<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/NCT04489446</url>
  </required_header>
  <id_info>
    <org_study_id>UNAB-003</org_study_id>
    <nct_id>NCT04489446</nct_id>
  </id_info>
  <brief_title>Sildenafil in COVID-19</brief_title>
  <official_title>Sildenafil for Treating Patients With COVID-19 and Perfusion Mismatch: A Pilot Randomised Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universidad Nacional Andres Bello</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hospital Naval Almirante Nef, Viña del Mar, Chile</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Universidad Nacional Andres Bello</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This randomised trial aims to assess the role of sildenafil in improving oxygenation amongst&#xD;
      hospitalised patients with COVID19.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Perfusion anomalies, namely hypoperfusion of healthy lung and vasoplegia with hyperperfusion&#xD;
      of diseased lung areas, have been recently described amongst patients with COVID19. In this&#xD;
      triple-blind pilot randomised trial, adult patients with high clinical suspicion of SARS-CoV2&#xD;
      infection and perfusion defects in a substraction computed tomography angiography will be&#xD;
      randomised in a 1:1 ratio to receive sildenafil or placebo. Informed consent will be obtained&#xD;
      from every included participant. Patients requiring mechanical ventilation at baseline will&#xD;
      be excluded, as will those who present a contraindication to sildenafil, previous users of&#xD;
      sildenafil, those requiring therapy with nitrates, patients in which an order to limit&#xD;
      therapeutic efforts has been issued, pregnant or breastfeeding women and those who decline to&#xD;
      participate in this study. The primary outcome for this trial wil be oxygenation changes in&#xD;
      blood gas analyses. Secondary outcomes will include clinical deterioration requiring&#xD;
      admission to an intensive care unit, requirement of high-flow nasal cannula or invasive&#xD;
      mechanical ventilation and overall survival. Patients will be followed-up until hospital&#xD;
      discharge or up to fifteen days after randomisation. Statistical analyses will be undertaken&#xD;
      by a statistician unaware of treatment allocation under the intention-to-treat principle.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 19, 2020</start_date>
  <completion_date type="Actual">June 30, 2021</completion_date>
  <primary_completion_date type="Actual">April 30, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</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>
    <intervention_model_description>Eligible participants will be randomised to either sildenafil or placebo for up to seven days.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Arterial Oxygenation</measure>
    <time_frame>One hour after sildenafil administration</time_frame>
    <description>Mean difference in alveolar oxygen pressure to inspired oxygen fraction (Pa/Fi) ratios.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Arterial Oxygenation</measure>
    <time_frame>Daily until the end of follow-up (up to 15 days after randomisation)</time_frame>
    <description>Mean difference in alveolar oxygen pressure to inspired oxygen fraction (Pa/Fi) ratios.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Alveolo-arterial gradient</measure>
    <time_frame>One hour after sildenafil administration</time_frame>
    <description>Mean difference in the alveolo-arterial gradient between study groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Alveolo-arterial gradient</measure>
    <time_frame>Daily until the end of follow-up (up to 15 days after randomisation)</time_frame>
    <description>Mean difference in the alveolo-arterial gradient between study groups.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Intensive care unit admission</measure>
    <time_frame>Up to two weeks after randomisation</time_frame>
    <description>Proportion of patients requiring admission to an intensive care unit in each study group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Noninvasive Mechanical Ventilation or Requirement of High-Flow Nasal Cannula</measure>
    <time_frame>Up to two weeks after randomisation</time_frame>
    <description>Proportion of patients requiring noninvasive mechanical ventilation o high-flow nasal cannula unit in each study group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Invasive mechanical ventilation</measure>
    <time_frame>Up to two weeks after randomisation</time_frame>
    <description>Proportion of patients requiring invasive mechanical ventilation in each study group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival</measure>
    <time_frame>Up to two weeks after randomisation</time_frame>
    <description>Proportion of patients that survived COVID19 in each study group</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Adverse events</measure>
    <time_frame>Up to two weeks after randomisation</time_frame>
    <description>Adverse events attributable to sildenafil use.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Covid19</condition>
  <condition>SARS-COV2 Infection</condition>
  <arm_group>
    <arm_group_label>Sildenafil</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients allocated to this arm will receive Sildenafil 25mg every 8 hours orally for up to seven consecutive days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients allocated to this arm will receive a placebo that will be similar in form to sildenafil pills in the interventional arm. These doses will be scheduled every 8 hours and wil be administered orally por up to seven consecutive days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sildenafil</intervention_name>
    <description>Patients allocated to this arm will receive Sildenafil 25mg every 8 hours orally for up to seven consecutive days.</description>
    <arm_group_label>Sildenafil</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Patients allocated to this arm will receive a matching placebo similar to Sildenafil pills used in the intervention arm. Placebos will be delivered orally every 8 hours for up to seven consecutive days.</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult participant with high clinical suspicion of a SARS-CoV2 infection.&#xD;
&#xD;
          -  Hypoperfusion of healthy lung areas in a substraction computed tomography angiography&#xD;
             within 24 hours of admission to the hospital.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Requirement of therapy with nitrates of nitrites&#xD;
&#xD;
          -  Arterial hypotension at presentation&#xD;
&#xD;
          -  Recent diagnosis of coronary artery disease (&lt;6 months)&#xD;
&#xD;
          -  Acute heart failure at presentation&#xD;
&#xD;
          -  Recent stroke (&lt; 6 months)&#xD;
&#xD;
          -  Chronic respiratory failure with CO2 retention&#xD;
&#xD;
          -  Known hypersensitivity to sildenafil&#xD;
&#xD;
          -  Advanced liver disease (Child-Pugh class B or higher)&#xD;
&#xD;
          -  Users of cytochrome P450 3A4 inhibitors (Erythromycin, Ketoconazole, Itraconazole,&#xD;
             Saquinavir)&#xD;
&#xD;
          -  Pulmonary hypertension&#xD;
&#xD;
          -  Chronic users of phosphodiesterase 5 inhibitors&#xD;
&#xD;
          -  Requirement of invasive mechanical ventilation at baseline&#xD;
&#xD;
          -  Decision to limit therapeutic efforts at baseline&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  History of retinitis pigmentosa&#xD;
&#xD;
          -  Known obstruction to left-ventricular outflow tract&#xD;
&#xD;
          -  Unwillingness to participate in the trial&#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>Mario Santamarina, MD</last_name>
    <role>Study Director</role>
    <affiliation>Hospital Naval Almirante Nef</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Felipe Martinez, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universidad Andres Bello</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Naval Almirante Nef</name>
      <address>
        <city>Viña Del Mar</city>
        <state>Valparaiso</state>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Chile</country>
  </location_countries>
  <link>
    <url>https://coronavirus.jhu.edu/map.html</url>
    <description>COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU)</description>
  </link>
  <reference>
    <citation>Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. Erratum In: Lancet. 2020 Mar 28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038.</citation>
    <PMID>32171076</PMID>
  </reference>
  <reference>
    <citation>Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med. 2020 Jun 25;58(7):1131-1134. doi: 10.1515/cclm-2020-0198. No abstract available.</citation>
    <PMID>32119647</PMID>
  </reference>
  <reference>
    <citation>Santamarina MG, Boisier D, Contreras R, Baque M, Volpacchio M, Beddings I. COVID-19: a hypothesis regarding the ventilation-perfusion mismatch. Crit Care. 2020 Jul 6;24(1):395. doi: 10.1186/s13054-020-03125-9. No abstract available.</citation>
    <PMID>32631389</PMID>
  </reference>
  <reference>
    <citation>Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, Raizada MK, Grant MB, Oudit GY. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ Res. 2020 May 8;126(10):1456-1474. doi: 10.1161/CIRCRESAHA.120.317015. Epub 2020 Apr 8.</citation>
    <PMID>32264791</PMID>
  </reference>
  <reference>
    <citation>Wu Z, Hu R, Zhang C, Ren W, Yu A, Zhou X. Elevation of plasma angiotensin II level is a potential pathogenesis for the critically ill COVID-19 patients. Crit Care. 2020 Jun 5;24(1):290. doi: 10.1186/s13054-020-03015-0. No abstract available.</citation>
    <PMID>32503680</PMID>
  </reference>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>July 25, 2020</study_first_submitted>
  <study_first_submitted_qc>July 25, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 28, 2020</study_first_posted>
  <last_update_submitted>September 27, 2021</last_update_submitted>
  <last_update_submitted_qc>September 27, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 29, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Universidad Nacional Andres Bello</investigator_affiliation>
    <investigator_full_name>Felipe Martinez Lomakin</investigator_full_name>
    <investigator_title>Investigator</investigator_title>
  </responsible_party>
  <keyword>COVID19</keyword>
  <keyword>SARS-COV2 Infection</keyword>
  <keyword>Sildenafil</keyword>
  <keyword>Phosphodiesterase 5 inhibitors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sildenafil Citrate</mesh_term>
  </intervention_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/NCT04489446
org study id: UNAB-003
nct id: NCT04489446
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
This randomised trial aims to assess the role of sildenafil in improving oxygenation amongst
      hospitalised patients with COVID19.
Perfusion anomalies, namely hypoperfusion of healthy lung and vasoplegia with hyperperfusion
      of diseased lung areas, have been recently described amongst patients with COVID19. In this
      triple-blind pilot randomised trial, adult patients with high clinical suspicion of SARS-CoV2
      infection and perfusion defects in a substraction computed tomography angiography will be
      randomised in a 1:1 ratio to receive sildenafil or placebo. Informed consent will be obtained
      from every included participant. Patients requiring mechanical ventilation at baseline will
      be excluded, as will those who present a contraindication to sildenafil, previous users of
      sildenafil, those requiring therapy with nitrates, patients in which an order to limit
      therapeutic efforts has been issued, pregnant or breastfeeding women and those who decline to
      participate in this study. The primary outcome for this trial wil be oxygenation changes in
      blood gas analyses. Secondary outcomes will include clinical deterioration requiring
      admission to an intensive care unit, requirement of high-flow nasal cannula or invasive
      mechanical ventilation and overall survival. Patients will be followed-up until hospital
      discharge or up to fifteen days after randomisation. Statistical analyses will be undertaken
      by a statistician unaware of treatment allocation under the intention-to-treat principle.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Eligible participants will be randomised to either sildenafil or placebo for up to seven days.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Arterial Oxygenation
time frame: One hour after sildenafil administration
description: Mean difference in alveolar oxygen pressure to inspired oxygen fraction (Pa/Fi) ratios.
measure: Arterial Oxygenation
time frame: Daily until the end of follow-up (up to 15 days after randomisation)
description: Mean difference in alveolar oxygen pressure to inspired oxygen fraction (Pa/Fi) ratios.
measure: Alveolo-arterial gradient
time frame: One hour after sildenafil administration
description: Mean difference in the alveolo-arterial gradient between study groups.
measure: Alveolo-arterial gradient
time frame: Daily until the end of follow-up (up to 15 days after randomisation)
description: Mean difference in the alveolo-arterial gradient between study groups.
measure: Intensive care unit admission
time frame: Up to two weeks after randomisation
description: Proportion of patients requiring admission to an intensive care unit in each study group
measure: Noninvasive Mechanical Ventilation or Requirement of High-Flow Nasal Cannula
time frame: Up to two weeks after randomisation
description: Proportion of patients requiring noninvasive mechanical ventilation o high-flow nasal cannula unit in each study group
measure: Invasive mechanical ventilation
time frame: Up to two weeks after randomisation
description: Proportion of patients requiring invasive mechanical ventilation in each study group
measure: Survival
time frame: Up to two weeks after randomisation
description: Proportion of patients that survived COVID19 in each study group
measure: Adverse events
time frame: Up to two weeks after randomisation
description: Adverse events attributable to sildenafil use.
arm group label: Sildenafil
arm group type: Experimental
description: Patients allocated to this arm will receive Sildenafil 25mg every 8 hours orally for up to seven consecutive days.
arm group label: Control
arm group type: Placebo Comparator
description: Patients allocated to this arm will receive a placebo that will be similar in form to sildenafil pills in the interventional arm. These doses will be scheduled every 8 hours and wil be administered orally por up to seven consecutive days.
intervention type: Drug
intervention name: Sildenafil
description: Patients allocated to this arm will receive Sildenafil 25mg every 8 hours orally for up to seven consecutive days.
arm group label: Sildenafil
intervention type: Drug
intervention name: Placebo
description: Patients allocated to this arm will receive a matching placebo similar to Sildenafil pills used in the intervention arm. Placebos will be delivered orally every 8 hours for up to seven consecutive days.
arm group label: Control
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mario Santamarina, MD
role: Study Director
affiliation: Hospital Naval Almirante Nef
last name: Felipe Martinez, MD, MSc
role: Principal Investigator
affiliation: Universidad Andres Bello
facility: 
country: Chile
url: https://coronavirus.jhu.edu/map.html
description: COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU)
citation: Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. Erratum In: Lancet. 2020 Mar 28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038.
PMID: 32171076
citation: Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med. 2020 Jun 25;58(7):1131-1134. doi: 10.1515/cclm-2020-0198. No abstract available.
PMID: 32119647
citation: Santamarina MG, Boisier D, Contreras R, Baque M, Volpacchio M, Beddings I. COVID-19: a hypothesis regarding the ventilation-perfusion mismatch. Crit Care. 2020 Jul 6;24(1):395. doi: 10.1186/s13054-020-03125-9. No abstract available.
PMID: 32631389
citation: Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, Raizada MK, Grant MB, Oudit GY. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ Res. 2020 May 8;126(10):1456-1474. doi: 10.1161/CIRCRESAHA.120.317015. Epub 2020 Apr 8.
PMID: 32264791
citation: Wu Z, Hu R, Zhang C, Ren W, Yu A, Zhou X. Elevation of plasma angiotensin II level is a potential pathogenesis for the critically ill COVID-19 patients. Crit Care. 2020 Jun 5;24(1):290. doi: 10.1186/s13054-020-03015-0. No abstract available.
PMID: 32503680
responsible party type: Principal Investigator
investigator affiliation: Universidad Nacional Andres Bello
investigator full name: Felipe Martinez Lomakin
investigator title: Investigator
mesh term: COVID-19
mesh term: Sildenafil Citrate
sharing ipd: Undecided