Sickle Cell DiseasePhase 2ENDONCT01732718
Effect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease
A Phase 2 study testing Atorvastatin in people with Sickle Cell Disease and Sickle Cell Nephropathy, run by University of North Carolina, Chapel Hill at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Sickle Cell Disease, Sickle Cell Nephropathy
- What is being tested?
- Atorvastatin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 13 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2013to 9 Jan 2018
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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;
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- 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.
Who cannot join
- 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;
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
UNC School of Medicine Clinical&Translational Research Ctr
Chapel Hill, North Carolina, 27599
About this study
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)
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.
Read the 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
- Being tested
- Atorvastatin, Placebo
- Keywords
- sickle cell disease, endothelial function, albuminuria, atorvastatin, soluble fms-like tyrosine kinase-1
- Medical subject headings
- Anemia, Sickle Cell, Albuminuria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtorvastatinDrug
Also called Lipitor®
40 mg tablet by mouth daily for 6 weeks
PlaceboDrug
Also called Sugar pill manufactured to mimic atorvastatin 40 mg tablet
Matching placebo tablet by mouth daily for 6 weeks
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Atorvastatin; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Baseline, 6 weeks
Secondary outcomes (13)
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.
Measured: Baseline, 6 weeks
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.
Measured: Baseline, 6 weeks
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.
Measured: Baseline, 6 weeks
Change From Baseline to Week 6 in Monocyte Activation
Flow cytometry performed to assess monocyte activation at baseline and at 6 weeks of treatment.
Measured: Baseline, 6 weeks
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.
Measured: Baseline, 6 weeks
Occurrence of Adverse Events.
Subjects will be evaluated for safety by patient self-report of adverse events and results of laboratory tests.
Measured: Continuously from randomization through end of study
Abnormal Physical Findings.
Subjects will be evaluated by physical examination and/or measurement of vital signs at each study visit.
Measured: Baseline, 2, 4, and 6 weeks during treatment, and at follow-up.
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.
Measured: Baseline, 6 weeks
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.
Measured: Baseline, 6 weeks
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.
Measured: Baseline, 6 weeks
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.
Measured: Baseline, 6 weeks
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.
Measured: Baseline, 6 weeks
Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet.
Echocardiogram will be used to assess TR jet before and after treatment.
Measured: Baseline, Week 6
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Nov 2012 (estimated)
- Study startSep 2013
- Primary completion9 Jan 2018
- Study completion9 Jan 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
- More trials run by University of North Carolina, Chapel HillThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of North Carolina, Chapel Hill
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor
- Investigators
- Kenneth I Ataga, MBBS, Principal investigator, University of North Caroina at Chapel Hill
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01732718
- Sponsor's protocol ID
- 11-1354
- Other IDs
- R01HL111659
- Acronym
- ENDO
- Status last verified
- Nov 2018
- First submitted
- 9 Nov 2012
- Last updated
- 18 Mar 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 18 Mar 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT01732718
- Acronym / sponsor ID
- ENDO / 11-1354
- Conditions
- Sickle Cell Disease, Sickle Cell Nephropathy
- Keywords
- sickle cell disease, endothelial function, albuminuria, atorvastatin, soluble fms-like tyrosine kinase-1
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- University of North Carolina, Chapel HillUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Sep 2013
- Primary completion
- 9 Jan 2018 (actual)
- Study completion
- 9 Jan 2018 (actual)
- First posted
- 26 Nov 2012 (estimated)
- Results
- Posted 5 Feb 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Atorvastatin, then Placebo | Experimental | Drug: Atorvastatin, Drug: PlaceboParticipants 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. |
| Placebo, Then Atorvastatin | Placebo comparator | Drug: Atorvastatin, Drug: PlaceboParticipants 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. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (9 listed)
- 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);
Key exclusion criteria (15 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AtorvastatinAlso: Lipitor®40 mg tablet by mouth daily for 6 weeks | Drug | Atorvastatin, then Placebo, Placebo, Then Atorvastatin |
| PlaceboAlso: Sugar pill manufactured to mimic atorvastatin 40 mg tabletMatching placebo tablet by mouth daily for 6 weeks | Drug | Atorvastatin, then Placebo, Placebo, Then Atorvastatin |
Primary outcome
Change From Baseline to Week 6 in Endothelial Function
Time frame: Baseline, 6 weeks
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).
13 secondary outcomes
Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation
Time frame: Baseline, 6 weeks
Change From Baseline to Week 6 in Heme Oxygenase Activity
Time frame: Baseline, 6 weeks
Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1)
Time frame: Baseline, 6 weeks
Change From Baseline to Week 6 in Monocyte Activation
Time frame: Baseline, 6 weeks
Change From Baseline to Week 6 in Renal Function
Time frame: Baseline, 6 weeks
Occurrence of Adverse Events.
Time frame: Continuously from randomization through end of study
Abnormal Physical Findings.
Time frame: Baseline, 2, 4, and 6 weeks during treatment, and at follow-up.
Change From Baseline to Week 6 in Rho/Rho Kinase Activity
Time frame: Baseline, 6 weeks
Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF)
Time frame: Baseline, 6 weeks
Mean Change From Baseline to Week 6 in Absolute Cell Counts
Time frame: Baseline, 6 weeks
Change From Baseline to Week 6 in Tissue Factor (TF) Expression
Time frame: Baseline, 6 weeks
Change From Baseline to Week 6 in TF-mediated sFLT Release From Monocytes
Time frame: Baseline, 6 weeks
Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet.
Time frame: Baseline, Week 6
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Mar 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kenneth I Ataga, MBBS principal investigator
University of North Caroina at Chapel Hill
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Atorvastatin in people with Sickle Cell Disease and Sickle Cell Nephropathy, run by University of North Carolina, Chapel Hill at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Feb 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change From Baseline to Week 6 in Endothelial Function (time frame: Baseline, 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Mar 2020.