Effect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease
Condition: Sickle Cell Disease; Sickle Cell Nephropathy
MeSH terms: Kidney Diseases; Albuminuria; Anemia, Sickle Cell
Intervention: Atorvastatin; Placebo
Intervention description: 40 mg tablet by mouth daily for 6 weeks; Matching placebo tablet by mouth daily for 6 weeks
Intervention MeSH terms: Atorvastatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: sickle cell disease; endothelial function; albuminuria; atorvastatin; soluble fms-like tyrosine kinase-1

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.
    

Eligibility 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 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.