<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/NCT04407273</url>
  </required_header>
  <id_info>
    <org_study_id>106/2020</org_study_id>
    <nct_id>NCT04407273</nct_id>
  </id_info>
  <brief_title>Statin Therapy and COVID-19 Infection</brief_title>
  <acronym>STACOV</acronym>
  <official_title>Statin Therapy and COVID-19 Infection (STACOV PROJECT)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut Investigacio Sanitaria Pere Virgili</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institut Investigacio Sanitaria Pere Virgili</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Considering that simvastatin, and probably statins in general, interfere with SARS-cov-2&#xD;
      cellular uptake and some inflammatory pathways activated by the virus, those patients on&#xD;
      statin therapy should be less vulnerable to infection and their clinical course and prognosis&#xD;
      should be better than that in individuals not on statin therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Statins reduce intracellular cholesterol synthesis by interfering with the limiting enzyme&#xD;
      HMGCoA reductase. A lower intracellular cholesterol concentration leads to activation of the&#xD;
      transcription factor SREBP 2 upregulating LDL receptor synthesis. In general, intracellular&#xD;
      cholesterol homeostasis achieves a new physiological equilibrium at lower cholesterol&#xD;
      concentrations. Moreover, the effect of cholesterol pathway inhibition has also an effect on&#xD;
      farnesyl and geranyl molecules formation influencing protein prenylation leading to changes&#xD;
      on inflammation and immunomodulation in vitro.&#xD;
&#xD;
      Changes in intracellular cholesterol alter cell membrane composition, particularly the&#xD;
      structures referred to cholesterol rafts that accommodate a huge number of cell surface&#xD;
      proteins as receptors. Theoretically, alterations in cholesterol rafts could derange the&#xD;
      function of some receptors Some preliminary studies on cell models have suggested that&#xD;
      statins could interfere the activity of some membrane viral receptors blunting its entry to&#xD;
      cell (Berraondo P et al CIMA nonpublished data). SARS-cov-2 goes into cells through the&#xD;
      Angiotensin Converser Enzyme 2 (ACE2) which is located in the surface of several cells&#xD;
      including lung cells. It has been suggested that simvastatin could have a role in SARS-cov-2&#xD;
      infection by blocking the virus entry to cell. However, atorvastatin has been shown to&#xD;
      increase ACE2 expression in animal models. Moreover, intracellular cholesterol content seems&#xD;
      to influence the virus uptake.&#xD;
&#xD;
      Severe SARS-cov-2 infection is mediated by an inflammatory storm resulting in a deep tissue&#xD;
      injury, endothelial damage, prothrombotic state and multiorgan failure. As mentioned above,&#xD;
      statins also have some potent anti-inflammatory effects as modulating TNF, the NFkB&#xD;
      transcription factor or blocking some members of the Tool Like Receptor family as TLR4-9 and&#xD;
      its downstream cofactor MYD88. This anti-inflammatory effect has been implicated in a better&#xD;
      prognosis of some diseases as HBV or HCV chronic infection, limiting the progression of&#xD;
      hepatic damage to chronic liver disease or hepatocarcinoma. The impact of statin use on&#xD;
      influenza epidemics has been repetitively assessed but contradictory or non-conclusive&#xD;
      results have been obtained. The combination of statins and angiotensin receptor blockers have&#xD;
      shown an important protective effect on other epidemics as Ebola, probably to their action on&#xD;
      endothelium protection. A protective effect of statins on pulmonary hypertension development&#xD;
      in a primate HIV model has also been reported. Although, in general all these pleiotropic&#xD;
      effects of statins have been shown in vitro and its clinical impact is not clear, a clinical&#xD;
      assay to test the efficacy of simvastatin on SARS-cov-2 is going on. Recently an&#xD;
      observational study including more than 8000 patients infected by Sars-Cov-2 showed the&#xD;
      protective effect of being on statins or ACE inhibitors. Taken into account its widespread&#xD;
      use and putative effects on viral entry, inflammation, immune mechanisms and endothelial&#xD;
      function, the use of standard therapies as statins have been postulated to target the host&#xD;
      response to new virus pandemics.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 14, 2020</start_date>
  <completion_date type="Actual">December 30, 2020</completion_date>
  <primary_completion_date type="Actual">August 20, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>SARS-cov-2 scale of severity (9 steps) in Covid-19 infected patients with statin therapy</measure>
