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

This study is enrolling participants by invitation only.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Kenneth Ataga, MD, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT01732718
First received: November 9, 2012
Last updated: September 4, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Sickle Cell Disease
Sickle Cell Nephropathy
Drug: Atorvastatin
Drug: Placebo for atorvastatin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • Change from Baseline in Endothelial Function at 6 Weeks [ Time Frame: Baseline, 6 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Change from baseline in plasma markers of endothelial activation at 6 weeks [ Time Frame: Baseline, 6 weeks ] [ Designated as safety issue: No ]
    Investigators will measure plasma levels of soluble vascular cell adhesion molecules (sVCAM) and soluble intracellular adhesion molecule (sICAM) at baseline and at 6 weeks of treatment.

  • Change from baseline in heme oxygenase activity at 6 weeks [ Time Frame: Baseline, 6 weeks ] [ Designated as safety issue: No ]
    The expression and activity of heme oxygenase-1(HO-1)will be determined at baseline and at 6 weeks of treatment.

  • Change from baseline in plasma levels of soluble fms-like tyrosine kinase-1 (sFLT-1) at 6 weeks. [ Time Frame: Baseline, 6 weeks ] [ Designated as safety issue: No ]
    Investigators will measure plasma levels of sFLT-1 at baseline and at 6 weeks of treatment.

  • Change from baseline in monocyte activation at 6 weeks. [ Time Frame: Baseline, 6 weeks ] [ Designated as safety issue: No ]
    Flow cytometry will be performed to assess monocyte activation at baseline and at 6 weeks of treatment.

  • Change from baseline in renal function at 6 weeks. [ Time Frame: Baseline, 6 weeks ] [ Designated as safety issue: No ]
    Investigators will assess the effect of atorvastatin on albuminuria by spot urine microalbuminuria/creatinine ratio measured at baseline and at 6 weeks of treatment.

  • Occurrence of adverse events. [ Time Frame: Continuously from randomization through end of study ] [ Designated as safety issue: Yes ]
    Subjects will be evaluated for safety by patient self-report of adverse events and results of laboratory tests.

  • Abnormal physical findings. [ Time Frame: Baseline, 2, 4, and 6 weeks during treatment, and at follow-up. ] [ Designated as safety issue: Yes ]
    Subjects will be evaluated by physical examination and/or measurement of vital signs at each study visit.

  • Change from baseline in rho/rho kinase activity at 6 weeks [ Time Frame: Baseline, 6 weeks ] [ Designated as safety issue: No ]
    The expression and activity of rho/rho kinase will be determined at baseline and at 6 weeks of treatment.

  • Change from baseline in plasma levels of vascular endothelial growth factor (VEGF) at 6 weeks. [ Time Frame: Baseline, 6 weeks ] [ Designated as safety issue: No ]
    Investigators will measure plasma levels of VEGF at baseline and at 6 weeks of treatment.

  • Change from baseline in absolute cell counts at 6 weeks. [ Time Frame: Baseline, 6 weeks ] [ Designated as safety issue: No ]
    Flow cytometry will be performed to assess absolute cell counts at baseline and at 6 weeks of treatment.

  • Change from baseline in tissue factor (TF) expression at 6 weeks. [ Time Frame: Baseline, 6 weeks ] [ Designated as safety issue: No ]
    Flow cytometry will be performed to assess TF expression at baseline and at 6 weeks of treatment.

  • Change from baseline in TF-mediated sFLT release from monocytes at 6 weeks. [ Time Frame: Baseline, 6 weeks ] [ Designated as safety issue: No ]
    Flow cytometry will be performed to assess TF-mediated sFLT release from monocytes at baseline and at 6 weeks of treatment.

  • Change from baseline to Week 6 in Tricuspid regurgitant (TR) jet. [ Time Frame: Baseline, Week 6 ] [ Designated as safety issue: No ]
    Echocardiogram will be used to assess TR jet before and after treatment.


Estimated Enrollment: 19
Study Start Date: September 2013
Estimated Study Completion Date: May 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Atorvastatin
Atorvastatin 40mg tablet once daily for 6 weeks
Drug: Atorvastatin
Subjects will receive either: 1)atorvastatin for 6 weeks, followed by a 4-week washout period, then receive the other intervention (placebo)for 6 weeks; or 2) the other intervention (placebo) for 6 weeks, washout for 4 weeks, then atorvastatin for 6 weeks.
Other Name: Lipitor®
Placebo Comparator: Placebo for atorvastatin
Placebo (for atorvastatin) 1 tablet once daily for 6 weeks
Drug: Placebo for atorvastatin
Inactive substance in tablet form made to mimic atorvastatin 40mg tablet
Other Name: Sugar pill manufactured to mimic atorvastatin 40 mg tablet

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

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01732718

Locations
United States, North Carolina
UNC School of Medicine Clinical&Translational Research Ctr
Chapel Hill, North Carolina, United States, 27599
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Investigators
Principal Investigator: Kenneth I Ataga, MBBS University of North Caroina at Chapel Hill
  More Information

No publications provided

Responsible Party: Kenneth Ataga, MD, Associate Professor of Medicine, Director, UNC Comprehensive Sickle Cell Program, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01732718     History of Changes
Other Study ID Numbers: 11-1354, R01HL111659
Study First Received: November 9, 2012
Last Updated: September 4, 2014
Health Authority: United States: Data and Safety Monitoring Board
United States: Food and Drug Administration
United States: Federal Government

Keywords provided by University of North Carolina, Chapel Hill:
sickle cell disease
endothelial function
albuminuria
atorvastatin
soluble fms-like tyrosine kinase-1

Additional relevant MeSH terms:
Albuminuria
Anemia, Sickle Cell
Kidney Diseases
Anemia
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies
Proteinuria
Signs and Symptoms
Urination Disorders
Urologic Diseases
Urological Manifestations
Atorvastatin
Anticholesteremic Agents
Antimetabolites
Enzyme Inhibitors
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014