<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01732718</url>
  </required_header>
  <id_info>
    <org_study_id>11-1354</org_study_id>
    <secondary_id>R01HL111659</secondary_id>
    <nct_id>NCT01732718</nct_id>
  </id_info>
  <brief_title>Effect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease</brief_title>
  <acronym>ENDO</acronym>
  <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)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of North Carolina, Chapel Hill</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this research study is to learn about the effect of the drug, atorvastatin, on&#xD;
      blood vessels in patients with sickle cell disease.&#xD;
&#xD;
      The primary hypothesis is that endothelial dysfunction is an important contributor to the&#xD;
      pathophysiology of albuminuria in SCD. The investigators propose that atorvastatin will&#xD;
      improve endothelial dysfunction, decrease levels of soluble fms-like tyrosine kinase-1&#xD;
      (sFLT-1), and decrease albuminuria in SCD patients.&#xD;
&#xD;
      Participants will be individuals with sickle cell disease, age 18 to 60, who have some degree&#xD;
      of albuminuria. A total of 19 subjects, males and females, will be enrolled. The study is&#xD;
      made up of Screening, Treatment, and Follow Up phases and has a cross-over design. After&#xD;
      patients are screened for eligibility, they will be randomized to receive atorvastatin or&#xD;
      placebo in the initial six-week treatment period. When that is complete, there will be a&#xD;
      four-week washout period before they begin another six-week treatment period. In the second&#xD;
      treatment period, they &quot;cross-over&quot; to the other treatment arm. Four weeks after the end of&#xD;
      the second treatment period, follow-up safety assessments will be done.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      It is well recognized that sickle cell disease (SCD) is characterized by a vasculopathy, with&#xD;
      involvement of multiple organs including the brain, lung, spleen, and kidney. This results in&#xD;
      multiple clinical complications, including ischemic stroke, pulmonary hypertension,&#xD;
      autosplenectomy, as well as albuminuria and chronic renal disease. Several recent studies&#xD;
      have confirmed the association of both albuminuria and renal dysfunction with&#xD;
      echocardiographically-defined pulmonary hypertension and other vasculopathic complications in&#xD;
      SCD, suggesting that they may share a similar pathophysiology. Despite the high prevalence of&#xD;
      albuminuria in patients with SCD and the known association of renal failure with increased&#xD;
      mortality, the pathophysiology and treatment of albuminuria in this setting remain poorly&#xD;
      defined.&#xD;
&#xD;
      The treatment options for nephropathy in SCD are limited. Although Angiotensin converting&#xD;
      enzyme (ACE) inhibitors are the &quot;standard of care&quot; in the treatment of patients with&#xD;
      proteinuria, there are to date no controlled, long-term studies confirming their efficacy and&#xD;
      safety in this setting.&#xD;
&#xD;
      In this study, the investigators will evaluate the efficacy and safety of atorvastatin in SCD&#xD;
      patients. At the completion of this trial, the investigators will have an improved&#xD;
      understanding of the contribution of endothelial dysfunction to the pathophysiology of&#xD;
      albuminuria in SCD. If the data support the hypothesis that atorvastatin is safe and&#xD;
      effective in this population, the investigators plan on carrying out adequately powered&#xD;
      studies to more definitively evaluate its safety and efficacy in the treatment and/or&#xD;
      prevention of albuminuria in SCD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2013</start_date>
  <completion_date type="Actual">January 9, 2018</completion_date>
  <primary_completion_date type="Actual">January 9, 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline to Week 6 in Endothelial Function</measure>
    <time_frame>Baseline, 6 weeks</time_frame>
    <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).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation</measure>
    <time_frame>Baseline, 6 weeks</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline to Week 6 in Heme Oxygenase Activity</measure>
    <time_frame>Baseline, 6 weeks</time_frame>
    <description>The expression and activity of heme oxygenase-1(HO-1)will be determined at baseline and at 6 weeks of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1)</measure>
    <time_frame>Baseline, 6 weeks</time_frame>
    <description>Investigators will measure plasma levels of soluble fms-like tyrosine kinase-1 (sFLT-1) at baseline and at 6 weeks of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline to Week 6 in Monocyte Activation</measure>
    <time_frame>Baseline, 6 weeks</time_frame>
    <description>Flow cytometry performed to assess monocyte activation at baseline and at 6 weeks of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline to Week 6 in Renal Function</measure>
    <time_frame>Baseline, 6 weeks</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of Adverse Events.</measure>
    <time_frame>Continuously from randomization through end of study</time_frame>
    <description>Subjects will be evaluated for safety by patient self-report of adverse events and results of laboratory tests.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Abnormal Physical Findings.</measure>
    <time_frame>Baseline, 2, 4, and 6 weeks during treatment, and at follow-up.</time_frame>
    <description>Subjects will be evaluated by physical examination and/or measurement of vital signs at each study visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline to Week 6 in Rho/Rho Kinase Activity</measure>
    <time_frame>Baseline, 6 weeks</time_frame>
    <description>The expression and activity of rho/rho kinase will be determined at baseline and at 6 weeks of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF)</measure>
    <time_frame>Baseline, 6 weeks</time_frame>
    <description>Investigators will measure plasma levels of vascular endothelial growth factor (VEGF) at baseline and at 6 weeks of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change From Baseline to Week 6 in Absolute Cell Counts</measure>
    <time_frame>Baseline, 6 weeks</time_frame>
    <description>Flow cytometry will be performed to assess absolute cell counts at baseline and at 6 weeks of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline to Week 6 in Tissue Factor (TF) Expression</measure>
    <time_frame>Baseline, 6 weeks</time_frame>
    <description>Flow cytometry will be performed to assess TF expression at baseline and at 6 weeks of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline to Week 6 in TF-mediated sFLT Release From Monocytes</measure>
    <time_frame>Baseline, 6 weeks</time_frame>
    <description>Flow cytometry will be performed to assess TF-mediated sFLT release from monocytes at baseline and at 6 weeks of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet.</measure>
    <time_frame>Baseline, Week 6</time_frame>
    <description>Echocardiogram will be used to assess TR jet before and after treatment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Sickle Cell Disease</condition>
  <condition>Sickle Cell Nephropathy</condition>
  <arm_group>
    <arm_group_label>Atorvastatin, then Placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo, Then Atorvastatin</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atorvastatin</intervention_name>
    <description>40 mg tablet by mouth daily for 6 weeks</description>
    <arm_group_label>Atorvastatin, then Placebo</arm_group_label>
    <arm_group_label>Placebo, Then Atorvastatin</arm_group_label>
    <other_name>Lipitor®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Matching placebo tablet by mouth daily for 6 weeks</description>
    <arm_group_label>Atorvastatin, then Placebo</arm_group_label>
    <arm_group_label>Placebo, Then Atorvastatin</arm_group_label>
    <other_name>Sugar pill manufactured to mimic atorvastatin 40 mg tablet</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Sickle cell anemia (HbSS) or Sickle-beta0 thalassemia (HbS-beta0thal) between ages of&#xD;
             18 and 60;&#xD;
&#xD;
          2. albuminuria (micro- or macroalbuminuria, defined as =/&gt; 30mg/g creatinine);&#xD;
&#xD;
          3. serum alanine aminotransferase (ALT) &lt;/= 2 times upper limits of normal and/or&#xD;
             gamma-glutamyl transferase (GGT) &lt;/= 3 times upper limits of normal;&#xD;
&#xD;
          4. platelet count &gt; 150,000 cu/mm;&#xD;
&#xD;
          5. normal baseline coagulation profile (PT, International Normalized Ratio (INR), and&#xD;
             PTT);&#xD;
&#xD;
          6. non-crisis, steady state with no severe pain episodes during the preceding 4 weeks,&#xD;
             and no documented infection in the 2 weeks prior to enrollment;&#xD;
&#xD;
          7. ability to understand the requirements of the study;&#xD;
&#xD;
          8. if a woman of childbearing potential, must use an adequate method of contraception;&#xD;
             and&#xD;
&#xD;
          9. if receiving hydroxyurea, ACE inhibitors or angiotensin blockers (ARB), should be on a&#xD;
             stable dose for at least 3 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. hypersensitivity to any component of atorvastatin, or history of adverse reaction to&#xD;
             statins;&#xD;
&#xD;
          2. pregnant or breastfeeding;&#xD;
&#xD;
          3. on statin therapy;&#xD;
&#xD;
          4. history of metastatic cancer;&#xD;
&#xD;
          5. current history of alcohol abuse;&#xD;
&#xD;
          6. history of diabetes mellitus or poorly controlled systemic hypertension;&#xD;
&#xD;
          7. end-stage renal disease;&#xD;
&#xD;
          8. total cholesterol level &lt; 80 mg/dL and LDL cholesterol &gt; 130 mg/dL;&#xD;
&#xD;
          9. on a chronic transfusion program;&#xD;
&#xD;
         10. ingested any investigational drugs within the past 4 weeks;&#xD;
&#xD;
         11. prior history of any myopathy;&#xD;
&#xD;
         12. allergy to nitroglycerin;&#xD;
&#xD;
         13. taking any of the following drugs: phosphodiesterase-5 inhibitors (e.g., sildenafil),&#xD;
             cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors (e.g., cyclosporine, protease&#xD;
             inhibitors), macrolide antibiotics (e.g., clarithromycin, erythromycin), fibric acid&#xD;
             derivatives (e.g. gemfibrozil), niacin, colchicines, antifungal agents (azole&#xD;
             derivatives), amiodarone, danazol, daptomycin, diltiazem, verapamil, eltrombopag,&#xD;
             everolimus, fosphenytoin, or lanthanum.&#xD;
&#xD;
        Patients will also be encouraged to avoid grape fruit juice and red yeast rice for the&#xD;
        duration of the study.&#xD;
&#xD;
        Atorvastatin is contraindicated during pregnancy and breast-feeding.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kenneth I Ataga, MBBS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of North Caroina at Chapel Hill</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UNC School of Medicine Clinical&amp;Translational Research Ctr</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>November 9, 2012</study_first_submitted>
  <study_first_submitted_qc>November 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 26, 2012</study_first_posted>
  <results_first_submitted>December 13, 2018</results_first_submitted>