    <time_frame>at the time of admission</time_frame>
    <description>Assess the difference in the WHO SARS-cov-2 scale of severity (9 steps) achieved by Covid-19 infected patients, admitted in the hospital, with and without background statin therapy comparable in age and gender distribution</description>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">2159</enrollment>
  <condition>COVID</condition>
  <condition>Statin</condition>
  <condition>Cardiovascular Diseases</condition>
  <arm_group>
    <arm_group_label>with statins</arm_group_label>
    <description>Covid-19 infected patients with statins</description>
  </arm_group>
  <arm_group>
    <arm_group_label>without statins</arm_group_label>
    <description>Covid-19 infected patients without statins</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>observational</intervention_name>
    <description>observational study</description>
    <arm_group_label>with statins</arm_group_label>
    <arm_group_label>without statins</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        This is a retrospective observational multicentre study based on clinical records review.&#xD;
&#xD;
        The following centres will take part in the study:&#xD;
&#xD;
        LIPIDCAS Group:&#xD;
&#xD;
          -  Hospital Universitari Sant Joan&#xD;
&#xD;
          -  Hospital Universitari Joan XXIII&#xD;
&#xD;
          -  Hospital Sant Pau i Santa Tecla&#xD;
&#xD;
          -  Hospital Verge de la Cinta&#xD;
&#xD;
          -  Pius Hospital de Valls&#xD;
&#xD;
          -  Hospital del Vendrell&#xD;
&#xD;
        Other centres from the LIPID AND ARTERIOSCLEROSIS UNITS NET (XULA) from Catalonia.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients ≥ 18 years old with a PCR or immunological confirmation of Covid-19&#xD;
             infection, admitted in the hospital for at least 24 hours, will be included.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients &lt; 18 years old.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
  </eligibility>
  <overall_official>
    <last_name>Lluís Masana, Dr</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut Investigacio Sanitaria Pere Virgili</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Facultat de Medicina i Ciències de la Salut de Reus</name>
      <address>
        <city>Reus</city>
        <state>Tarragona</state>
        <zip>43201</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <results_reference>
    <citation>Masana L, Correig E, Rodriguez-Borjabad C, Anoro E, Arroyo JA, Jerico C, Pedragosa A, Miret M, Naf S, Pardo A, Perea V, Perez-Bernalte R, Plana N, Ramirez-Montesinos R, Royuela M, Soler C, Urquizu-Padilla M, Zamora A, Pedro-Botet J. Effect of statin therapy on SARS-CoV-2 infection-related mortality in hospitalized patients. Eur Heart J Cardiovasc Pharmacother. 2022 Feb 16;8(2):157-164. doi: 10.1093/ehjcvp/pvaa128.</citation>
    <PMID>33135047</PMID>
  </results_reference>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>May 27, 2020</study_first_submitted>
  <study_first_submitted_qc>May 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 29, 2020</study_first_posted>
  <last_update_submitted>March 9, 2021</last_update_submitted>
  <last_update_submitted_qc>March 9, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 11, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Institut Investigacio Sanitaria Pere Virgili</investigator_affiliation>
    <investigator_full_name>LUIS MASANA, MD</investigator_full_name>
    <investigator_title>Dr</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiovascular Diseases</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <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>May 14, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/73/NCT04407273/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT04407273
org study id: 106/2020
nct id: NCT04407273
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Considering that simvastatin, and probably statins in general, interfere with SARS-cov-2
      cellular uptake and some inflammatory pathways activated by the virus, those patients on
      statin therapy should be less vulnerable to infection and their clinical course and prognosis
      should be better than that in individuals not on statin therapy.
Statins reduce intracellular cholesterol synthesis by interfering with the limiting enzyme
      HMGCoA reductase. A lower intracellular cholesterol concentration leads to activation of the
      transcription factor SREBP 2 upregulating LDL receptor synthesis. In general, intracellular
      cholesterol homeostasis achieves a new physiological equilibrium at lower cholesterol
      concentrations. Moreover, the effect of cholesterol pathway inhibition has also an effect on
      farnesyl and geranyl molecules formation influencing protein prenylation leading to changes
      on inflammation and immunomodulation in vitro.

