<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/NCT02205775</url>
  </required_header>
  <id_info>
    <org_study_id>2009-013622-17</org_study_id>
    <nct_id>NCT02205775</nct_id>
  </id_info>
  <brief_title>Rosuvastatin for Reduction of Myocardial Damage and Systemic Inflammation During Coronary Angioplasty</brief_title>
  <acronym>REMEDY</acronym>
  <official_title>Rosuvastatin for Reduction of Myocardial Damage and Systemic Inflammation During Coronary Angioplasty - The REMEDY Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>G. d'Annunzio University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Working Group Aterosclerosi, Trombosi e Biologia Vascolare</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>G. d'Annunzio University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Myocardial necrosis is relatively frequent after percutaneous coronary intervention and is&#xD;
      associated with higher mortality during the follow-up.&#xD;
&#xD;
      Since anti-inflammatory properties of statins have been demonstrated and the benefit of&#xD;
      statins in acute coronary syndromes have been proven, this study aims at testing the&#xD;
      hypothesis that the pre-procedural intensive statin treatment reduce the extent of&#xD;
      peri-procedural necrosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Myocardial necrosis, assessed by creatine kinase-MB (CK-MB) elevation, is relatively frequent&#xD;
      after percutaneous coronary intervention (PCI), occurring in up to 40% of cases. Although&#xD;
      most patients remain asymptomatic and with no changes in cardiac function, even a mild&#xD;
      release of CK-MB is associated with higher mortality during the follow-up. A number of&#xD;
      treatment strategies have been proposed to limit myocardial damage during PCI, but procedural&#xD;
      ischemic myocardial injury remains the most frequent complication after coronary angioplasty.&#xD;
&#xD;
      Several randomized studies have demonstrated the beneficial effects of therapy with HMG-CoA&#xD;
      reductase inhibitors (statins) in patients with already established coronary artery disease&#xD;
      or in normal subjects with hypercholesterolemia in primary prevention, and retrospective&#xD;
      observational studies have suggested that pre-treatment with statins might reduce the&#xD;
      incidence of myocardial infarction after coronary intervention. This benefit was confirmed in&#xD;
      patients with non-ST segment elevation acute coronary syndromes (NSTE-ACS) undergoing PCI,&#xD;
      who received 80 mg atorvastatin 12 h before PCI, with a further 40-mg pre-procedure, as&#xD;
      compared with placebo.&#xD;
&#xD;
      The mechanisms underlying the beneficial effects of statins in ischemic conditions are not&#xD;
      completely clear. Previous studies have suggested that the anti-inflammatory effect of&#xD;
      statins may play a role, showing that the benefit was higher in patients with high C-reactive&#xD;
      protein. Since an inflammatory status before angioplasty, as detected by high levels of&#xD;
      C-reactive protein, is associated with a higher risk of peri-procedural myocardial necrosis&#xD;
      and adverse cardiac events during the follow-up, the anti-inflammatory effects of statins&#xD;
      might contribute to reduce myocardial necrosis, by reducing to the microembolization&#xD;
      occurring during coronary intervention. Statin administration also rapidly improves&#xD;
      endothelial function. Thus, even short-term treatment with statins (unable to provide LDL&#xD;
      reduction persistent enough to decrease the atherosclerotic burden) may have important&#xD;
      effects on endothelial function and inflammation. In patients undergoing PCI, reduction of&#xD;
      peri-procedural myocardial injury after pre-treatment with statins is paralleled by a&#xD;
      concomitant attenuation of post-procedural increase of intercellular cell adhesion molecule-1&#xD;
      (ICAM-1) and E-selectin plasma levels, thus reinforcing the concept that a reduction of&#xD;
      endothelial inflammatory response may explain peri-procedural protective effect of statins.&#xD;
&#xD;
      Statins induce heme oxygenase-1 (HO-1) expression in vitro and are reported to have&#xD;
      pleiotropic benefits that reduce oxidative stress in the vasculature and in various&#xD;
      extravascular tissues Two anti-inflammatory cytokines, interleukin-10 (IL-10) and&#xD;
      transforming growth factor-beta, play a critical role in the modulation of immunoinflammatory&#xD;
      cell infiltration in the atherosclerotic intima and the mechanism underlying the protective&#xD;
      effects of IL-10 against inflammatory cell infiltration involves heme oxygenase-1 (HO-1).&#xD;
      Moreover, statins can efficiently increase levels of endothelial progenitor cells (EPCs),&#xD;
      contributing to vascular repair, in patients with coronary heart disease and in patients with&#xD;
      chronic heart failure, and augment EPC proliferative capacity, in a way similar to vascular&#xD;
      endothelial growth factor (VEGF).&#xD;
&#xD;
      Therefore, this study is directed at:&#xD;
&#xD;
        1. documenting whether the immediate pre-procedural administration of a statin at a high&#xD;
           dosage may reduce the extent of peri-procedural MI compared with placebo on the&#xD;
           background of the best current medical therapy;&#xD;
&#xD;
        2. proving that treatment with rosuvastatin, a hydrophilic statin, at the proposed dosage,&#xD;
           is at least comparable (and possibly superior) to atorvastatin at the proposed dosage on&#xD;
           top of standard treatment in inducing a significant reduction of peri-procedural damage&#xD;
           previously documented with atorvastatin in the presence of a 1-week pre-treatment at 40&#xD;
           mg/day (12);&#xD;
&#xD;
        3. characterizing the relevance of HMG-CoA reductase inhibition (vs largely HMGCoA&#xD;
           reductase-independent cholesterol lowering) in this phenomenon;&#xD;
&#xD;
        4. providing a mechanistic explanation for such effects, investigating the role of 1) HO-1&#xD;
           and 2) EPCs in the context of peri-PCI myocardial damage.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    difficult recruitment&#xD;
  </why_stopped>
  <start_date>May 2010</start_date>
  <completion_date type="Actual">June 2012</completion_date>