  <results_first_submitted_qc>January 14, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">February 5, 2019</results_first_posted>
  <last_update_submitted>March 16, 2020</last_update_submitted>
  <last_update_submitted_qc>March 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 18, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>sickle cell disease</keyword>
  <keyword>endothelial function</keyword>
  <keyword>albuminuria</keyword>
  <keyword>atorvastatin</keyword>
  <keyword>soluble fms-like tyrosine kinase-1</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Albuminuria</mesh_term>
    <mesh_term>Anemia, Sickle Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atorvastatin</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 13, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/18/NCT01732718/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Atorvastatin, Then Placebo</title>
          <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.&#xD;
Atorvastatin: 40 mg tablet by mouth daily for 6 weeks&#xD;
Placebo: Matching placebo tablet by mouth daily for 6 weeks</description>
        </group>
        <group group_id="P2">
          <title>Placebo, Then Atorvastatin</title>
          <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.&#xD;
Atorvastatin: 40 mg tablet by mouth daily for 6 weeks&#xD;
Placebo: Matching placebo tablet by mouth daily for 6 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>First Intervention</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout (4 Weeks)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Second Intervention</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>All Study Participants</title>
          <description>Participants who were randomized to receive either Atorvastatin 40 mg or Placebo (matching Atorvastatin 40 mg)</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="13"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="48" lower_limit="44" upper_limit="54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline to Week 6 in Endothelial Function</title>
        <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).</description>
        <time_frame>Baseline, 6 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to Week 6 in Endothelial Function</title>
          <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).</description>
          <units>% diameter change</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.44" lower_limit="-2.66" upper_limit="4.43"/>
                    <measurement group_id="O2" value="0.69" lower_limit="-1.94" upper_limit="3.18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.51</p_value>
            <method>Student t-test followed by ANOVA</method>
            <method_desc>Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation</title>
        <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.</description>
        <time_frame>Baseline, 6 weeks</time_frame>
        <population>Investigators elected to look at only one marker of vascular endothelial injury, i.e. sVCAM, so there is no data for sICAM.</population>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation</title>
          <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.</description>
          <population>Investigators elected to look at only one marker of vascular endothelial injury, i.e. sVCAM, so there is no data for sICAM.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.99" lower_limit="-58.8" upper_limit="41.7"/>
                    <measurement group_id="O2" value="7.54" lower_limit="-75.2" upper_limit="149.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.74</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline to Week 6 in Heme Oxygenase Activity</title>
        <description>The expression and activity of heme oxygenase-1(HO-1)will be determined at baseline and at 6 weeks of treatment.</description>
        <time_frame>Baseline, 6 weeks</time_frame>
        <population>Data not collected</population>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to Week 6 in Heme Oxygenase Activity</title>
          <description>The expression and activity of heme oxygenase-1(HO-1)will be determined at baseline and at 6 weeks of treatment.</description>
          <population>Data not collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1)</title>
        <description>Investigators will measure plasma levels of soluble fms-like tyrosine kinase-1 (sFLT-1) at baseline and at 6 weeks of treatment.</description>
        <time_frame>Baseline, 6 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1)</title>
          <description>Investigators will measure plasma levels of soluble fms-like tyrosine kinase-1 (sFLT-1) at baseline and at 6 weeks of treatment.</description>
          <units>pg/mL</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.2" lower_limit="-47.1" upper_limit="47.7"/>
                    <measurement group_id="O2" value="36.9" lower_limit="-20.9" upper_limit="129.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.31</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline to Week 6 in Monocyte Activation</title>
        <description>Flow cytometry performed to assess monocyte activation at baseline and at 6 weeks of treatment.</description>
        <time_frame>Baseline, 6 weeks</time_frame>
        <population>The stored samples did not survive the freeze/thaw process and as such, this data was not attainable.</population>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to Week 6 in Monocyte Activation</title>
          <description>Flow cytometry performed to assess monocyte activation at baseline and at 6 weeks of treatment.</description>
          <population>The stored samples did not survive the freeze/thaw process and as such, this data was not attainable.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline to Week 6 in Renal Function</title>
        <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.</description>
        <time_frame>Baseline, 6 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to Week 6 in Renal Function</title>
          <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.</description>
          <units>ug per mg</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="28.8" lower_limit="-28.6" upper_limit="237.1"/>
                    <measurement group_id="O2" value="74.9" lower_limit="-15.2" upper_limit="373.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.57</p_value>
            <method>see comments for explanation</method>
            <method_desc>albuminuria examined as continuous variable (linear mixed model to analyze effect) and categorical generalized variable (estimating equation approach)</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Occurrence of Adverse Events.</title>
        <description>Subjects will be evaluated for safety by patient self-report of adverse events and results of laboratory tests.</description>
        <time_frame>Continuously from randomization through end of study</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Occurrence of Adverse Events.</title>
          <description>Subjects will be evaluated for safety by patient self-report of adverse events and results of laboratory tests.</description>
          <units>events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                    <measurement group_id="O2" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Abnormal Physical Findings.</title>
        <description>Subjects will be evaluated by physical examination and/or measurement of vital signs at each study visit.</description>
        <time_frame>Baseline, 2, 4, and 6 weeks during treatment, and at follow-up.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Baseline-Atorvastatin</title>
            <description>Participants receiving Atorvastatin 40 mg tablets once daily for 6 weeks</description>
          </group>
          <group group_id="O2">
            <title>Week 4-Atorvastatin</title>
            <description>Participants receiving Atorvastatin 40 mg tablets once daily for 6 weeks</description>
          </group>
          <group group_id="O3">
            <title>Week 6-Atorvastatin</title>
            <description>Participants receiving Atorvastatin 40 mg tablets once daily for 6 weeks</description>
          </group>
          <group group_id="O4">
            <title>Baseline-Placebo</title>
            <description>Participants receiving Placebo once daily for 6 weeks</description>
          </group>
          <group group_id="O5">
            <title>Week 4-Placebo</title>
            <description>Participants receiving Placebo once daily for 6 weeks</description>
          </group>
          <group group_id="O6">
            <title>Week 6-Placebo</title>
            <description>Participants receiving Placebo once daily for 6 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Abnormal Physical Findings.</title>
          <description>Subjects will be evaluated by physical examination and/or measurement of vital signs at each study visit.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="13"/>
                <count group_id="O3" value="13"/>
                <count group_id="O4" value="13"/>
                <count group_id="O5" value="13"/>
                <count group_id="O6" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline to Week 6 in Rho/Rho Kinase Activity</title>
        <description>The expression and activity of rho/rho kinase will be determined at baseline and at 6 weeks of treatment.</description>
        <time_frame>Baseline, 6 weeks</time_frame>
        <population>Due to loss of key study personnel these data were not collected</population>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to Week 6 in Rho/Rho Kinase Activity</title>
          <description>The expression and activity of rho/rho kinase will be determined at baseline and at 6 weeks of treatment.</description>
          <population>Due to loss of key study personnel these data were not collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF)</title>
        <description>Investigators will measure plasma levels of vascular endothelial growth factor (VEGF) at baseline and at 6 weeks of treatment.</description>
        <time_frame>Baseline, 6 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF)</title>
          <description>Investigators will measure plasma levels of vascular endothelial growth factor (VEGF) at baseline and at 6 weeks of treatment.</description>
          <units>pg/mL</units>
          <param>Mean</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.99" lower_limit="-29.4" upper_limit="7.8"/>
                    <measurement group_id="O2" value="-10.5" lower_limit="-50.4" upper_limit="9.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.64</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change From Baseline to Week 6 in Absolute Cell Counts</title>
        <description>Flow cytometry will be performed to assess absolute cell counts at baseline and at 6 weeks of treatment.</description>
        <time_frame>Baseline, 6 weeks</time_frame>
        <population>Intent was to perform analysis using flow cytometry but cells did not survive thawing. Decision was made to use CBC laboratory values for absolute monocyte (AMC), lymphocyte (ALC) and neutrophil (ANC) counts to perform the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change From Baseline to Week 6 in Absolute Cell Counts</title>
          <description>Flow cytometry will be performed to assess absolute cell counts at baseline and at 6 weeks of treatment.</description>
          <population>Intent was to perform analysis using flow cytometry but cells did not survive thawing. Decision was made to use CBC laboratory values for absolute monocyte (AMC), lymphocyte (ALC) and neutrophil (ANC) counts to perform the analysis.</population>
          <units>10^9 cells/L</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AMC</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.07" lower_limit="-0.26" upper_limit="0.12"/>
                    <measurement group_id="O2" value="0.15" lower_limit="-0.11" upper_limit="0.41"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ALC</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.08" lower_limit="-0.34" upper_limit="0.49"/>
                    <measurement group_id="O2" value="-0.22" lower_limit="-0.85" upper_limit="0.42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ANC</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.18" lower_limit="-0.96" upper_limit="0.61"/>
                    <measurement group_id="O2" value="-0.55" lower_limit="-1.91" upper_limit="0.81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Comparison of the change in AMC</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1469</p_value>
            <method>t-test, 1 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Comparison of the change in ALC</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.2382</p_value>
            <method>t-test, 1 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Comparison of the change in ANC</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.5833</p_value>
            <method>t-test, 1 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline to Week 6 in Tissue Factor (TF) Expression</title>
        <description>Flow cytometry will be performed to assess TF expression at baseline and at 6 weeks of treatment.</description>
        <time_frame>Baseline, 6 weeks</time_frame>
        <population>The stored samples did not survive the freeze/thaw process and as such, this data was not attainable.</population>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to Week 6 in Tissue Factor (TF) Expression</title>
          <description>Flow cytometry will be performed to assess TF expression at baseline and at 6 weeks of treatment.</description>
          <population>The stored samples did not survive the freeze/thaw process and as such, this data was not attainable.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline to Week 6 in TF-mediated sFLT Release From Monocytes</title>
        <description>Flow cytometry will be performed to assess TF-mediated sFLT release from monocytes at baseline and at 6 weeks of treatment.</description>
        <time_frame>Baseline, 6 weeks</time_frame>
        <population>The stored samples did not survive the freeze/thaw process and as such, this data was not attainable.</population>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to Week 6 in TF-mediated sFLT Release From Monocytes</title>
          <description>Flow cytometry will be performed to assess TF-mediated sFLT release from monocytes at baseline and at 6 weeks of treatment.</description>
          <population>The stored samples did not survive the freeze/thaw process and as such, this data was not attainable.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet.</title>
        <description>Echocardiogram will be used to assess TR jet before and after treatment.</description>
        <time_frame>Baseline, Week 6</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Atorvastatin</title>
            <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet.</title>
          <description>Echocardiogram will be used to assess TR jet before and after treatment.</description>
          <units>m/sec</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.80" lower_limit="-1.64" upper_limit="3.24"/>
                    <measurement group_id="O2" value="-0.05" lower_limit="-0.69" upper_limit="0.56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.5184</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Beginning with the first intervention and throughout washout and second intervention and then for 4 weeks after end of treatment</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Atorvastatin</title>
          <description>Participants who received Atorvastatin 40 mg tablet in either the first or the second intervention</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Participants who received placebo tablet (matching Atorvastatin 40 mg) in either the first or the second intervention</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Heart Palpitations and Fainting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Pain Crisis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Low ANC</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea and Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Headaches/Head Pressure</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dry Skin</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Axillary Adenopathy</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Influenza B</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Left Wrist Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Low O2 Saturation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Pain Crisis Treated at Home</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Edema of Lower Extremity</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Leg Ulcer</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>This study was limited by its small sample size.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Kenneth Ataga, MD</name_or_title>
      <organization>University of North Carolina at Chapel Hill</organization>
      <phone>901-448-2813</phone>
      <email>kataga@uthsc.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01732718
org study id: 11-1354
secondary id: R01HL111659
nct id: NCT01732718
lead sponsor: 
collaborator: 
has dmc: Yes
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.
