Sickle Cell Disease, Sickle Cell Nephropathy
Conditions
Keywords
sickle cell disease, endothelial function, albuminuria, atorvastatin, soluble fms-like tyrosine kinase-1
Brief summary
The purpose of this research study is to learn about the effect of the drug, atorvastatin, on blood vessels in patients with sickle cell disease. The primary hypothesis is that endothelial dysfunction is an important contributor to the pathophysiology of albuminuria in SCD. The investigators propose that atorvastatin will improve endothelial dysfunction, decrease levels of soluble fms-like tyrosine kinase-1 (sFLT-1), and decrease albuminuria in SCD patients. Participants will be individuals with sickle cell disease, age 18 to 60, who have some degree of albuminuria. A total of 19 subjects, males and females, will be enrolled. The study is made up of Screening, Treatment, and Follow Up phases and has a cross-over design. After patients are screened for eligibility, they will be randomized to receive atorvastatin or placebo in the initial six-week treatment period. When that is complete, there will be a four-week washout period before they begin another six-week treatment period. In the second treatment period, they cross-over to the other treatment arm. Four weeks after the end of the second treatment period, follow-up safety assessments will be done.
Detailed description
It is well recognized that sickle cell disease (SCD) is characterized by a vasculopathy, with involvement of multiple organs including the brain, lung, spleen, and kidney. This results in multiple clinical complications, including ischemic stroke, pulmonary hypertension, autosplenectomy, as well as albuminuria and chronic renal disease. Several recent studies have confirmed the association of both albuminuria and renal dysfunction with echocardiographically-defined pulmonary hypertension and other vasculopathic complications in SCD, suggesting that they may share a similar pathophysiology. Despite the high prevalence of albuminuria in patients with SCD and the known association of renal failure with increased mortality, the pathophysiology and treatment of albuminuria in this setting remain poorly defined. The treatment options for nephropathy in SCD are limited. Although Angiotensin converting enzyme (ACE) inhibitors are the standard of care in the treatment of patients with proteinuria, there are to date no controlled, long-term studies confirming their efficacy and safety in this setting. In this study, the investigators will evaluate the efficacy and safety of atorvastatin in SCD patients. At the completion of this trial, the investigators will have an improved understanding of the contribution of endothelial dysfunction to the pathophysiology of albuminuria in SCD. If the data support the hypothesis that atorvastatin is safe and effective in this population, the investigators plan on carrying out adequately powered studies to more definitively evaluate its safety and efficacy in the treatment and/or prevention of albuminuria in SCD.
Interventions
DRUGAtorvastatin
40 mg tablet by mouth daily for 6 weeks
DRUGPlacebo
Matching placebo tablet by mouth daily for 6 weeks
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Sickle cell anemia (HbSS) or Sickle-beta0 thalassemia (HbS-beta0thal) between ages of 18 and 60; 2. albuminuria (micro- or macroalbuminuria, defined as =/\> 30mg/g creatinine); 3. serum alanine aminotransferase (ALT) \</= 2 times upper limits of normal and/or gamma-glutamyl transferase (GGT) \</= 3 times upper limits of normal; 4. platelet count \> 150,000 cu/mm; 5. normal baseline coagulation profile (PT, International Normalized Ratio (INR), and PTT); 6. non-crisis, steady state with no severe pain episodes during the preceding 4 weeks, and no documented infection in the 2 weeks prior to enrollment; 7. ability to understand the requirements of the study; 8. if a woman of childbearing potential, must use an adequate method of contraception; and 9. if receiving hydroxyurea, ACE inhibitors or angiotensin blockers (ARB), should be on a stable dose for at least 3 months.
Exclusion criteria
1. hypersensitivity to any component of atorvastatin, or history of adverse reaction to statins; 2. pregnant or breastfeeding; 3. on statin therapy; 4. history of metastatic cancer; 5. current history of alcohol abuse; 6. history of diabetes mellitus or poorly controlled systemic hypertension; 7. end-stage renal disease; 8. total cholesterol level \< 80 mg/dL and LDL cholesterol \> 130 mg/dL; 9. on a chronic transfusion program; 10. ingested any investigational drugs within the past 4 weeks; 11. prior history of any myopathy; 12. allergy to nitroglycerin; 13. taking any of the following drugs: phosphodiesterase-5 inhibitors (e.g., sildenafil), cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors (e.g., cyclosporine, protease inhibitors), macrolide antibiotics (e.g., clarithromycin, erythromycin), fibric acid derivatives (e.g. gemfibrozil), niacin, colchicines, antifungal agents (azole derivatives), amiodarone, danazol, daptomycin, diltiazem, verapamil, eltrombopag, everolimus, fosphenytoin, or lanthanum. Patients will also be encouraged to avoid grape fruit juice and red yeast rice for the duration of the study. Atorvastatin is contraindicated during pregnancy and breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 6 in Endothelial Function | Baseline, 6 weeks | Endothelial function will be assessed using ultrasound imaging of the brachial artery, with measurement of endothelium-dependent (flow-mediated) and endothelium-independent (nitroglycerin-mediated) dilation of the artery measured in millimeters (mm). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 6 in Heme Oxygenase Activity | Baseline, 6 weeks | The expression and activity of heme oxygenase-1(HO-1)will be determined at baseline and at 6 weeks of treatment. |
| Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1) | Baseline, 6 weeks | Investigators will measure plasma levels of soluble fms-like tyrosine kinase-1 (sFLT-1) at baseline and at 6 weeks of treatment. |
| Change From Baseline to Week 6 in Monocyte Activation | Baseline, 6 weeks | Flow cytometry performed to assess monocyte activation at baseline and at 6 weeks of treatment. |
| Change From Baseline to Week 6 in Renal Function | Baseline, 6 weeks | Investigators will assess the effect of atorvastatin on albuminuria by spot urine microalbuminuria/creatinine ratio measured at baseline and at 6 weeks of treatment. |
| Occurrence of Adverse Events. | Continuously from randomization through end of study | Subjects will be evaluated for safety by patient self-report of adverse events and results of laboratory tests. |
| Abnormal Physical Findings. | Baseline, 2, 4, and 6 weeks during treatment, and at follow-up. | Subjects will be evaluated by physical examination and/or measurement of vital signs at each study visit. |
| Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation | Baseline, 6 weeks | Investigators will measure plasma levels of soluble vascular cell adhesion molecules (sVCAM) and soluble intracellular adhesion molecule (sICAM) at baseline and at 6 weeks of treatment. |
| Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF) | Baseline, 6 weeks | Investigators will measure plasma levels of vascular endothelial growth factor (VEGF) at baseline and at 6 weeks of treatment. |
| Mean Change From Baseline to Week 6 in Absolute Cell Counts | Baseline, 6 weeks | Flow cytometry will be performed to assess absolute cell counts at baseline and at 6 weeks of treatment. |
| Change From Baseline to Week 6 in Tissue Factor (TF) Expression | Baseline, 6 weeks | Flow cytometry will be performed to assess TF expression at baseline and at 6 weeks of treatment. |
| Change From Baseline to Week 6 in TF-mediated sFLT Release From Monocytes | Baseline, 6 weeks | Flow cytometry will be performed to assess TF-mediated sFLT release from monocytes at baseline and at 6 weeks of treatment. |
| Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet. | Baseline, Week 6 | Echocardiogram will be used to assess TR jet before and after treatment. |
| Change From Baseline to Week 6 in Rho/Rho Kinase Activity | Baseline, 6 weeks | The expression and activity of rho/rho kinase will be determined at baseline and at 6 weeks of treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants who were randomized to receive either Atorvastatin 40 mg or Placebo (matching Atorvastatin 40 mg) | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 48 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment United States | 13 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 7 / 13 | 6 / 13 |
| serious Total, serious adverse events | 1 / 13 | 3 / 13 |
Outcome results
Primary
Change From Baseline to Week 6 in Endothelial Function
Endothelial function will be assessed using ultrasound imaging of the brachial artery, with measurement of endothelium-dependent (flow-mediated) and endothelium-independent (nitroglycerin-mediated) dilation of the artery measured in millimeters (mm).
Time frame: Baseline, 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atorvastatin | Change From Baseline to Week 6 in Endothelial Function | 1.44 % diameter change |
| Placebo | Change From Baseline to Week 6 in Endothelial Function | 0.69 % diameter change |
p-value: 0.51Student t-test followed by ANOVA
Secondary
Abnormal Physical Findings.
Subjects will be evaluated by physical examination and/or measurement of vital signs at each study visit.
Time frame: Baseline, 2, 4, and 6 weeks during treatment, and at follow-up.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin | Abnormal Physical Findings. | 0 participants |
| Placebo | Abnormal Physical Findings. | 2 participants |
| Week 6-Atorvastatin | Abnormal Physical Findings. | 1 participants |
| Baseline-Placebo | Abnormal Physical Findings. | 1 participants |
| Week 4-Placebo | Abnormal Physical Findings. | 0 participants |
| Week 6-Placebo | Abnormal Physical Findings. | 1 participants |
Secondary
Change From Baseline to Week 6 in Heme Oxygenase Activity
The expression and activity of heme oxygenase-1(HO-1)will be determined at baseline and at 6 weeks of treatment.
Time frame: Baseline, 6 weeks
Population: Data not collected
Secondary
Change From Baseline to Week 6 in Monocyte Activation
Flow cytometry performed to assess monocyte activation at baseline and at 6 weeks of treatment.
Time frame: Baseline, 6 weeks
Population: The stored samples did not survive the freeze/thaw process and as such, this data was not attainable.
Secondary
Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1)
Investigators will measure plasma levels of soluble fms-like tyrosine kinase-1 (sFLT-1) at baseline and at 6 weeks of treatment.
Time frame: Baseline, 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atorvastatin | Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1) | 19.2 pg/mL |
| Placebo | Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1) | 36.9 pg/mL |
p-value: 0.31Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF)
Investigators will measure plasma levels of vascular endothelial growth factor (VEGF) at baseline and at 6 weeks of treatment.
Time frame: Baseline, 6 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Atorvastatin | Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF) | -3.99 pg/mL |
| Placebo | Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF) | -10.5 pg/mL |
p-value: 0.64Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation
Investigators will measure plasma levels of soluble vascular cell adhesion molecules (sVCAM) and soluble intracellular adhesion molecule (sICAM) at baseline and at 6 weeks of treatment.
Time frame: Baseline, 6 weeks
Population: Investigators elected to look at only one marker of vascular endothelial injury, i.e. sVCAM, so there is no data for sICAM.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Atorvastatin | Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation | 22.99 ng/mL |
| Placebo | Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation | 7.54 ng/mL |
p-value: 0.74Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline to Week 6 in Renal Function
Investigators will assess the effect of atorvastatin on albuminuria by spot urine microalbuminuria/creatinine ratio measured at baseline and at 6 weeks of treatment.
Time frame: Baseline, 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atorvastatin | Change From Baseline to Week 6 in Renal Function | 28.8 ug per mg |
| Placebo | Change From Baseline to Week 6 in Renal Function | 74.9 ug per mg |
p-value: 0.57see comments for explanation
Secondary
Change From Baseline to Week 6 in Rho/Rho Kinase Activity
The expression and activity of rho/rho kinase will be determined at baseline and at 6 weeks of treatment.
Time frame: Baseline, 6 weeks
Population: Due to loss of key study personnel these data were not collected
Secondary
Change From Baseline to Week 6 in TF-mediated sFLT Release From Monocytes
Flow cytometry will be performed to assess TF-mediated sFLT release from monocytes at baseline and at 6 weeks of treatment.
Time frame: Baseline, 6 weeks
Population: The stored samples did not survive the freeze/thaw process and as such, this data was not attainable.
Secondary
Change From Baseline to Week 6 in Tissue Factor (TF) Expression
Flow cytometry will be performed to assess TF expression at baseline and at 6 weeks of treatment.
Time frame: Baseline, 6 weeks
Population: The stored samples did not survive the freeze/thaw process and as such, this data was not attainable.
Secondary
Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet.
Echocardiogram will be used to assess TR jet before and after treatment.
Time frame: Baseline, Week 6
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Atorvastatin | Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet. | 0.80 m/sec |
| Placebo | Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet. | -0.05 m/sec |
p-value: 0.5184Wilcoxon (Mann-Whitney)
Secondary
Mean Change From Baseline to Week 6 in Absolute Cell Counts
Flow cytometry will be performed to assess absolute cell counts at baseline and at 6 weeks of treatment.
Time frame: Baseline, 6 weeks
Population: Intent was to perform analysis using flow cytometry but cells did not survive thawing. Decision was made to use CBC laboratory values for absolute monocyte (AMC), lymphocyte (ALC) and neutrophil (ANC) counts to perform the analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Atorvastatin | Mean Change From Baseline to Week 6 in Absolute Cell Counts | AMC | -0.07 10^9 cells/L |
| Atorvastatin | Mean Change From Baseline to Week 6 in Absolute Cell Counts | ALC | 0.08 10^9 cells/L |
| Atorvastatin | Mean Change From Baseline to Week 6 in Absolute Cell Counts | ANC | -0.18 10^9 cells/L |
| Placebo | Mean Change From Baseline to Week 6 in Absolute Cell Counts | AMC | 0.15 10^9 cells/L |
| Placebo | Mean Change From Baseline to Week 6 in Absolute Cell Counts | ALC | -0.22 10^9 cells/L |
| Placebo | Mean Change From Baseline to Week 6 in Absolute Cell Counts | ANC | -0.55 10^9 cells/L |
Comparison: Comparison of the change in AMCp-value: 0.1469t-test, 1 sided
Comparison: Comparison of the change in ALCp-value: 0.2382t-test, 1 sided
Comparison: Comparison of the change in ANCp-value: 0.5833t-test, 1 sided
Secondary
Occurrence of Adverse Events.
Subjects will be evaluated for safety by patient self-report of adverse events and results of laboratory tests.
Time frame: Continuously from randomization through end of study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin | Occurrence of Adverse Events. | 9 events |
| Placebo | Occurrence of Adverse Events. | 13 events |