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| Name | Class |
|---|---|
| Department of Health and Human Services | FED |
| FDA Office of Orphan Products Development | FED |
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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).
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Carolyn C Hoppe, M.D. | UCSF Benioff Children's Hospital Oakland | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital and Research Center Oakland | Oakland | California | 94609 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 7149170 | Background | Hebbel RP. Extracorpuscular factors in the pathogenesis of sickle cell disease. Am J Pediatr Hematol Oncol. 1982 Fall;4(3):316-9. | |
| 9169483 | 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. |
| Label | URL |
|---|---|
| Children's Hospital and Research Center Oakland Official Website | View source |
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There were no significant events following enrollment after inclusion and exclusion criteria were met.
During the study period (05/2006-09/2010), eligible adult and adolescent SCD subjects followed at the CHRCO Sickle Cell Center were approached about participation in this trial. Subjects were enrolled at "steady-state" (i.e., no acute illness or acute SCD-related complications) during a routine clinic visit.
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| ID | Title | Description |
|---|---|---|
| FG000 | Simvastatin, 3 Escalating Dose Groups | Simvastatin was given in a dose-escalating fashion to 3 sequential dose groups: dose level 1= 20 mg/day, dose level 2= 40 mg/day, dose level 3= 80 mg/day The number of subjects starting each dose level are new cohorts of subjects. Determination of clinical safety in the first dose level group was required in order to begin enrollment in the second dose level group and ultimately the third dose group. Enrollment in the third dose level was discontinued early due to newly reported FDA warnings regarding high dose (80mg/day) simvastatin. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose Level 1 |
|
| ||||||||||||||||||||||||
| Dose Level 2 |
| |||||||||||||||||||||||||
| Dose Level 3 |
|
42 subjects started the study; of these,12 were withdrawn from the study and 30 completed the study: dose level 1 (n=16); dose level 2 (n=12), dose level 3 (n=2). Only those participants who completed the study were included in the final analyses (n=30).
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| ID | Title | Description |
|---|---|---|
| BG000 | 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). 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Other Pre-specified | 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. | All participants for whom plasma biomarker levels were recorded at baseline and 21 days | Posted | Mean | Standard Deviation | micromolar | Baseline, 21 days |
|
39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Simvastatin, Dose 1 | Simvastatin given in a dose-escalating fashion to 3 sequential dosage groups (20 mg/day, 40 mg/day, 80 mg/day). Dose 1 = 20mg/day for 21 days, followed by 4-day drug taper. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| sickle cell acute chest syndrome | Vascular disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| elevated serum creatine kinase level | General disorders | Systematic Assessment | Increase in serum creatine kinase (CK) levels: 4 subjects: asymptomatic (AE, grade 1) 2 subjects: with myalgias (AE, grade 2) |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Carolyn Hoppe, Principal Investigator | Children's Hospital & Research Center Oakland | (510)428-3193 | choppe@mail.cho.org |
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| ID | Term |
|---|---|
| D000755 | Anemia, Sickle Cell |
| D057772 | Vascular System Injuries |
| ID | Term |
|---|---|
| D000745 | Anemia, Hemolytic, Congenital |
| D000743 | Anemia, Hemolytic |
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
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| ID | Term |
|---|---|
| D019821 | Simvastatin |
| ID | Term |
|---|---|
| D008148 | Lovastatin |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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|
| Baseline, 21 days |
| Change in Plasma Hs-CRP Levels | Change in plasma high sensitivity C-reactive protein levels in subjects treated with simvastatin | Baseline, 21 days |
| Change in Plasma IL-6 Levels | Change in plasma IL-6 level after treatment with simvastatin | Baseline, 21 days |
| Change in Plasma VEGF Levels | Change in plasma vascular endothelial adhesion molecule-1 levels after treatment with simvastatin | Baseline, 21 days |
| Change in Plasma VCAM1 Levels | Change in plasma vascular cellular adhesion molecule-1 levels after treatment with simvastatin | Baseline, 21 days |
| Change in Plasma TF Levels | Change in plasma tissue factor (TF) levels after treatment with simvastatin | Baseline, 21 days |
