Back to resultsEffect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease (ENDO)
Primary Purpose
Sickle Cell Disease, Sickle Cell Nephropathy
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Atorvastatin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Sickle Cell Disease focused on measuring sickle cell disease, endothelial function, albuminuria, atorvastatin, soluble fms-like tyrosine kinase-1
Eligibility Criteria
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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.
Sites / Locations
- UNC School of Medicine Clinical&Translational Research Ctr
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Atorvastatin, then Placebo
Placebo, Then Atorvastatin
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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).
Secondary Outcome Measures
Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation
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 to Week 6 in Heme Oxygenase Activity
The expression and activity of heme oxygenase-1(HO-1)will be determined at baseline and at 6 weeks of treatment.
Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1)
Investigators will measure plasma levels of soluble fms-like tyrosine kinase-1 (sFLT-1) at baseline and at 6 weeks of treatment.
Change From Baseline to Week 6 in Monocyte Activation
Flow cytometry performed to assess monocyte activation at baseline and at 6 weeks of treatment.
Change From Baseline to Week 6 in Renal Function
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.
Subjects will be evaluated for safety by patient self-report of adverse events and results of laboratory tests.
Abnormal Physical Findings.
Subjects will be evaluated by physical examination and/or measurement of vital signs at each study visit.
Change From Baseline to Week 6 in Rho/Rho Kinase Activity
The expression and activity of rho/rho kinase will be determined at baseline and at 6 weeks of treatment.
Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF)
Investigators will measure plasma levels of vascular endothelial growth factor (VEGF) at baseline and at 6 weeks of treatment.
Mean Change From Baseline to Week 6 in Absolute Cell Counts
Flow cytometry will be performed to assess absolute cell counts at baseline and at 6 weeks of treatment.
Change From Baseline to Week 6 in Tissue Factor (TF) Expression
Flow cytometry will be performed to assess TF expression at baseline and at 6 weeks of treatment.
Change From Baseline to Week 6 in TF-mediated sFLT Release From Monocytes
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.
Echocardiogram will be used to assess TR jet before and after treatment.
Full Information
NCT ID
NCT01732718
First Posted
November 9, 2012
Last Updated
March 16, 2020
Sponsor
University of North Carolina, Chapel Hill
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT01732718
Brief Title
Effect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease
Acronym
ENDO
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
2. Study Status
Record Verification Date
November 2018
Overall Recruitment Status
Completed
Study Start Date
September 2013 (undefined)
Primary Completion Date
January 9, 2018 (Actual)
Study Completion Date
January 9, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of North Carolina, Chapel Hill
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease, Sickle Cell Nephropathy
Keywords
sickle cell disease, endothelial function, albuminuria, atorvastatin, soluble fms-like tyrosine kinase-1
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
13 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Atorvastatin, then Placebo
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo, Then Atorvastatin
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Atorvastatin
Other Intervention Name(s)
Lipitor®
Intervention Description
40 mg tablet by mouth daily for 6 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Sugar pill manufactured to mimic atorvastatin 40 mg tablet
Intervention Description
Matching placebo tablet by mouth daily for 6 weeks
Primary Outcome Measure Information:
Title
Change From Baseline to Week 6 in Endothelial Function
Description
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).
Time Frame
Baseline, 6 weeks
Secondary Outcome Measure Information:
Title
Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation
Description
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.
Time Frame
Baseline, 6 weeks
Title
Change From Baseline to Week 6 in Heme Oxygenase Activity
Description
The expression and activity of heme oxygenase-1(HO-1)will be determined at baseline and at 6 weeks of treatment.
Time Frame
Baseline, 6 weeks
Title
Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1)
Description
Investigators will measure plasma levels of soluble fms-like tyrosine kinase-1 (sFLT-1) at baseline and at 6 weeks of treatment.
Time Frame
Baseline, 6 weeks
Title
Change From Baseline to Week 6 in Monocyte Activation
Description
Flow cytometry performed to assess monocyte activation at baseline and at 6 weeks of treatment.
Time Frame
Baseline, 6 weeks
Title
Change From Baseline to Week 6 in Renal Function
Description
Investigators will assess the effect of atorvastatin on albuminuria by spot urine microalbuminuria/creatinine ratio measured at baseline and at 6 weeks of treatment.
Time Frame
Baseline, 6 weeks
Title
Occurrence of Adverse Events.
Description
Subjects will be evaluated for safety by patient self-report of adverse events and results of laboratory tests.
Time Frame
Continuously from randomization through end of study
Title
Abnormal Physical Findings.
Description
Subjects will be evaluated by physical examination and/or measurement of vital signs at each study visit.
Time Frame
Baseline, 2, 4, and 6 weeks during treatment, and at follow-up.
Title
Change From Baseline to Week 6 in Rho/Rho Kinase Activity
Description
The expression and activity of rho/rho kinase will be determined at baseline and at 6 weeks of treatment.
Time Frame
Baseline, 6 weeks
Title
Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF)
Description
Investigators will measure plasma levels of vascular endothelial growth factor (VEGF) at baseline and at 6 weeks of treatment.
Time Frame
Baseline, 6 weeks
Title
Mean Change From Baseline to Week 6 in Absolute Cell Counts
Description
Flow cytometry will be performed to assess absolute cell counts at baseline and at 6 weeks of treatment.
Time Frame
Baseline, 6 weeks
Title
Change From Baseline to Week 6 in Tissue Factor (TF) Expression
Description
Flow cytometry will be performed to assess TF expression at baseline and at 6 weeks of treatment.
Time Frame
Baseline, 6 weeks
Title
Change From Baseline to Week 6 in TF-mediated sFLT Release From Monocytes
Description
Flow cytometry will be performed to assess TF-mediated sFLT release from monocytes at baseline and at 6 weeks of treatment.
Time Frame
Baseline, 6 weeks
Title
Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet.
Description
Echocardiogram will be used to assess TR jet before and after treatment.
Time Frame
Baseline, Week 6
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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.
Exclusion Criteria:
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kenneth I Ataga, MBBS
Organizational Affiliation
University of North Caroina at Chapel Hill
Official's Role
Principal Investigator
Facility Information:
Facility Name
UNC School of Medicine Clinical&Translational Research Ctr
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Effect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease
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