Clinical trial NCT01732718: Effect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sickle Cell Disease
Sickle Cell Nephropathy
Keywords: sickle cell disease
endothelial function
albuminuria
atorvastatin
soluble fms-like tyrosine kinase-1
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2012-11-26
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change From Baseline to Week 6 in Endothelial Function
timeFrame: Baseline, 6 weeks
Secondary outcomes:
measure: Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation
timeFrame: Baseline, 6 weeks
measure: Change From Baseline to Week 6 in Heme Oxygenase Activity
timeFrame: Baseline, 6 weeks
measure: Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1)
timeFrame: Baseline, 6 weeks
measure: Change From Baseline to Week 6 in Monocyte Activation
timeFrame: Baseline, 6 weeks
measure: Change From Baseline to Week 6 in Renal Function
timeFrame: Baseline, 6 weeks
measure: Occurrence of Adverse Events.
timeFrame: Continuously from randomization through end of study
measure: Abnormal Physical Findings.
timeFrame: Baseline, 2, 4, and 6 weeks during treatment, and at follow-up.
measure: Change From Baseline to Week 6 in Rho/Rho Kinase Activity
timeFrame: Baseline, 6 weeks
measure: Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF)
timeFrame: Baseline, 6 weeks
measure: Mean Change From Baseline to Week 6 in Absolute Cell Counts
timeFrame: Baseline, 6 weeks
measure: Change From Baseline to Week 6 in Tissue Factor (TF) Expression
timeFrame: Baseline, 6 weeks
measure: Change From Baseline to Week 6 in TF-mediated sFLT Release From Monocytes
timeFrame: Baseline, 6 weeks
measure: Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet.
timeFrame: Baseline, Week 6
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: UNC School of Medicine Clinical&Translational Research Ctr
state: North Carolina
Study officials:
affiliation: University of North Caroina at Chapel Hill
name: Kenneth I Ataga, MBBS
role: PRINCIPAL_INVESTIGATOR
References: