<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/NCT03041753</url>
  </required_header>
  <id_info>
    <org_study_id>RF-2011-02348240</org_study_id>
    <nct_id>NCT03041753</nct_id>
  </id_info>
  <brief_title>Reperfusion Injury After Stroke Study</brief_title>
  <acronym>RISKS</acronym>
  <official_title>Reperfusion Injury After Cerebral Ischemia: an &quot;in Vivo&quot; Study Using Neuro-imaging Markers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Ospedaliero-Universitaria Careggi</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Health, Italy</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Azienda Ospedaliero-Universitaria Careggi</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: stroke is a major cause of death and disability. Intravenous thrombolysis and&#xD;
      mechanical thrombectomy are able to re-open occluded vessels and save the ischemic tissue&#xD;
      from death. However, recanalization of the occluded vessel may trigger activation of&#xD;
      detrimental molecular pathways and exacerbate blood brain barrier (BBB) disruption,&#xD;
      eventually determining hemorrhagic transformation (HT) or cerebral edema (CE), causing the&#xD;
      so-called &quot;reperfusion injury&quot;. There is increasing evidence that a number of factors&#xD;
      measurable as circulating biomarkers, particularly metalloproteinases (MMP), contribute to&#xD;
      reperfusion brain injury. Preliminary data show that BBB disruption can be traced in vivo by&#xD;
      Computed Tomography Perfusion (CTP) imaging. The aim of this study is to evaluate the effects&#xD;
      of circulating and imaging biomarkers in relation to reperfusion injury.&#xD;
&#xD;
      Methods: consecutive patients presenting with acute ischemic stroke in the anterior&#xD;
      circulation territory, scoring≥7 on NIHSS, candidates to intravenous thrombolysis or to&#xD;
      endovascular treatment, will be enrolled in one hospital centre. Circulating levels of pro-,&#xD;
      anti-inflammatory, immunomodulatory factors, metalloproteinases and their&#xD;
      inductors/inhibitors, factors of endothelial dysfunction and fibrin resistance to lysis will&#xD;
      be measured in blood samples taken from each patients pre-thrombolysis and 24 hours after&#xD;
      thrombolysis. Biomarker levels will be studied in relation to CTP measures of BBB&#xD;
      permeability and in relation to imaging signs of reperfusion injury after acute&#xD;
      interventions, such as hemorrhagic transformation and cerebral edema.&#xD;
&#xD;
      Results: enrollment started on October 2015. As of January 2017, 70 patients have been&#xD;
      included. Results are expected by the end of 2018 with an estimated sample size of 140&#xD;
      patients. Using a definite protocol, a prospective collection of data, and an adequate number&#xD;
      of patients assuring statistically powered data, this study will integrate clinical&#xD;
      information with imaging and biological factors involved in reperfusion injury after cerebral&#xD;
      ischemia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study design:&#xD;
&#xD;
      This is an observational hospital-based study that will include 140 patients with ischemic&#xD;
      stroke in the anterior circulation within 12 hours from last seen well, treated either with&#xD;
      intravenous thrombolysis or endovascular thrombectomy. Included patients have National&#xD;
      Institutes of Health Stroke Scale (NIHSS) ≥7. Both circulating biomarkers sampling and CT&#xD;
      Perfusion will be performed before acute interventions. Clinical/functional and imaging&#xD;
      assessments will be repeated 24 hours after interventions and at 3 months after stroke.&#xD;
&#xD;
      Work Methodology:&#xD;
&#xD;
      Stroke severity will be measured using the NIHSS, post-stroke disability by the modified&#xD;
      Rankin Scale (mRS) administered at 3 months by visit or phone interview. Investigators will&#xD;
      rate hemorrhagic transformation (HT) grade using the European Cooperative Acute Stroke Study&#xD;
      (ECASS II) criteria and CE according to the Safe Implementation of Thrombolysis in&#xD;
      Stroke-Monitoring Study (SITS-MOST) protocol.&#xD;
&#xD;
      Cerebral imaging will include baseline plain CT, CT angiography and CT perfusion at baseline.&#xD;
      CT will be repeated at 24 h, and at any time when clinical deterioration will be observed.&#xD;
      Collection of imaging data will be blinded to both clinical and laboratory data. Baseline and&#xD;
      follow up CT scans will be assessed by three stroke physicians (FA, BP, VP) for presence of&#xD;
      early ischemic signs (Alberta Stroke Programme Early CT score, hyperdensity of middle&#xD;
      cerebral artery), presence and severity of small vessel disease markers (white matter&#xD;
      changes, preexisting lacunar infarcts, brain atrophy), presence and grading of HT, when&#xD;
      present. Perfusion maps will be generated for each patient with a deconvolution-based&#xD;
      delay-insensitive algorithm. For permeability calculation, an adiabatic approximation of&#xD;
      distributed parameter analysis will be used. Permeability maps will be generated by a&#xD;
      dedicated software. Recanalization rate will be assessed at 24 hours with either CT&#xD;
      angiography, Magnetic Resonance angiography or transcranial doppler. In case of effective&#xD;
      recanalization (Thrombolysis In Cerebral Infarction scale=2b/3) at the end of endovascular&#xD;
      procedure and clinical improvement, recanalization will not be reassessed at 24 hours.&#xD;
&#xD;
      Laboratory protocol:&#xD;
&#xD;
      Blood will be collected in tubes with anticoagulant, as well as in tubes without&#xD;
      anticoagulant, before starting and 24 h after thrombolysis. Tubes will be centrifuged at room&#xD;
      temperature at 1500 × g for 15 min, and the supernatants will be stored in aliquots at -80°C.&#xD;
&#xD;
      Statistical analysis:&#xD;
&#xD;
      Pearson χ2 will be used to test for significance while comparing categorical variables and&#xD;
      ANOVA test for numeric variables. To analyze differences in biomarkers levels between&#xD;
      baseline and 24 h, a non-parametric Mann-Whitney U test will be used because of relatively&#xD;