| 15280085 | 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. |
| 15001449 | 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. |
| 14704223 | 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. |
| 11001897 | 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. |
| 10597756 | 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. |
| 11728362 | 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. |
| 9042813 | 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. |
| 9371854 | 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. |
| 9576754 | 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. |
| 12579034 | 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. |
| 14990351 | 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. |
| 10930436 | 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. |
| 12673844 | 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. |
| 11701455 | 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. |
| 10665838 | 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. |
| 21477202 | Result | 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. |
| NHLBI Website - Sickle Cell Disease | View source |
| Medline Plus: Sickle Cell Anemia | View source |
| CHO Library: Sickle Cell Disease Information | View source |
| CHO Sickle Cell Program: National Center for Sickle Cell Disease | View source |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Sickle cell genotype | Number | participants |
|
| Simvastatin, Dose Level 2 |
All participants received 40 mg of simvastatin once daily |
| OG002 | Simvastatin, Dose Level 3 | subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage |
|
|
|
| Other Pre-specified | Change in Plasma Hs-CRP Levels | Change in plasma high sensitivity C-reactive protein levels in subjects treated with simvastatin | Posted | Mean | Standard Deviation | mg/L | Baseline, 21 days |
|
|
|
| Other Pre-specified | Change in Plasma IL-6 Levels | Change in plasma IL-6 level after treatment with simvastatin | Posted | Mean | Standard Deviation | pg/mL | Baseline, 21 days |
|
|
|
| Other Pre-specified | Change in Plasma VEGF Levels | Change in plasma vascular endothelial adhesion molecule-1 levels after treatment with simvastatin | Posted | Mean | Standard Deviation | pg/mL | Baseline, 21 days |
|
|
|
| Other Pre-specified | Change in Plasma VCAM1 Levels | Change in plasma vascular cellular adhesion molecule-1 levels after treatment with simvastatin | Posted | Mean | Standard Deviation | ng/mL | Baseline, 21 days |
|
|
|
| Other Pre-specified | Change in Plasma TF Levels | Change in plasma tissue factor (TF) levels after treatment with simvastatin | Posted | Mean | Standard Deviation | pg/mL | Baseline, 21 days |
|
|
|
| Primary | Change in Total Cholesterol Level | Change in serum total cholesterol level after treatment with simvastatin | Posted | Mean | Standard Deviation | mg/dL | Baseline, 21 days |
|
|
|
| Primary | Change in Hemoglobin Level | Change in plasma hemoglobin (Hb) level after treatment with simvastatin | Posted | Mean | Standard Deviation | gm/dL | Baseline, 21 days |
|
|
|
| Primary | Change in Serum Creatine Kinase Levels | Change in serum creatine kinase (CK) levels after treatment with simvastatin | Posted | Mean | Standard Deviation | U/L | Baseline, 21 days |
|
|
|
| Primary | Change in Serum Alanine Transaminase (ALT) Levels | Change in serum alanine transaminase (ALT) after treatment with simvastatin | Posted | Mean | Standard Deviation | U/L | Baseline, 21 days |
|
|
|
| Primary | Change in Serum Creatinine Levels | Change in serum creatinine (Cr) levels after treatment with simvastatin | Posted | Mean | Standard Deviation | mg/dL | Baseline, 21 days |
|
|
|
| 1 |
| 20 |
| 3 |
| 20 |
| EG001 | Simvastatin, Dose 2 | Simvastatin given in a dose-escalating fashion to 3 sequential dosage groups (20 mg/day, 40 mg/day, 80 mg/day). Dose 2 = 40mg/day for 21 days, followed by a 4-day taper. | 1 | 20 | 3 | 20 |
| EG002 | Simvastatin, Dose 3 | Simvastatin given in a dose-escalating fashion to 3 sequential dosage groups (20 mg/day, 40 mg/day, 80 mg/day). Dose 3 = 80mg/day for 21 days, followed by 4-day drug taper. Enrollment in this group discontinued early due to FDA warning re. high dose simvastatin | 0 | 2 | 1 | 2 |
| sickle cell vaso-occlusive pain episode | Vascular disorders | Non-systematic Assessment | vaso-occlusive pain event requiring hospitalization, parenteral opioid treatment |
|
|
| sickle cell vaso-occlusive pain event | Blood and lymphatic system disorders | Non-systematic Assessment | vaso-occlusive pain event, requiring oral opioids, not hospitalized |
|
| myalgia | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | muscle pain associated with increase in serum creatine kinase level. occurred in 2 subjects:
|
|
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| D006425 |
| Hemic and Lymphatic Diseases |
| D006453 | Hemoglobinopathies |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D014947 | Wounds and Injuries |
| D006844 |
| Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |