Effect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease

NCT ID: NCT01732718

Last Updated: 2020-03-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-30
• Study Completion Date: 2018-01-09

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.

Conditions

Sickle Cell Disease; Sickle Cell Nephropathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Atorvastatin, then Placebo

Participants first received Atorvastatin 40 mg tablets once daily for 6 weeks. After a washout period of 4 weeks, they then received placebo (matching Atorvastatin 40 mg tablets) once daily for 6 weeks.

Group Type: EXPERIMENTAL

Atorvastatin

Intervention Type: DRUG

40 mg tablet by mouth daily for 6 weeks

Placebo

Intervention Type: DRUG

Matching placebo tablet by mouth daily for 6 weeks

Placebo, Then Atorvastatin

Participants first received Placebo (matching Atorvastatin 40 mg tablets) once daily for 6 weeks. After a washout period of 4 weeks, they then received Atorvastatin 40 mg tablets once daily for 6 weeks.

Group Type: PLACEBO_COMPARATOR

Atorvastatin

Intervention Type: DRUG

40 mg tablet by mouth daily for 6 weeks

Placebo

Intervention Type: DRUG

Matching placebo tablet by mouth daily for 6 weeks

Interventions

Atorvastatin

40 mg tablet by mouth daily for 6 weeks

Intervention Type: DRUG

Placebo

Matching placebo tablet by mouth daily for 6 weeks

Intervention Type: DRUG

Other Intervention Names

Lipitor®; Sugar pill manufactured to mimic atorvastatin 40 mg tablet

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kenneth I Ataga, MBBS

Role: PRINCIPAL_INVESTIGATOR

University of North Caroina at Chapel Hill

Locations

UNC School of Medicine Clinical&Translational Research Ctr

Chapel Hill, North Carolina, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

R01HL111659

Identifier Type: NIH

Identifier Source: secondary_id

View Link

11-1354

Identifier Type: -

Identifier Source: org_study_id