
simvastatin
statin drugs
nitric oxide donors
vascular injury

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Simvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors