<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/NCT02225834</url>
  </required_header>
  <id_info>
    <org_study_id>21770</org_study_id>
    <nct_id>NCT02225834</nct_id>
  </id_info>
  <brief_title>Atorvastatin in Acute Stroke Treatment</brief_title>
  <official_title>Effects of Early Atorvastatin Treatment During the Acute Phase of Stroke on Immunoinflammatory Markers and Outcome in Patients With Acute Ischemic Stroke Classified as LAAS According TOAST Classification</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Palermo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Palermo</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Recent clinical trials and meta-analyses of b-hydroxy-bmethylglutaryl coenzyme A (HMG-CoA)&#xD;
      reductase inhibitors (statins) have demonstrated a significant reduction in ischemic stroke&#xD;
      in patients with a history of coronary artery disease, both with and without elevations of&#xD;
      serum cholesterol. Recent data suggest that statins have other beneficial properties in&#xD;
      addition to the retardation of atherosclerosis. Asahi et al demonstred that Statins increased&#xD;
      eNOS and tPA mRNA levels but did not change mRNA levels of PAI-1 and that In eNOS knockout&#xD;
      mice, atorvastatin reduced the volume of ischemic tissue and improved neurologic outcomes&#xD;
      after arterial occlusion by blood clot emboli. In addition to their lipid-lowering effects,&#xD;
      it has been speculated that statins may also have beneficial effects on cerebral circulation&#xD;
      and brain parenchyma during ischaemic stroke and reperfusion. Aslanyan et al reported that&#xD;
      statin use was associated with reduced mortality at 1 month during the follow-up.&#xD;
&#xD;
      In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of&#xD;
      atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events,&#xD;
      despite a small increase in the incidence of hemorrhagic stroke period .&#xD;
&#xD;
      Recently the investigators group reported that lacunar strokes compared to nonlacunar ones&#xD;
      exhibited significantly lower plasma levels of TNF-α and IL1-β, P-selectin and ICAM-1 24-72 h&#xD;
      and 7-10 days after stroke onset (4). At extracranial arterial territories, inflammation&#xD;
      plays a crucial role mediating all the stages of the atherosclerosis process . Similarly,&#xD;
      thrombosis and defective fibrinolysis may also contribute to the progression of&#xD;
      atherosclerotic lesions . Interestingly, both mechanisms might have a relevant role in the&#xD;
      pathogenesis of intracranial large artery atherosclerosis and ischemic stroke Moreover our&#xD;
      group showed that Patients with cardioembolic and atherothrombotic stroke subtypes showed&#xD;
      significantly higher median plasma levels of TNF-α, IL-6, IL-1β whereas the lacunar subtype&#xD;
      showed significantly lower median plasma levels of TNF-α, IL-6 and IL-1β and that&#xD;
      immunoinflammatory marker plasma levels are significantly related to ischemic lesion volume.&#xD;
&#xD;
      A meta-analysis showed that statins may possess antithrombotic property because these drugs&#xD;
      were reported to reduce periprocedural infarction in patients undergoing percutaneous&#xD;
      coronary intervention .&#xD;
&#xD;
      This clinical benefit was detected after median, 0.5 days of treatment with statins&#xD;
      (indicating that statins could potentially exert an antithrombotic effect even earlier than&#xD;
      supposed from pharmacological studies.&#xD;
&#xD;
      Violi et al recently showed the first evidence that atorvastatin acutely and simultaneously&#xD;
      decreases oxidative stress and platelet activation by directly inhibiting platelet Nox2 and&#xD;
      ultimately platelet isoprostanes and thromboxane A2 so providinf a rationale for the use of&#xD;
      statins to prevent or modulate coronary thrombosis.&#xD;
&#xD;
      Whereas recent data suggest that inflammatory reactions are involved in the pathogenesis and&#xD;
      progression of cerebral ischaemia , no study has evaluated effects of atorvastatin 80 mg/day&#xD;
      after a recent stroke on stroke outcome and on immunoinflammatory markers so to evaluate&#xD;
      acute antithrombotic and anti-inflammatory effects of atorvastatin also in acute&#xD;
      cerebrovascular event setting.&#xD;
&#xD;
      On this basis the primary objective of the study was to evaluate the separate effects of&#xD;
      atorvastatin in vivo on immunoinflammatory markers and on stroke prognosis in patients with&#xD;
      recent acute ischemic stroke classified as atherothrombotic.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Material and Methods The investigators will enroll patients with a diagnosis of acute&#xD;
      ischemic stroke admitted to the Internal Medicine Department at the University of Palermo&#xD;
      between November 2011 and October 2014. The controlsubjects were patients admitted, in the&#xD;
      same period, to our Internal Medicine Department for any cause different from acute&#xD;
      cardiovascular and cerebrovascular events or exclusion criteria. Every subject with ischemic&#xD;
      stroke was matched for age (±3 years), sex, and cardiovascular risk factor prevalence with&#xD;
      one control subject&#xD;
&#xD;
      Study Hypothesis and Patient Population:&#xD;
&#xD;
      The primary hypothesis of the study is that treatment with 80 mg of atorvastatin per day&#xD;
      administered early at admission after acute ischemic stroke would reduce immunoinflammatory&#xD;
      activation of the acute phase and that this immunoinflammatory modulation could have a&#xD;
      possible effect on prognosis of ischemic stroke evaluated by some outcome indicators.&#xD;
&#xD;
      Eligible patients are men and women over 18 years of age who had an acute ischemic stroke&#xD;
      Patients with inflammatory or infectious diseases, cancer, hematological diseases and severe&#xD;
      renal or liver failure, as well as those who were under treatment with anti-inflammatory will&#xD;
      be excluded Stroke was defined by focal neurological signs or symptoms thought to be of&#xD;
      vascular origin that persisted for &gt;24 h, confirmed by brain CT and/or MRI in baseline&#xD;
      conditions Cardiovascular risk factors will be evaluated for both subjects and controls on&#xD;
      the basis of the following criteria: type 2 diabetes will be determined using a clinically&#xD;
      based algorithm that considered age at onset, presenting weight and symptoms, family history,&#xD;
      onset ofinsulin treatment, and history of ketoacidosis. Atrial fibrillation will be diagnosed&#xD;
      when present on the admission ECG. Hypertension was present when a patient had received&#xD;
      antihypertensive treatment before admission or when hypertension was diagnosed during the&#xD;
      hospital stay by repeated detection of blood pressure ≥160/95 mmHg. Hypercholesterolemia was&#xD;
      defined as total serum cholesterol ≥200 mg/dl or on the basis of a clinical history of&#xD;
      hypercholesterolemia or statin treatment.&#xD;
&#xD;
      The studyIs pending of approvationby the Ethics Committee of the &quot;Policlinico P. Giaccone&quot; of&#xD;
      Palermo. Written informed consent wasobtained for all patients.&#xD;
&#xD;
      The type of acute ischemic stroke will be classified according to the TOAST classification&#xD;
      (Adams et al., 1993): 1) Large Artery Athero- Sclerosis (LAAS); 2) CardioEmbolic Infarct&#xD;
      (CEI); 3) LACunar infarct (LAC); 4) stroke of Other Determined Etiology (ODE); 5) stroke of&#xD;
      UnDetermined Etiology (UDE).&#xD;
&#xD;
      • Large artery atherosclerosis (LAAS) These patients will have clinical and brain imaging&#xD;
      findings of either significant (≥50%) stenosis or occlusion of a major brain artery or branch&#xD;
      cortical artery, presumably due to atherosclerosis. Clinical findings include those of&#xD;
      cerebral cortical impairment (aphasia, neglect, restricted motor involvement, etc.) or brain&#xD;
      stem or cerebellar dysfunction. Cortical or cerebellar lesions and brain stem or subcortical&#xD;
      hemispheric infarcts greater than 1.5 cm in diameter on CT or MRI are considered to be of&#xD;
      potential large artery atherosclerotic origin. Supportive evidence by duplex imaging or&#xD;
      arteriography of a stenosis of greater than 50% of an appropriate intracranial or&#xD;
      extracranial artery is needed. Diagnostic studies should exclude potential sources of&#xD;
      cardiogenic embolism.&#xD;
&#xD;
      Patient evaluation and blood sample collection All the ischemic stroke patients will undergo:&#xD;
      medical history with recordi ng of potential stroke risk factors, blood and coagulation&#xD;
      tests, 12-lead ECG, 24 h electrocardiography monitoring, trans-thoracic echocardiography,&#xD;
      carotid ultrasound, brain CT or MRI at admission (repeated between the third and the seventh&#xD;
      days of stroke onset).&#xD;
&#xD;
      Blood samples will be obtained in the non-fasting state. After 10 min of rest in the supine&#xD;
      position, vital signs were recorded and blood samples were collected from the antecubital&#xD;
      vein. EDTA-anticoagulated peripheral blood was drawn from each patient within 12 h from&#xD;
      symptom onset. Serum and plasma were immediately separated by centrifugation and stored in&#xD;
      aliquots at -80 °C until analysis.&#xD;
&#xD;
      The investigators will evaluate plasma levels of IL-1β, TNF-α, IL-6 and IL-10, Eselectin,&#xD;
      P-selectin, sICAM-1 and sVCAM-1 as markers of immunoinflammatory activation, VWF plasma&#xD;
      levels as a marker of endothelial dysfunction, TPA-antigen and PAI-1 plasma levels as&#xD;
      thrombotic/ fibrinolytic markers.&#xD;
&#xD;
      These laboratory evaluation will be done at 72 h and at one week after symptom onset.&#xD;
&#xD;
      IL-1β, TNF-α, IL-6 and IL-10 and VWFantigen were measured using a sandwich ELISA (Human&#xD;
      IL-1β, TNF-α, IL-6 and IL-10 Quantikine, R&amp;D Systems (VWF ELISA kitdurian, Instrumentation&#xD;
      Laboratory, Milano, Italy); VCAM-1, ICAM-1, E-selectin, P-selectin, PAI-1 and TPAantigen will&#xD;
      be measured by commercial bioimmunoassay (Human sICAM-1, sVCAM-I, sE-selectin and sP-selectin&#xD;
      Parameter, Quantikine, R&amp;D Systems, Gentaur AssayMax Human Plasminogen Activator Inhibitor-1&#xD;
      (PAI-1) ELISA Kit, Gentaur AssayMax Tissue Plasminogen Activator (TPA) ELISA Kit).&#xD;
&#xD;
      The minimum detectable concentrations for the diagnostic tests were: TNF alpha: 1.6 pg/mL,&#xD;
      IL-1β: b1 pg/mL; IL-6:b0.70 pg/mL; IL-10: N3.9 pg/mL; ICAM-1:b0.35 ng/mL;VCAM-1:0.6 ng/mL;&#xD;
      E-Selectin: b0.1 ng /mL; P-Selectin:b0.5 ng/mL; vWF:1.0%;TPA: 0.3 pg/ml; PAI-1: b50 pg/ml.&#xD;
      Intra-assay and inter-assay coefficients of variation were: TNF alpha: 4.2% and 4.6%; IL-1β:&#xD;
      3.3% and 4.2%; IL-6: 1.6% and 3.3%; IL-10: 4.3% and 7.5%; ICAM-1: 4.8% and 6.1%; VCAM-1: 3.5%&#xD;
      and 7.7%; ESelectin: 4.8% and 5.7%; P-Selectin: 4.9% and 8.8%; vWF: 5% and 10%; TPA: 4.8% and&#xD;
      5%; PAI-1: 5.7% and 8.3%.&#xD;
&#xD;
      As outcome indicators the investigators will use evaluation of acute neurological deficit by&#xD;
      means National Institutes of Health Stroke Scale, at 72 hours and 7 days after admission and&#xD;
      evaluation of disability at 7 days after admission by means modified Rankin Scale&#xD;
      Neurological deficit score on admission was evaluated by the NIHSS. The National Institutes&#xD;
      of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to&#xD;
      objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items,&#xD;
      each of which scores a specific ability between a 0 and 4. For each item, a score of 0&#xD;
      typically indicates normal function in that specific ability, while a higher score is&#xD;
      indicative of some level of impairment. The individual scores from each item are summed in&#xD;
      order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the&#xD;
      minimum score being a 0 Disability at 7 days was evaluated by modified Rankin Scale (mRS)&#xD;
      that is a commonly used scale for measuring the degree of disability or dependence in the&#xD;
      daily activities of people who have suffered a stroke.&#xD;
&#xD;
      The scale runs from 0-6, running from perfect health without symptoms to death.&#xD;
&#xD;
        -  0 - No symptoms.&#xD;
&#xD;
        -  1 - No significant disability. Able to carry out all usual activities, despite some&#xD;
           symptoms.&#xD;
&#xD;
        -  2 - Slight disability. Able to look after own affairs without assistance, but unable to&#xD;
           carry out all previous activities.&#xD;
&#xD;
        -  3 - Moderate disability. Requires some help, but able to walk unassisted.&#xD;
&#xD;
        -  4 - Moderately severe disability. Unable to attend to own bodily needs without&#xD;
           assistance, and unable to walk unassisted.&#xD;
&#xD;
        -  5 - Severe disability. Requires constant nursing care and attention, bedridden,&#xD;
           incontinent.&#xD;
&#xD;
        -  6 - Dead. Treatment protocol&#xD;
&#xD;
      Patients will be randomized to these two treatment:&#xD;
&#xD;
      Group A: treatment with atorvastatin 80 mg (once-daily) from admission day until discharge&#xD;
      Group B: No treatment with atorvastatin 80 mg until discharge, after discharge treatment with&#xD;
      atorvastatin 80 mg will be started&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2011</start_date>
  <completion_date type="Actual">March 2014</completion_date>
  <primary_completion_date type="Actual">January 2014</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>NIHSS score at 72 hour</measure>
    <time_frame>72 hours</time_frame>
    <description>differences with regard of NIHSS score at 72 hours</description>
  </primary_outcome>
  <primary_outcome>
    <measure>differences in msRankin score</measure>
    <time_frame>72 hours</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma levels of inflammatory cytokines at 72 hours</measure>
    <time_frame>72 hours</time_frame>
    <description>differences with regard of plasma levels of TNF-alfa, IL-1 beta, IL-6, E-Selectin, P-Selectin, ICAM-1, V-CAM1, VWF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Outcome measure ( rankin score)</measure>
    <time_frame>seven days</time_frame>
    <description>differences in msRankin score at seven day after admission</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Ischemic Stroke</condition>
  <arm_group>
    <arm_group_label>early Atorvastatin treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ischemic stroke patients treated with with atorvastatin 80 mg at admission until discharge</description>
  </arm_group>
  <arm_group>
    <arm_group_label>no early treatment with atorvastatin</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Ischemic stroke patients not treated with with atorvastatin 80 mg until discharge</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atorvastatin</intervention_name>
    <description>treatment with atorvastatin 80 mg (once-daily) from admission day until discharge</description>
    <arm_group_label>early Atorvastatin treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Eligible patients were men and women over 18 years of age who had an acute ischemic&#xD;
             stroke with a symptom time onset &lt; 48 hours&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with inflammatory or infectious diseases, cancer, hematological diseases and&#xD;
             severe renal or liver failure, as well as those who were under treatment with&#xD;
             anti-inflammatory were excluded&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Internal Medicine Ward, University of Palermo</name>
      <address>
        <city>Palermo</city>
        <zip>90127</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
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  <verification_date>August 2014</verification_date>
  <study_first_submitted>March 11, 2014</study_first_submitted>
  <study_first_submitted_qc>August 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 26, 2014</study_first_posted>
  <last_update_submitted>August 25, 2014</last_update_submitted>
  <last_update_submitted_qc>August 25, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 26, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Palermo</investigator_affiliation>
    <investigator_full_name>Antonino Tuttolomondo</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>Atorvastatin, ischemic stroke, cytokines</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stroke</mesh_term>
    <mesh_term>Ischemic Stroke</mesh_term>
    <mesh_term>Ischemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atorvastatin</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02225834
org study id: 21770
nct id: NCT02225834
lead sponsor: 
has dmc: No
Recent clinical trials and meta-analyses of b-hydroxy-bmethylglutaryl coenzyme A (HMG-CoA)
      reductase inhibitors (statins) have demonstrated a significant reduction in ischemic stroke
      in patients with a history of coronary artery disease, both with and without elevations of
      serum cholesterol. Recent data suggest that statins have other beneficial properties in
      addition to the retardation of atherosclerosis. Asahi et al demonstred that Statins increased
      eNOS and tPA mRNA levels but did not change mRNA levels of PAI-1 and that In eNOS knockout
      mice, atorvastatin reduced the volume of ischemic tissue and improved neurologic outcomes
      after arterial occlusion by blood clot emboli. In addition to their lipid-lowering effects,
      it has been speculated that statins may also have beneficial effects on cerebral circulation
      and brain parenchyma during ischaemic stroke and reperfusion. Aslanyan et al reported that
      statin use was associated with reduced mortality at 1 month during the follow-up.

      In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of
      atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events,
      despite a small increase in the incidence of hemorrhagic stroke period .

      Recently the investigators group reported that lacunar strokes compared to nonlacunar ones
      exhibited significantly lower plasma levels of TNF-α and IL1-β, P-selectin and ICAM-1 24-72 h
      and 7-10 days after stroke onset (4). At extracranial arterial territories, inflammation
      plays a crucial role mediating all the stages of the atherosclerosis process . Similarly,
      thrombosis and defective fibrinolysis may also contribute to the progression of
      atherosclerotic lesions . Interestingly, both mechanisms might have a relevant role in the
      pathogenesis of intracranial large artery atherosclerosis and ischemic stroke Moreover our
      group showed that Patients with cardioembolic and atherothrombotic stroke subtypes showed
      significantly higher median plasma levels of TNF-α, IL-6, IL-1β whereas the lacunar subtype
      showed significantly lower median plasma levels of TNF-α, IL-6 and IL-1β and that
      immunoinflammatory marker plasma levels are significantly related to ischemic lesion volume.

      A meta-analysis showed that statins may possess antithrombotic property because these drugs
      were reported to reduce periprocedural infarction in patients undergoing percutaneous
      coronary intervention .

      This clinical benefit was detected after median, 0.5 days of treatment with statins
      (indicating that statins could potentially exert an antithrombotic effect even earlier than
      supposed from pharmacological studies.

      Violi et al recently showed the first evidence that atorvastatin acutely and simultaneously
      decreases oxidative stress and platelet activation by directly inhibiting platelet Nox2 and
      ultimately platelet isoprostanes and thromboxane A2 so providinf a rationale for the use of
      statins to prevent or modulate coronary thrombosis.

      Whereas recent data suggest that inflammatory reactions are involved in the pathogenesis and
      progression of cerebral ischaemia , no study has evaluated effects of atorvastatin 80 mg/day
      after a recent stroke on stroke outcome and on immunoinflammatory markers so to evaluate
      acute antithrombotic and anti-inflammatory effects of atorvastatin also in acute
      cerebrovascular event setting.

      On this basis the primary objective of the study was to evaluate the separate effects of
      atorvastatin in vivo on immunoinflammatory markers and on stroke prognosis in patients with
      recent acute ischemic stroke classified as atherothrombotic.
Material and Methods The investigators will enroll patients with a diagnosis of acute
      ischemic stroke admitted to the Internal Medicine Department at the University of Palermo
      between November 2011 and October 2014. The controlsubjects were patients admitted, in the
      same period, to our Internal Medicine Department for any cause different from acute
      cardiovascular and cerebrovascular events or exclusion criteria. Every subject with ischemic
      stroke was matched for age (±3 years), sex, and cardiovascular risk factor prevalence with
      one control subject

      Study Hypothesis and Patient Population:

      The primary hypothesis of the study is that treatment with 80 mg of atorvastatin per day
      administered early at admission after acute ischemic stroke would reduce immunoinflammatory
      activation of the acute phase and that this immunoinflammatory modulation could have a
      possible effect on prognosis of ischemic stroke evaluated by some outcome indicators.