      large statistical variations. As a main explanatory variable, we will use single patient's&#xD;
      baseline levels and relative pre- and post-thrombolysis variation (Δ median value) of&#xD;
      Metalloproteinases(MMP) 2-3-9 and Tissue Inhibitors of Metalloproteinases (TIMP)1-2 levels,&#xD;
      calculated according to the formula: (24-hour post-thrombolysis MMP or TIMP-pre-thrombolysis&#xD;
      MMP or TIMP)/pre-thrombolysis MMP or TIMP. Baseline levels and Δ values will be analyzed in&#xD;
      relation to demographic and clinical features and across subgroups of patients with different&#xD;
      outcomes. The net effect of each biomarker in study (baseline, 24 h, and Δ values) on&#xD;
      outcomes will be also estimated by both logistic regression and ordinal models, including&#xD;
      potentially confounding covariates. Novel candidates that will emerge over the course of the&#xD;
      study will be considered for analysis In case of skewed distribution of biomarker values,&#xD;
      authors will consider the possibility of log-transformation of data.&#xD;
&#xD;
      Milestones:&#xD;
&#xD;
      Phase 1 (6 months): a) Project protocol establishment; b) Dedicated database for data&#xD;
      collection construction; c) CTP protocol determination; d) Training on recruiting staff Phase&#xD;
      2 (36 months): a) Baseline patients cohort enrollment; b) Imaging data collection c)&#xD;
      Circulating biomarker collection; d) Follow-up assessments (3 months after enrolment) Phase 3&#xD;
      (6 months): a) Post-processing of neuroimaging acquired at baseline ; b) Data completeness&#xD;
      and consistency control; c) Data analysis; d) Dissemination of results&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>September 2015</start_date>
  <completion_date type="Anticipated">November 2018</completion_date>
  <primary_completion_date type="Anticipated">August 2018</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients with hemorrhagic transformation (type 2 OR any type of parenchyma hemorrhage according to ECASS II criteria) OR cerebral edema (comprising at least 1/3 of the hemisphere OR causing midline shift) at 24h CT</measure>
    <time_frame>24 hours from symptom onset</time_frame>
    <description>Relevant Hemorrhagic Transformation OR Relevant Cerebral Edema</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Categorical shift in mRS score at 3 months</measure>
    <time_frame>3 months from symptom onset</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Symptomatic hemorrhagic transformation</measure>
    <time_frame>24 hours from symptom onset</time_frame>
    <description>any deterioration in NIHSS score or death combined with intracerebral hemorrhage of any type</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">140</enrollment>
  <condition>Ischemic Stroke</condition>
  <arm_group>
    <arm_group_label>Intervention group</arm_group_label>
    <description>ischemic stroke patients in the anterior circulation territory (NIHSS ≥7) within 12 hours from last seen well, treated either with systemic thrombolysis or endovascular treatment.</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood; thrombus eventually taken during endovascular procedure&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        This is an observational hospital-based study that will include 140 ischemic stroke&#xD;
        patients in the anterior circulation territory (NIHSS ≥7) within 12 hours from last seen&#xD;
        well, treated either with systemic thrombolysis or endovascular treatment&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ischemic stroke patients in the anterior circulation territory&#xD;
&#xD;
          -  NIHSS ≥7&#xD;
&#xD;
          -  within 12 hours from last seen well&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Controindications for iodine contrast medium&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Domenico Inzitari, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florence</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Domenico Inzitari, MD</last_name>
    <phone>0557947447</phone>
    <email>domenico.inzitari@unifi.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Benedetta Piccardi, MD</last_name>
    <email>bpiccardi@hotmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Careggi University Hospital, Stroke Unit</name>
      <address>
        <city>Florence</city>
        <zip>50134</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>August 23, 2016</study_first_submitted>
  <study_first_submitted_qc>February 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 3, 2017</study_first_posted>
  <last_update_submitted>February 2, 2017</last_update_submitted>
  <last_update_submitted_qc>February 2, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 3, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Florence</investigator_affiliation>
    <investigator_full_name>Domenico Inzitari</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>stroke</keyword>
  <keyword>thrombolysis</keyword>
  <keyword>metalloproteinases</keyword>
  <keyword>blood brain barrier</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>Reperfusion Injury</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03041753
org study id: RF-2011-02348240
nct id: NCT03041753
lead sponsor: 
collaborator: 
has dmc: Yes
Background: stroke is a major cause of death and disability. Intravenous thrombolysis and
      mechanical thrombectomy are able to re-open occluded vessels and save the ischemic tissue
      from death. However, recanalization of the occluded vessel may trigger activation of
      detrimental molecular pathways and exacerbate blood brain barrier (BBB) disruption,
      eventually determining hemorrhagic transformation (HT) or cerebral edema (CE), causing the
      so-called "reperfusion injury". There is increasing evidence that a number of factors
      measurable as circulating biomarkers, particularly metalloproteinases (MMP), contribute to
      reperfusion brain injury. Preliminary data show that BBB disruption can be traced in vivo by
      Computed Tomography Perfusion (CTP) imaging. The aim of this study is to evaluate the effects
      of circulating and imaging biomarkers in relation to reperfusion injury.

      Methods: consecutive patients presenting with acute ischemic stroke in the anterior
      circulation territory, scoring≥7 on NIHSS, candidates to intravenous thrombolysis or to
      endovascular treatment, will be enrolled in one hospital centre. Circulating levels of pro-,
      anti-inflammatory, immunomodulatory factors, metalloproteinases and their
      inductors/inhibitors, factors of endothelial dysfunction and fibrin resistance to lysis will
      be measured in blood samples taken from each patients pre-thrombolysis and 24 hours after
      thrombolysis. Biomarker levels will be studied in relation to CTP measures of BBB
      permeability and in relation to imaging signs of reperfusion injury after acute
      interventions, such as hemorrhagic transformation and cerebral edema.

      Results: enrollment started on October 2015. As of January 2017, 70 patients have been
      included. Results are expected by the end of 2018 with an estimated sample size of 140
      patients. Using a definite protocol, a prospective collection of data, and an adequate number
      of patients assuring statistically powered data, this study will integrate clinical
      information with imaging and biological factors involved in reperfusion injury after cerebral
      ischemia.
Study design:

      This is an observational hospital-based study that will include 140 patients with ischemic
      stroke in the anterior circulation within 12 hours from last seen well, treated either with
      intravenous thrombolysis or endovascular thrombectomy. Included patients have National
      Institutes of Health Stroke Scale (NIHSS) ≥7. Both circulating biomarkers sampling and CT
      Perfusion will be performed before acute interventions. Clinical/functional and imaging
      assessments will be repeated 24 hours after interventions and at 3 months after stroke.

      Work Methodology:

      Stroke severity will be measured using the NIHSS, post-stroke disability by the modified
      Rankin Scale (mRS) administered at 3 months by visit or phone interview. Investigators will
      rate hemorrhagic transformation (HT) grade using the European Cooperative Acute Stroke Study
      (ECASS II) criteria and CE according to the Safe Implementation of Thrombolysis in
      Stroke-Monitoring Study (SITS-MOST) protocol.

      Cerebral imaging will include baseline plain CT, CT angiography and CT perfusion at baseline.
      CT will be repeated at 24 h, and at any time when clinical deterioration will be observed.
      Collection of imaging data will be blinded to both clinical and laboratory data. Baseline and
      follow up CT scans will be assessed by three stroke physicians (FA, BP, VP) for presence of
      early ischemic signs (Alberta Stroke Programme Early CT score, hyperdensity of middle
      cerebral artery), presence and severity of small vessel disease markers (white matter
      changes, preexisting lacunar infarcts, brain atrophy), presence and grading of HT, when
      present. Perfusion maps will be generated for each patient with a deconvolution-based
      delay-insensitive algorithm. For permeability calculation, an adiabatic approximation of
      distributed parameter analysis will be used. Permeability maps will be generated by a
      dedicated software. Recanalization rate will be assessed at 24 hours with either CT
      angiography, Magnetic Resonance angiography or transcranial doppler. In case of effective
      recanalization (Thrombolysis In Cerebral Infarction scale=2b/3) at the end of endovascular
      procedure and clinical improvement, recanalization will not be reassessed at 24 hours.

      Laboratory protocol:

      Blood will be collected in tubes with anticoagulant, as well as in tubes without
      anticoagulant, before starting and 24 h after thrombolysis. Tubes will be centrifuged at room
      temperature at 1500 × g for 15 min, and the supernatants will be stored in aliquots at -80°C.

      Statistical analysis:

      Pearson χ2 will be used to test for significance while comparing categorical variables and
      ANOVA test for numeric variables. To analyze differences in biomarkers levels between
      baseline and 24 h, a non-parametric Mann-Whitney U test will be used because of relatively
      large statistical variations. As a main explanatory variable, we will use single patient's
      baseline levels and relative pre- and post-thrombolysis variation (Δ median value) of
      Metalloproteinases(MMP) 2-3-9 and Tissue Inhibitors of Metalloproteinases (TIMP)1-2 levels,
      calculated according to the formula: (24-hour post-thrombolysis MMP or TIMP-pre-thrombolysis
      MMP or TIMP)/pre-thrombolysis MMP or TIMP. Baseline levels and Δ values will be analyzed in
      relation to demographic and clinical features and across subgroups of patients with different
      outcomes. The net effect of each biomarker in study (baseline, 24 h, and Δ values) on
      outcomes will be also estimated by both logistic regression and ordinal models, including
      potentially confounding covariates. Novel candidates that will emerge over the course of the
      study will be considered for analysis In case of skewed distribution of biomarker values,
      authors will consider the possibility of log-transformation of data.

      Milestones:

      Phase 1 (6 months): a) Project protocol establishment; b) Dedicated database for data
      collection construction; c) CTP protocol determination; d) Training on recruiting staff Phase
      2 (36 months): a) Baseline patients cohort enrollment; b) Imaging data collection c)
      Circulating biomarker collection; d) Follow-up assessments (3 months after enrolment) Phase 3
      (6 months): a) Post-processing of neuroimaging acquired at baseline ; b) Data completeness
      and consistency control; c) Data analysis; d) Dissemination of results
observational model: Cohort
time perspective: Prospective
measure: Number of patients with hemorrhagic transformation (type 2 OR any type of parenchyma hemorrhage according to ECASS II criteria) OR cerebral edema (comprising at least 1/3 of the hemisphere OR causing midline shift) at 24h CT
time frame: 24 hours from symptom onset
description: Relevant Hemorrhagic Transformation OR Relevant Cerebral Edema
measure: Categorical shift in mRS score at 3 months
time frame: 3 months from symptom onset
measure: Symptomatic hemorrhagic transformation
time frame: 24 hours from symptom onset
description: any deterioration in NIHSS score or death combined with intracerebral hemorrhage of any type
arm group label: Intervention group
description: ischemic stroke patients in the anterior circulation territory (NIHSS ≥7) within 12 hours from last seen well, treated either with systemic thrombolysis or endovascular treatment.
Blood; thrombus eventually taken during endovascular procedure
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Domenico Inzitari, MD
role: Principal Investigator
affiliation: University of Florence
last name: Domenico Inzitari, MD
phone: 0557947447
email: domenico.inzitari@unifi.it
last name: Benedetta Piccardi, MD
email: bpiccardi@hotmail.com
facility: 
status: Recruiting
country: Italy
responsible party type: Principal Investigator
investigator affiliation: University of Florence
investigator full name: Domenico Inzitari
investigator title: Professor
mesh term: Stroke
mesh term: Ischemic Stroke
mesh term: Reperfusion Injury
sharing ipd: Undecided