      Changes in intracellular cholesterol alter cell membrane composition, particularly the
      structures referred to cholesterol rafts that accommodate a huge number of cell surface
      proteins as receptors. Theoretically, alterations in cholesterol rafts could derange the
      function of some receptors Some preliminary studies on cell models have suggested that
      statins could interfere the activity of some membrane viral receptors blunting its entry to
      cell (Berraondo P et al CIMA nonpublished data). SARS-cov-2 goes into cells through the
      Angiotensin Converser Enzyme 2 (ACE2) which is located in the surface of several cells
      including lung cells. It has been suggested that simvastatin could have a role in SARS-cov-2
      infection by blocking the virus entry to cell. However, atorvastatin has been shown to
      increase ACE2 expression in animal models. Moreover, intracellular cholesterol content seems
      to influence the virus uptake.

      Severe SARS-cov-2 infection is mediated by an inflammatory storm resulting in a deep tissue
      injury, endothelial damage, prothrombotic state and multiorgan failure. As mentioned above,
      statins also have some potent anti-inflammatory effects as modulating TNF, the NFkB
      transcription factor or blocking some members of the Tool Like Receptor family as TLR4-9 and
      its downstream cofactor MYD88. This anti-inflammatory effect has been implicated in a better
      prognosis of some diseases as HBV or HCV chronic infection, limiting the progression of
      hepatic damage to chronic liver disease or hepatocarcinoma. The impact of statin use on
      influenza epidemics has been repetitively assessed but contradictory or non-conclusive
      results have been obtained. The combination of statins and angiotensin receptor blockers have
      shown an important protective effect on other epidemics as Ebola, probably to their action on
      endothelium protection. A protective effect of statins on pulmonary hypertension development
      in a primate HIV model has also been reported. Although, in general all these pleiotropic
      effects of statins have been shown in vitro and its clinical impact is not clear, a clinical
      assay to test the efficacy of simvastatin on SARS-cov-2 is going on. Recently an
      observational study including more than 8000 patients infected by Sars-Cov-2 showed the
      protective effect of being on statins or ACE inhibitors. Taken into account its widespread
      use and putative effects on viral entry, inflammation, immune mechanisms and endothelial
      function, the use of standard therapies as statins have been postulated to target the host
      response to new virus pandemics.
observational model: Case-Only
time perspective: Prospective
measure: SARS-cov-2 scale of severity (9 steps) in Covid-19 infected patients with statin therapy
time frame: at the time of admission
description: Assess the difference in the WHO SARS-cov-2 scale of severity (9 steps) achieved by Covid-19 infected patients, admitted in the hospital, with and without background statin therapy comparable in age and gender distribution
arm group label: with statins
description: Covid-19 infected patients with statins
arm group label: without statins
description: Covid-19 infected patients without statins
intervention type: Drug
intervention name: observational
description: observational study
arm group label: with statins
arm group label: without statins
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
last name: Lluís Masana, Dr
role: Principal Investigator
affiliation: Institut Investigacio Sanitaria Pere Virgili
facility: 
country: Spain
citation: Masana L, Correig E, Rodriguez-Borjabad C, Anoro E, Arroyo JA, Jerico C, Pedragosa A, Miret M, Naf S, Pardo A, Perea V, Perez-Bernalte R, Plana N, Ramirez-Montesinos R, Royuela M, Soler C, Urquizu-Padilla M, Zamora A, Pedro-Botet J. Effect of statin therapy on SARS-CoV-2 infection-related mortality in hospitalized patients. Eur Heart J Cardiovasc Pharmacother. 2022 Feb 16;8(2):157-164. doi: 10.1093/ehjcvp/pvaa128.
PMID: 33135047
responsible party type: Principal Investigator
investigator affiliation: Institut Investigacio Sanitaria Pere Virgili
investigator full name: LUIS MASANA, MD
investigator title: Dr
mesh term: Cardiovascular Diseases
sharing ipd: No
provided document: 