Effect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease
Information source: University of North Carolina, Chapel Hill
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Sickle Cell Disease; Sickle Cell Nephropathy
Intervention: Atorvastatin (Drug); Placebo for atorvastatin (Drug)
Phase: Phase 2
Status: Enrolling by invitation
Sponsored by: University of North Carolina, Chapel Hill Official(s) and/or principal investigator(s): Kenneth I Ataga, MBBS, Principal Investigator, Affiliation: University of North Caroina at Chapel Hill
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 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.
Clinical Details
Official title: The Effect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease (in the Grant Entitled: Endothelial Dysfunction in the Pathogenesis of Sickle Cell Nephropathy)
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Change from Baseline in Endothelial Function at 6 Weeks
Secondary outcome: Change from baseline in plasma markers of endothelial activation at 6 weeksChange from baseline in heme oxygenase activity at 6 weeks Change from baseline in plasma levels of soluble fms-like tyrosine kinase-1 (sFLT-1) at 6 weeks. Change from baseline in monocyte activation at 6 weeks. Change from baseline in renal function at 6 weeks. Occurrence of adverse events. Abnormal physical findings. Change from baseline in rho/rho kinase activity at 6 weeks Change from baseline in plasma levels of vascular endothelial growth factor (VEGF) at 6 weeks. Change from baseline in absolute cell counts at 6 weeks. Change from baseline in tissue factor (TF) expression at 6 weeks. Change from baseline in TF-mediated sFLT release from monocytes at 6 weeks. Change from baseline to Week 6 in Tricuspid regurgitant (TR) jet.
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 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.
Eligibility
Minimum age: 18 Years.
Maximum age: 60 Years.
Gender(s): Both.
Criteria:
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;
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.
Locations and Contacts
UNC School of Medicine Clinical&Translational Research Ctr, Chapel Hill, North Carolina 27599, United States
Additional Information
Starting date: September 2013
Last updated: September 4, 2014
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