      Eligible patients are men and women over 18 years of age who had an acute ischemic stroke
      Patients with inflammatory or infectious diseases, cancer, hematological diseases and severe
      renal or liver failure, as well as those who were under treatment with anti-inflammatory will
      be excluded Stroke was defined by focal neurological signs or symptoms thought to be of
      vascular origin that persisted for >24 h, confirmed by brain CT and/or MRI in baseline
      conditions Cardiovascular risk factors will be evaluated for both subjects and controls on
      the basis of the following criteria: type 2 diabetes will be determined using a clinically
      based algorithm that considered age at onset, presenting weight and symptoms, family history,
      onset ofinsulin treatment, and history of ketoacidosis. Atrial fibrillation will be diagnosed
      when present on the admission ECG. Hypertension was present when a patient had received
      antihypertensive treatment before admission or when hypertension was diagnosed during the
      hospital stay by repeated detection of blood pressure ≥160/95 mmHg. Hypercholesterolemia was
      defined as total serum cholesterol ≥200 mg/dl or on the basis of a clinical history of
      hypercholesterolemia or statin treatment.

      The studyIs pending of approvationby the Ethics Committee of the "Policlinico P. Giaccone" of
      Palermo. Written informed consent wasobtained for all patients.

      The type of acute ischemic stroke will be classified according to the TOAST classification
      (Adams et al., 1993): 1) Large Artery Athero- Sclerosis (LAAS); 2) CardioEmbolic Infarct
      (CEI); 3) LACunar infarct (LAC); 4) stroke of Other Determined Etiology (ODE); 5) stroke of
      UnDetermined Etiology (UDE).

      • Large artery atherosclerosis (LAAS) These patients will have clinical and brain imaging
      findings of either significant (≥50%) stenosis or occlusion of a major brain artery or branch
      cortical artery, presumably due to atherosclerosis. Clinical findings include those of
      cerebral cortical impairment (aphasia, neglect, restricted motor involvement, etc.) or brain
      stem or cerebellar dysfunction. Cortical or cerebellar lesions and brain stem or subcortical
      hemispheric infarcts greater than 1.5 cm in diameter on CT or MRI are considered to be of
      potential large artery atherosclerotic origin. Supportive evidence by duplex imaging or
      arteriography of a stenosis of greater than 50% of an appropriate intracranial or
      extracranial artery is needed. Diagnostic studies should exclude potential sources of
      cardiogenic embolism.

      Patient evaluation and blood sample collection All the ischemic stroke patients will undergo:
      medical history with recordi ng of potential stroke risk factors, blood and coagulation
      tests, 12-lead ECG, 24 h electrocardiography monitoring, trans-thoracic echocardiography,
      carotid ultrasound, brain CT or MRI at admission (repeated between the third and the seventh
      days of stroke onset).

      Blood samples will be obtained in the non-fasting state. After 10 min of rest in the supine
      position, vital signs were recorded and blood samples were collected from the antecubital
      vein. EDTA-anticoagulated peripheral blood was drawn from each patient within 12 h from
      symptom onset. Serum and plasma were immediately separated by centrifugation and stored in
      aliquots at -80 °C until analysis.

      The investigators will evaluate plasma levels of IL-1β, TNF-α, IL-6 and IL-10, Eselectin,
      P-selectin, sICAM-1 and sVCAM-1 as markers of immunoinflammatory activation, VWF plasma
      levels as a marker of endothelial dysfunction, TPA-antigen and PAI-1 plasma levels as
      thrombotic/ fibrinolytic markers.

      These laboratory evaluation will be done at 72 h and at one week after symptom onset.

      IL-1β, TNF-α, IL-6 and IL-10 and VWFantigen were measured using a sandwich ELISA (Human
      IL-1β, TNF-α, IL-6 and IL-10 Quantikine, R&D Systems (VWF ELISA kitdurian, Instrumentation
      Laboratory, Milano, Italy); VCAM-1, ICAM-1, E-selectin, P-selectin, PAI-1 and TPAantigen will
      be measured by commercial bioimmunoassay (Human sICAM-1, sVCAM-I, sE-selectin and sP-selectin
      Parameter, Quantikine, R&D Systems, Gentaur AssayMax Human Plasminogen Activator Inhibitor-1
      (PAI-1) ELISA Kit, Gentaur AssayMax Tissue Plasminogen Activator (TPA) ELISA Kit).

      The minimum detectable concentrations for the diagnostic tests were: TNF alpha: 1.6 pg/mL,
      IL-1β: b1 pg/mL; IL-6:b0.70 pg/mL; IL-10: N3.9 pg/mL; ICAM-1:b0.35 ng/mL;VCAM-1:0.6 ng/mL;
      E-Selectin: b0.1 ng /mL; P-Selectin:b0.5 ng/mL; vWF:1.0%;TPA: 0.3 pg/ml; PAI-1: b50 pg/ml.
      Intra-assay and inter-assay coefficients of variation were: TNF alpha: 4.2% and 4.6%; IL-1β:
      3.3% and 4.2%; IL-6: 1.6% and 3.3%; IL-10: 4.3% and 7.5%; ICAM-1: 4.8% and 6.1%; VCAM-1: 3.5%
      and 7.7%; ESelectin: 4.8% and 5.7%; P-Selectin: 4.9% and 8.8%; vWF: 5% and 10%; TPA: 4.8% and
      5%; PAI-1: 5.7% and 8.3%.

      As outcome indicators the investigators will use evaluation of acute neurological deficit by
      means National Institutes of Health Stroke Scale, at 72 hours and 7 days after admission and
      evaluation of disability at 7 days after admission by means modified Rankin Scale
      Neurological deficit score on admission was evaluated by the NIHSS. The National Institutes
      of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to
      objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items,
      each of which scores a specific ability between a 0 and 4. For each item, a score of 0
      typically indicates normal function in that specific ability, while a higher score is
      indicative of some level of impairment. The individual scores from each item are summed in
      order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the
      minimum score being a 0 Disability at 7 days was evaluated by modified Rankin Scale (mRS)
      that is a commonly used scale for measuring the degree of disability or dependence in the
      daily activities of people who have suffered a stroke.

      The scale runs from 0-6, running from perfect health without symptoms to death.

        -  0 - No symptoms.

        -  1 - No significant disability. Able to carry out all usual activities, despite some
           symptoms.

        -  2 - Slight disability. Able to look after own affairs without assistance, but unable to
           carry out all previous activities.

        -  3 - Moderate disability. Requires some help, but able to walk unassisted.

        -  4 - Moderately severe disability. Unable to attend to own bodily needs without
           assistance, and unable to walk unassisted.

        -  5 - Severe disability. Requires constant nursing care and attention, bedridden,
           incontinent.

        -  6 - Dead. Treatment protocol

      Patients will be randomized to these two treatment:

      Group A: treatment with atorvastatin 80 mg (once-daily) from admission day until discharge
      Group B: No treatment with atorvastatin 80 mg until discharge, after discharge treatment with
      atorvastatin 80 mg will be started
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: NIHSS score at 72 hour
time frame: 72 hours
description: differences with regard of NIHSS score at 72 hours
measure: differences in msRankin score
time frame: 72 hours
measure: Plasma levels of inflammatory cytokines at 72 hours
time frame: 72 hours
description: differences with regard of plasma levels of TNF-alfa, IL-1 beta, IL-6, E-Selectin, P-Selectin, ICAM-1, V-CAM1, VWF
measure: Outcome measure ( rankin score)
time frame: seven days
description: differences in msRankin score at seven day after admission
arm group label: early Atorvastatin treatment
arm group type: Experimental
description: Ischemic stroke patients treated with with atorvastatin 80 mg at admission until discharge
arm group label: no early treatment with atorvastatin
arm group type: No Intervention
description: Ischemic stroke patients not treated with with atorvastatin 80 mg until discharge
intervention type: Drug
intervention name: Atorvastatin
description: treatment with atorvastatin 80 mg (once-daily) from admission day until discharge
arm group label: early Atorvastatin treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Italy
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responsible party type: Principal Investigator
investigator affiliation: University of Palermo
investigator full name: Antonino Tuttolomondo
investigator title: Assistant Professor
mesh term: Stroke
mesh term: Ischemic Stroke
mesh term: Ischemia
mesh term: Atorvastatin