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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change From Baseline to Week 6 in Endothelial Function
time frame: Baseline, 6 weeks
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).
measure: Change From Baseline to Week 6 in Plasma Markers of Endothelial Activation
time frame: Baseline, 6 weeks
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.
measure: Change From Baseline to Week 6 in Heme Oxygenase Activity
time frame: Baseline, 6 weeks
description: The expression and activity of heme oxygenase-1(HO-1)will be determined at baseline and at 6 weeks of treatment.
measure: Change From Baseline to Week 6 in Plasma Levels of Soluble Fms-like Tyrosine Kinase-1 (sFLT-1)
time frame: Baseline, 6 weeks
description: Investigators will measure plasma levels of soluble fms-like tyrosine kinase-1 (sFLT-1) at baseline and at 6 weeks of treatment.
measure: Change From Baseline to Week 6 in Monocyte Activation
time frame: Baseline, 6 weeks
description: Flow cytometry performed to assess monocyte activation at baseline and at 6 weeks of treatment.
measure: Change From Baseline to Week 6 in Renal Function
time frame: Baseline, 6 weeks
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.
measure: Occurrence of Adverse Events.
time frame: Continuously from randomization through end of study
description: Subjects will be evaluated for safety by patient self-report of adverse events and results of laboratory tests.
measure: Abnormal Physical Findings.
time frame: Baseline, 2, 4, and 6 weeks during treatment, and at follow-up.
description: Subjects will be evaluated by physical examination and/or measurement of vital signs at each study visit.
measure: Change From Baseline to Week 6 in Rho/Rho Kinase Activity
time frame: Baseline, 6 weeks
description: The expression and activity of rho/rho kinase will be determined at baseline and at 6 weeks of treatment.
measure: Change From Baseline to Week 6 in Plasma Levels of Vascular Endothelial Growth Factor (VEGF)
time frame: Baseline, 6 weeks
description: Investigators will measure plasma levels of vascular endothelial growth factor (VEGF) at baseline and at 6 weeks of treatment.
measure: Mean Change From Baseline to Week 6 in Absolute Cell Counts
time frame: Baseline, 6 weeks
description: Flow cytometry will be performed to assess absolute cell counts at baseline and at 6 weeks of treatment.
measure: Change From Baseline to Week 6 in Tissue Factor (TF) Expression
time frame: Baseline, 6 weeks
description: Flow cytometry will be performed to assess TF expression at baseline and at 6 weeks of treatment.
measure: Change From Baseline to Week 6 in TF-mediated sFLT Release From Monocytes
time frame: Baseline, 6 weeks
description: Flow cytometry will be performed to assess TF-mediated sFLT release from monocytes at baseline and at 6 weeks of treatment.
measure: Change From Baseline to Week 6 in Tricuspid Regurgitant (TR) Jet.
time frame: Baseline, Week 6
description: Echocardiogram will be used to assess TR jet before and after treatment.
arm group label: Atorvastatin, then Placebo
arm group type: Experimental
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 group label: Placebo, Then Atorvastatin
arm group type: Placebo Comparator
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: Atorvastatin
description: 40 mg tablet by mouth daily for 6 weeks
arm group label: Atorvastatin, then Placebo
arm group label: Placebo, Then Atorvastatin
other name: Lipitor®
intervention type: Drug
intervention name: Placebo
description: Matching placebo tablet by mouth daily for 6 weeks
arm group label: Atorvastatin, then Placebo
arm group label: Placebo, Then Atorvastatin
other name: Sugar pill manufactured to mimic atorvastatin 40 mg tablet
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Kenneth I Ataga, MBBS
role: Principal Investigator
affiliation: University of North Caroina at Chapel Hill
facility: 
country: United States
responsible party type: Sponsor
mesh term: Kidney Diseases
mesh term: Albuminuria
mesh term: Anemia, Sickle Cell
mesh term: Atorvastatin
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: This study was limited by its small sample size.
point of contact: 