  <primary_completion_date type="Actual">March 2012</primary_completion_date>
  <phase>Phase 3</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>myocardial injury</measure>
    <time_frame>up to 48 hours</time_frame>
    <description>The proportion of patients with a post-procedural increase of any measured marker of myocardial injury (CK-MB, troponin I or troponin T) above upper normal limits, measured at any of the post-PCI determinations at up to 48 hours</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Major adverse cardiac events</measure>
    <time_frame>1 month</time_frame>
    <description>The combined occurrence of major adverse cardiac events (MACE), including death, myocardial infarction, stroke or the need for unplanned revascularization from the time of the procedure until the end of a 1-month follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum creatinine</measure>
    <time_frame>6, 24 and 48 h</time_frame>
    <description>Any post-procedural increase in serum creatinine or decrease in creatinine clearance (Cockcroft-Gault formula)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HO-1</measure>
    <time_frame>6, 24 and 48 h</time_frame>
    <description>Changes in HO-1 levels/biologic activity among treated groups(only for sites participating in the specific substudies)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>endothelial progenitor cells (EPCs)</measure>
    <time_frame>6, 24 and 48 h</time_frame>
    <description>Changes in EPC levels/biologic activity among treated groups (only for sites participating in the specific substudies)</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">280</enrollment>
  <condition>Stable Coronary Artery Disease Undergoing PCI</condition>
  <arm_group>
    <arm_group_label>twice placebo before PCI</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>atorvastatin 80 + 40 mg pre PCI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>rosuvastatin 40 + 40 mg before PCI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>rosuvastatin 5 + ezetimibe 10 mg twice before PCI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atorvastatin</intervention_name>
    <description>80 + 40 mg pre PCI</description>
    <arm_group_label>atorvastatin 80 + 40 mg pre PCI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rosuvastatin</intervention_name>
    <description>40 + 40 mg before PCI</description>
    <arm_group_label>rosuvastatin 40 + 40 mg before PCI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rosuvastatin</intervention_name>
    <description>5 mg twice before PCI (+ 10 mg ezetimibe)</description>
    <arm_group_label>rosuvastatin 5 + ezetimibe 10 mg twice before PCI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ezetimibe</intervention_name>
    <description>10 mg twice before PCI (+ 5 mg rosuvastatin)</description>
    <arm_group_label>rosuvastatin 5 + ezetimibe 10 mg twice before PCI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>twice before PCI</description>
    <arm_group_label>twice placebo before PCI</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        - suspected CAD for which an indication to PCI is given: both patients with stable CAD, and&#xD;
        stable post-acute coronary syndromes (ACS), both with ST-segment elevation (STEMI) and&#xD;
        without ST-segment elevation (NSTE-ACS) patients, provided that markers of myocardial&#xD;
        necrosis (CK-MB, troponins) are stabilized (i.e., with variations &lt;20% in two consecutive&#xD;
        measurements obtained at ≥6 h time distance before PCI, according to the universal&#xD;
        definition of peri-procedural myocardial infarction).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  any previously known increase in liver enzymes (AST, ALT) ascribed to liver&#xD;
             dysfunction at baseline;&#xD;
&#xD;
          -  history of liver toxicity or myopathy on previous treatment with statins;&#xD;
&#xD;
          -  left ventricular ejection fraction &lt;30%;&#xD;
&#xD;
          -  renal insufficiency, with creatinine &gt;2 mg/dL at baseline;&#xD;
&#xD;
          -  ongoing treatment with high-dose statins (atorvastatin 80 mg/d or rosuvastatin 40&#xD;
             mg/d);&#xD;
&#xD;
          -  pregnant or lactating women.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Raffaele De Caterina, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Università G. d'Annunzio</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>SS. Annunziata Hospital</name>
      <address>
        <city>Chieti</city>
        <state>CH</state>
        <zip>66100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fondazione IRCCS Policlinico S. Matteo</name>
      <address>
        <city>Pavia</city>
        <state>PV</state>
        <zip>27100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>A.O. S. Anna e S. Sebastiano - II Università di Napoli</name>
      <address>
        <city>Caserta</city>
        <zip>81100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda ASL 6 - P. Ospedaliero Livorno</name>
      <address>
        <city>Livorno</city>
        <zip>57100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Civile G. Fornaroli</name>
      <address>
        <city>Magenta</city>
        <zip>20013</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera - Ospedale San Paolo</name>
      <address>
        <city>Milano</city>
        <zip>20142</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>February 2011</verification_date>
  <study_first_submitted>July 30, 2014</study_first_submitted>
  <study_first_submitted_qc>July 30, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 31, 2014</study_first_posted>
  <last_update_submitted>July 30, 2014</last_update_submitted>
  <last_update_submitted_qc>July 30, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 31, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>G. d'Annunzio University</investigator_affiliation>
    <investigator_full_name>Raffaele De Caterina</investigator_full_name>
    <investigator_title>Professor, Director - Institute of Cardiology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atorvastatin</mesh_term>
    <mesh_term>Rosuvastatin Calcium</mesh_term>
    <mesh_term>Ezetimibe</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/NCT02205775
org study id: 2009-013622-17
nct id: NCT02205775
lead sponsor: 
collaborator: 
has dmc: Yes
Myocardial necrosis is relatively frequent after percutaneous coronary intervention and is
      associated with higher mortality during the follow-up.

      Since anti-inflammatory properties of statins have been demonstrated and the benefit of
      statins in acute coronary syndromes have been proven, this study aims at testing the
      hypothesis that the pre-procedural intensive statin treatment reduce the extent of
      peri-procedural necrosis.
Myocardial necrosis, assessed by creatine kinase-MB (CK-MB) elevation, is relatively frequent
      after percutaneous coronary intervention (PCI), occurring in up to 40% of cases. Although
      most patients remain asymptomatic and with no changes in cardiac function, even a mild
      release of CK-MB is associated with higher mortality during the follow-up. A number of
      treatment strategies have been proposed to limit myocardial damage during PCI, but procedural
      ischemic myocardial injury remains the most frequent complication after coronary angioplasty.

      Several randomized studies have demonstrated the beneficial effects of therapy with HMG-CoA
      reductase inhibitors (statins) in patients with already established coronary artery disease
      or in normal subjects with hypercholesterolemia in primary prevention, and retrospective
      observational studies have suggested that pre-treatment with statins might reduce the
      incidence of myocardial infarction after coronary intervention. This benefit was confirmed in
      patients with non-ST segment elevation acute coronary syndromes (NSTE-ACS) undergoing PCI,
      who received 80 mg atorvastatin 12 h before PCI, with a further 40-mg pre-procedure, as
      compared with placebo.

      The mechanisms underlying the beneficial effects of statins in ischemic conditions are not
      completely clear. Previous studies have suggested that the anti-inflammatory effect of
      statins may play a role, showing that the benefit was higher in patients with high C-reactive
      protein. Since an inflammatory status before angioplasty, as detected by high levels of
      C-reactive protein, is associated with a higher risk of peri-procedural myocardial necrosis
      and adverse cardiac events during the follow-up, the anti-inflammatory effects of statins
      might contribute to reduce myocardial necrosis, by reducing to the microembolization
      occurring during coronary intervention. Statin administration also rapidly improves
      endothelial function. Thus, even short-term treatment with statins (unable to provide LDL
      reduction persistent enough to decrease the atherosclerotic burden) may have important
      effects on endothelial function and inflammation. In patients undergoing PCI, reduction of
      peri-procedural myocardial injury after pre-treatment with statins is paralleled by a
      concomitant attenuation of post-procedural increase of intercellular cell adhesion molecule-1
      (ICAM-1) and E-selectin plasma levels, thus reinforcing the concept that a reduction of
      endothelial inflammatory response may explain peri-procedural protective effect of statins.

      Statins induce heme oxygenase-1 (HO-1) expression in vitro and are reported to have
      pleiotropic benefits that reduce oxidative stress in the vasculature and in various
      extravascular tissues Two anti-inflammatory cytokines, interleukin-10 (IL-10) and
      transforming growth factor-beta, play a critical role in the modulation of immunoinflammatory
      cell infiltration in the atherosclerotic intima and the mechanism underlying the protective
      effects of IL-10 against inflammatory cell infiltration involves heme oxygenase-1 (HO-1).
      Moreover, statins can efficiently increase levels of endothelial progenitor cells (EPCs),
      contributing to vascular repair, in patients with coronary heart disease and in patients with
      chronic heart failure, and augment EPC proliferative capacity, in a way similar to vascular
      endothelial growth factor (VEGF).

      Therefore, this study is directed at:

        1. documenting whether the immediate pre-procedural administration of a statin at a high
           dosage may reduce the extent of peri-procedural MI compared with placebo on the
           background of the best current medical therapy;

        2. proving that treatment with rosuvastatin, a hydrophilic statin, at the proposed dosage,
           is at least comparable (and possibly superior) to atorvastatin at the proposed dosage on
           top of standard treatment in inducing a significant reduction of peri-procedural damage
           previously documented with atorvastatin in the presence of a 1-week pre-treatment at 40
           mg/day (12);

        3. characterizing the relevance of HMG-CoA reductase inhibition (vs largely HMGCoA
           reductase-independent cholesterol lowering) in this phenomenon;

        4. providing a mechanistic explanation for such effects, investigating the role of 1) HO-1
           and 2) EPCs in the context of peri-PCI myocardial damage.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: myocardial injury
time frame: up to 48 hours
description: The proportion of patients with a post-procedural increase of any measured marker of myocardial injury (CK-MB, troponin I or troponin T) above upper normal limits, measured at any of the post-PCI determinations at up to 48 hours
measure: Major adverse cardiac events
time frame: 1 month
description: The combined occurrence of major adverse cardiac events (MACE), including death, myocardial infarction, stroke or the need for unplanned revascularization from the time of the procedure until the end of a 1-month follow-up.
measure: Serum creatinine
time frame: 6, 24 and 48 h
description: Any post-procedural increase in serum creatinine or decrease in creatinine clearance (Cockcroft-Gault formula)
measure: HO-1
time frame: 6, 24 and 48 h
description: Changes in HO-1 levels/biologic activity among treated groups(only for sites participating in the specific substudies)
measure: endothelial progenitor cells (EPCs)
time frame: 6, 24 and 48 h
description: Changes in EPC levels/biologic activity among treated groups (only for sites participating in the specific substudies)
arm group label: twice placebo before PCI
arm group type: Placebo Comparator
arm group label: atorvastatin 80 + 40 mg pre PCI
arm group type: Experimental
arm group label: rosuvastatin 40 + 40 mg before PCI
arm group type: Experimental
arm group label: rosuvastatin 5 + ezetimibe 10 mg twice before PCI
arm group type: Experimental
intervention type: Drug
intervention name: Atorvastatin
description: 80 + 40 mg pre PCI
arm group label: atorvastatin 80 + 40 mg pre PCI
intervention type: Drug
intervention name: Rosuvastatin
description: 40 + 40 mg before PCI
arm group label: rosuvastatin 40 + 40 mg before PCI
intervention type: Drug
intervention name: Rosuvastatin
description: 5 mg twice before PCI (+ 10 mg ezetimibe)
arm group label: rosuvastatin 5 + ezetimibe 10 mg twice before PCI
intervention type: Drug
intervention name: Ezetimibe
description: 10 mg twice before PCI (+ 5 mg rosuvastatin)
arm group label: rosuvastatin 5 + ezetimibe 10 mg twice before PCI
intervention type: Drug
intervention name: placebo
description: twice before PCI
arm group label: twice placebo before PCI
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Raffaele De Caterina, Prof
role: Principal Investigator
affiliation: Università G. d'Annunzio
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: G. d'Annunzio University
investigator full name: Raffaele De Caterina
investigator title: Professor, Director - Institute of Cardiology
mesh term: Coronary Artery Disease
mesh term: Inflammation
mesh term: Atorvastatin
mesh term: Rosuvastatin Calcium
mesh term: Ezetimibe