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

NCT01732718 | Completed Phase 2 Results DMC

• 2 other identifiers: 11-1354R01HL111659
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 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.

Conditions

Sickle Cell Disease; Sickle Cell Nephropathy

Keywords

sickle cell disease; endothelial function; albuminuria; atorvastatin; soluble fms-like tyrosine kinase-1

Outcome Measures

Primary Outcomes (1)

• 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).

  Baseline, 6 weeks

Secondary Outcomes (13)

• Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation

  Baseline, 6 weeks

• Change From Baseline to Week 6 in Heme Oxygenase Activity

  Baseline, 6 weeks

• Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1)

  Baseline, 6 weeks

• Change From Baseline to Week 6 in Monocyte Activation

  Baseline, 6 weeks

• Change From Baseline to Week 6 in Renal Function

  Baseline, 6 weeks

Study Arms (2)

Atorvastatin, then Placebo

EXPERIMENTAL

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.

Drug: Atorvastatin; Drug: Placebo

Placebo, Then Atorvastatin

PLACEBO COMPARATOR

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.

Drug: Atorvastatin; Drug: Placebo

Interventions

Atorvastatin DRUG

40 mg tablet by mouth daily for 6 weeks

Also known as: Lipitor®

Atorvastatin, then Placebo; Placebo, Then Atorvastatin

Placebo DRUG

Matching placebo tablet by mouth daily for 6 weeks

Also known as: Sugar pill manufactured to mimic atorvastatin 40 mg tablet

Atorvastatin, then Placebo; Placebo, Then Atorvastatin

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Sickle cell anemia (HbSS) or Sickle-beta0 thalassemia (HbS-beta0thal) between ages of 18 and 60;
• albuminuria (micro- or macroalbuminuria, defined as =/\> 30mg/g creatinine);
• serum alanine aminotransferase (ALT) \</= 2 times upper limits of normal and/or gamma-glutamyl transferase (GGT) \</= 3 times upper limits of normal;
• platelet count \> 150,000 cu/mm;
• normal baseline coagulation profile (PT, International Normalized Ratio (INR), and PTT);
• 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;
• ability to understand the requirements of the study;
• if a woman of childbearing potential, must use an adequate method of contraception; and
• if receiving hydroxyurea, ACE inhibitors or angiotensin blockers (ARB), should be on a stable dose for at least 3 months.

You may not qualify if:

• hypersensitivity to any component of atorvastatin, or history of adverse reaction to statins;
• pregnant or breastfeeding;
• on statin therapy;
• history of metastatic cancer;
• current history of alcohol abuse;
• history of diabetes mellitus or poorly controlled systemic hypertension;
• end-stage renal disease;
• total cholesterol level \< 80 mg/dL and LDL cholesterol \> 130 mg/dL;
• on a chronic transfusion program;
• ingested any investigational drugs within the past 4 weeks;
• prior history of any myopathy;
• allergy to nitroglycerin;
• 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.

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

UNC School of Medicine Clinical&Translational Research Ctr

Chapel Hill, North Carolina, 27599, United States

Location

MeSH Terms

Conditions

Anemia, Sickle Cell; Albuminuria

Interventions

Atorvastatin; Sugars; Tablets

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Proteinuria; Urination Disorders; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urological Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Carbohydrates; Dosage Forms; Pharmaceutical Preparations

Limitations and Caveats

This study was limited by its small sample size.

Results Point of Contact

• Title: Kenneth Ataga, MD
• Organization: University of North Carolina at Chapel Hill

kataga@uthsc.edu

901-448-2813

Study Officials

• Kenneth I Ataga, MBBS

  University of North Caroina at Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2012
• First Posted: November 26, 2012
• Study Start: September 1, 2013
• Primary Completion: January 9, 2018
• Study Completion: January 9, 2018
• Last Updated: March 18, 2020
• Results First Posted: February 5, 2019

Record last verified: 2018-11

Locations

US (1)