Sickle Cell Disease
Conditions
Keywords
sickle cell disease, simvastatin, statin drugs, nitric oxide donors, vascular injury
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.
Interventions
DRUGSimvastatin
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.
Sponsors
Department of Health and Human Services
FDA Office of Orphan Products Development
UCSF Benioff Children's Hospital Oakland
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hemoglobin Level | Baseline, 21 days | Change in plasma hemoglobin (Hb) level after treatment with simvastatin |
| Change in Serum Creatine Kinase Levels | Baseline, 21 days | Change in serum creatine kinase (CK) levels after treatment with simvastatin |
| Change in Total Cholesterol Level | Baseline, 21 days | Change in serum total cholesterol level after treatment with simvastatin |
| Change in Serum Alanine Transaminase (ALT) Levels | Baseline, 21 days | Change in serum alanine transaminase (ALT) after treatment with simvastatin |
| Change in Serum Creatinine Levels | Baseline, 21 days | Change in serum creatinine (Cr) levels after treatment with simvastatin |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma NOx Levels | 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 TF Levels | Baseline, 21 days | Change in plasma tissue factor (TF) levels after treatment with simvastatin |
| Change in Plasma Hs-CRP Levels | Baseline, 21 days | Change in plasma high sensitivity C-reactive protein levels in subjects treated with simvastatin |
| Change in Plasma IL-6 Levels | Baseline, 21 days | Change in plasma IL-6 level after treatment with simvastatin |
| Change in Plasma VEGF Levels | Baseline, 21 days | Change in plasma vascular endothelial adhesion molecule-1 levels after treatment with simvastatin |
| Change in Plasma VCAM1 Levels | Baseline, 21 days | Change in plasma vascular cellular adhesion molecule-1 levels after treatment with simvastatin |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
There were no significant events following enrollment after inclusion and exclusion criteria were met.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Dose Level 1 | Lost to Follow-up | 4 |
| Dose Level 1 | Physician Decision | 2 |
| Dose Level 1 | Withdrawal by Subject | 2 |
| Dose Level 2 | Lost to Follow-up | 2 |
| Dose Level 2 | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Simvastatin, Dose Escalation |
|---|---|
| Age Continuous | 25 years STANDARD_DEVIATION 11.5 |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 21 Participants |
| Sickle cell genotype Compound heterozygous Hb S and Hb C (SC) | 10 participants |
| Sickle cell genotype Homozygous Hb S (SS or S/beta0 thalassemia) | 20 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 20 | 3 / 20 | 1 / 2 |
| serious Total, serious adverse events | 1 / 20 | 1 / 20 | 0 / 2 |
Outcome results
Primary
Change in Hemoglobin Level
Change in plasma hemoglobin (Hb) level after treatment with simvastatin
Time frame: Baseline, 21 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin, Dose Level 1 | Change in Hemoglobin Level | -0.2 gm/dL | Standard Deviation 0.1 |
| Simvastatin, Dose Level 2 | Change in Hemoglobin Level | 0.1 gm/dL | Standard Deviation 0.2 |
| Simvastatin, Dose Level 3 | Change in Hemoglobin Level | -0.4 gm/dL | Standard Deviation 0.1 |
Primary
Change in Serum Alanine Transaminase (ALT) Levels
Change in serum alanine transaminase (ALT) after treatment with simvastatin
Time frame: Baseline, 21 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin, Dose Level 1 | Change in Serum Alanine Transaminase (ALT) Levels | 4 U/L | Standard Deviation 3 |
| Simvastatin, Dose Level 2 | Change in Serum Alanine Transaminase (ALT) Levels | 3 U/L | Standard Deviation 4 |
| Simvastatin, Dose Level 3 | Change in Serum Alanine Transaminase (ALT) Levels | -3 U/L | Standard Deviation 2 |
Primary
Change in Serum Creatine Kinase Levels
Change in serum creatine kinase (CK) levels after treatment with simvastatin
Time frame: Baseline, 21 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin, Dose Level 1 | Change in Serum Creatine Kinase Levels | 57 U/L | Standard Deviation 88 |
| Simvastatin, Dose Level 2 | Change in Serum Creatine Kinase Levels | 20 U/L | Standard Deviation 34 |
| Simvastatin, Dose Level 3 | Change in Serum Creatine Kinase Levels | 62 U/L | Standard Deviation 20 |
Primary
Change in Serum Creatinine Levels
Change in serum creatinine (Cr) levels after treatment with simvastatin
Time frame: Baseline, 21 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin, Dose Level 1 | Change in Serum Creatinine Levels | 0.03 mg/dL | Standard Deviation 0.03 |
| Simvastatin, Dose Level 2 | Change in Serum Creatinine Levels | 0.04 mg/dL | Standard Deviation 0.06 |
| Simvastatin, Dose Level 3 | Change in Serum Creatinine Levels | -0.1 mg/dL | Standard Deviation 0.1 |
Primary
Change in Total Cholesterol Level
Change in serum total cholesterol level after treatment with simvastatin
Time frame: Baseline, 21 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin, Dose Level 1 | Change in Total Cholesterol Level | -16 mg/dL | Standard Deviation 2 |
| Simvastatin, Dose Level 2 | Change in Total Cholesterol Level | -18 mg/dL | Standard Deviation 10 |
| Simvastatin, Dose Level 3 | Change in Total Cholesterol Level | -18 mg/dL | Standard Deviation 4 |
Other Pre-specified
Change in Plasma Hs-CRP Levels
Change in plasma high sensitivity C-reactive protein levels in subjects treated with simvastatin
Time frame: Baseline, 21 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin, Dose Level 1 | Change in Plasma Hs-CRP Levels | -7.7 mg/L | Standard Deviation 14.2 |
| Simvastatin, Dose Level 2 | Change in Plasma Hs-CRP Levels | -3.6 mg/L | Standard Deviation 4.8 |
Other Pre-specified
Change in Plasma IL-6 Levels
Change in plasma IL-6 level after treatment with simvastatin
Time frame: Baseline, 21 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin, Dose Level 1 | Change in Plasma IL-6 Levels | -0.6 pg/mL | Standard Deviation 0.9 |
| Simvastatin, Dose Level 2 | Change in Plasma IL-6 Levels | -0.3 pg/mL | Standard Deviation 0.3 |
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.
Time frame: Baseline, 21 days
Population: All participants for whom plasma biomarker levels were recorded at baseline and 21 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin, Dose Level 1 | Change in Plasma NOx Levels | 7 micromolar | Standard Deviation 1 |
| Simvastatin, Dose Level 2 | Change in Plasma NOx Levels | 19.7 micromolar | Standard Deviation 12 |
Comparison: Ho: There is no change in plasma biomarker levels before and after simivastatin treatment. With 12 patients in each group and assuming a 5% risk of Type I error (two-tailed α = 0.05) and estimated SD for the change in NOx (or sVCAM-1) of 48%, power will be 80% to detect a 40% change from baseline for each group, and a 55% difference in the change in biomarker levels between dose groups. Matched paired t-tests were used to measure changes in biomarker levels from baseline.p-value: <0.05t-test, 2 sided
Other Pre-specified
Change in Plasma TF Levels
Change in plasma tissue factor (TF) levels after treatment with simvastatin
Time frame: Baseline, 21 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin, Dose Level 1 | Change in Plasma TF Levels | -9 pg/mL | Standard Deviation 32 |
| Simvastatin, Dose Level 2 | Change in Plasma TF Levels | -36 pg/mL | Standard Deviation 54 |
Other Pre-specified
Change in Plasma VCAM1 Levels
Change in plasma vascular cellular adhesion molecule-1 levels after treatment with simvastatin
Time frame: Baseline, 21 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin, Dose Level 1 | Change in Plasma VCAM1 Levels | -44 ng/mL | Standard Deviation 58 |
| Simvastatin, Dose Level 2 | Change in Plasma VCAM1 Levels | -86 ng/mL | Standard Deviation 103 |
Other Pre-specified
Change in Plasma VEGF Levels
Change in plasma vascular endothelial adhesion molecule-1 levels after treatment with simvastatin
Time frame: Baseline, 21 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin, Dose Level 1 | Change in Plasma VEGF Levels | -164 pg/mL | Standard Deviation 40 |
| Simvastatin, Dose Level 2 | Change in Plasma VEGF Levels | -30 pg/mL | Standard Deviation 20 |