<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/NCT04467931</url>
  </required_header>
  <id_info>
    <org_study_id>00132408</org_study_id>
    <nct_id>NCT04467931</nct_id>
  </id_info>
  <brief_title>ACEI or ARB and COVID-19 Severity and Mortality in US Veterans</brief_title>
  <official_title>Association Between Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use and COVID-19 Severity and Mortality Among US Veterans</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Utah</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>VA Salt Lake City Health Care System</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Wake Forest University Health Sciences</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Johns Hopkins Bloomberg School of Public Health</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Boston University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Northwestern University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Edith Nourse Rogers Memorial Veterans Hospital</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>Columbia University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>MedStar Georgetown University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Utah</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</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>
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for&#xD;
      COVID-19, enters type II pneumocytes using angiotensin-converting enzyme 2 (ACE2). It is&#xD;
      unclear whether ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) increase,&#xD;
      decrease, or have no significant effect on ACE2 expression or activity. Therefore, ACEI and&#xD;
      ARB may be harmful, beneficial, or have no impact on Coronavirus Disease 2019 severity and&#xD;
      mortality. The Specific Aims of this observational study are: (1) Among SARS-CoV-2-positive&#xD;
      outpatients, compare all-cause hospitalization and mortality rates between: 1.1 Current users&#xD;
      of a range of doses of ACEI/ARB- vs. non- ACEI/ARB-based regimens, and 1.2 Current users of a&#xD;
      range of doses of ACEI- vs. ARB-based regimens, and (2) Among those hospitalized for&#xD;
      COVID-19, compare all-cause mortality between: 2.1 Current users of a range of doses of&#xD;
      ACEI/ARB- vs. non- ACEI/ARB-based regimens, and 2.2 Current users of a range of doses of&#xD;
      ACEI- vs. ARB-based regimens.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The Coronavirus Disease 2019 (COVID-19) pandemic has killed &gt;129,000 Americans as of June 30,&#xD;
      2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for&#xD;
      COVID-19, enters type II pneumocytes using angiotensin-converting enzyme 2 (ACE2). ACE&#xD;
      inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase ACE2 expression.&#xD;
      Theoretically, if ACEI/ARB use increases ACE2 expression in the lungs, ACEI/ARBs could&#xD;
      promote SARS-CoV-2 entry into type II pneumocytes and worsen COVID-19 infection. In contrast,&#xD;
      other evidence suggests that ACEI/ARBs may mitigate virus-induced inflammatory responses in&#xD;
      the lungs by upregulating ACE2-mediated generation of the vasodilator and anti-inflammatory&#xD;
      protein angiotensin-(1-7), thereby preventing tissue damage. Few data exist on the direction&#xD;
      or magnitude of the association between ACEI/ARB use and COVID-19 severity, and whether these&#xD;
      associations differ between ACEIs and ARBs. Because ACEI/ARBs are among the most commonly&#xD;
      used prescription medications, it is critical to determine if ACEI/ARB users have a&#xD;
      differential risk of more severe COVID-19 infection compared to non-users. The objective of&#xD;
      this study is to reduce morbidity and mortality of the COVID-19 pandemic by generating timely&#xD;
      evidence on the direction and magnitude of the association between ACEI/ARB use and COVID-19&#xD;
      severity and mortality.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 19, 2020</start_date>
  <completion_date type="Actual">December 31, 2020</completion_date>
  <primary_completion_date type="Actual">October 21, 2020</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>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>All-Cause-Hospitalization or All-Cause Mortality</measure>
    <time_frame>Through study completion (October 21, 2020).</time_frame>
    <description>For outpatient Veterans with a positive SARS-CoV-2 test (Aims 1.1 and 1.2), the primary outcome is a composite of time to all-cause hospitalization or all-cause mortality.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>All-Cause Mortality</measure>
    <time_frame>Through study completion (October 21, 2020).</time_frame>
    <description>For Veterans hospitalized with COVID-19 (Aims 2.1 and 2.2), the primary outcome is time to all-cause mortality.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>ICU admission</measure>
    <time_frame>Through study completion (October 21, 2020).</time_frame>
    <description>For aims 1 and 2, a secondary outcome will be time to intensive care unit (ICU) admission.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanical ventilation</measure>
    <time_frame>Through study completion (October 21, 2020).</time_frame>
    <description>For aim 2, a secondary outcome will be time to mechanical ventilation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dialysis</measure>
    <time_frame>Through study completion (October 21, 2020).</time_frame>
    <description>For aim 2, a secondary outcome will be time to in-hospital dialysis.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Negative control outcomes (Gastrointestinal bleed or urinary tract infection)</measure>
    <time_frame>Through study completion (October 21, 2020).</time_frame>
    <description>Time to first occurrence of gastrointestinal bleed or urinary tract infection. This will be a negative control outcome.</description>
  </other_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Actual">22213</enrollment>
  <condition>Hypertension</condition>
  <condition>COVID</condition>
  <arm_group>
    <arm_group_label>1.1 Outpatient SARS-CoV-2 Positive, ACEI/ARB vs non-ACEI/ARB</arm_group_label>
    <description>Among Veterans with treated hypertension and without compelling indications who test positive for SARS-CoV-2, compare all-cause hospitalization and all-cause mortality rates between current users of a range of doses of ACEI/ARB- vs. non-ACEI/ARB-based regimens.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>1.2 Outpatient SARS-CoV-2 Positive, ACEI vs. ARB</arm_group_label>
    <description>Among Veterans with treated hypertension who test positive for SARS-CoV-2, compare all-cause hospitalization and all-cause mortality rates between current users of a range of doses of ACEI- vs. ARB-based regimens.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2.1 COVID-19 Hospitalized, ACEI/ARB vs non-ACEI/ARB</arm_group_label>
    <description>Among Veterans with treated hypertension and without compelling indications who are hospitalized for COVID-19, compare all-cause mortality rates between current users of a range of doses of ACEI/ARB- vs. non-ACEI/ARB-based regimens.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2.2 COVID-19 Hospitalized, ACEI vs. ARB</arm_group_label>
    <description>Among Veterans with treated hypertension who are hospitalized for COVID-19, compare all-cause mortality rates between current users of a range of doses of ACEI- vs. ARB-based regimens.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ACEI/ARB</intervention_name>
    <description>Veterans will be categorized as exposed to ACEI/ARB if they have one or more pharmacy fills for an oral ACEI or an ARB in the 90 days (± 14 days) prior to each Veteran's index date. Sacubitril/valsartan (Brand name: Entresto®) will be excluded from ARB exposures.</description>
    <arm_group_label>1.1 Outpatient SARS-CoV-2 Positive, ACEI/ARB vs non-ACEI/ARB</arm_group_label>
    <arm_group_label>2.1 COVID-19 Hospitalized, ACEI/ARB vs non-ACEI/ARB</arm_group_label>
    <other_name>benazepril</other_name>
    <other_name>captopril</other_name>
    <other_name>enalapril</other_name>
    <other_name>fosinopril</other_name>
    <other_name>lisinopril</other_name>
    <other_name>moexipril</other_name>
    <other_name>perindopril</other_name>
    <other_name>quinapril</other_name>
    <other_name>ramipril</other_name>
    <other_name>trandolapril</other_name>
    <other_name>azilsartan</other_name>
    <other_name>candesartan</other_name>
    <other_name>eprosartan</other_name>
    <other_name>irbesartan</other_name>
    <other_name>losartan</other_name>
    <other_name>olmesartan</other_name>
    <other_name>telmisartan</other_name>
    <other_name>valsartan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Non-ACEI/ARB</intervention_name>
    <description>Veterans will be categorized as exposed to a non-ACEI/ARB if they have one or more pharmacy fills for an oral non-ACEI or ARB medication in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an ACEI/ARB medication in the 90 days (± 14 days) prior to each Veteran's index date. Specific drug classes include: aldosterone receptor antagonist, beta-blocker, calcium channel blocker, centrally-acting drug, direct arterial vasodilator, direct renin inhibitor, thiazide diuretic, loop diuretic, and potassium sparing diuretic.</description>
    <arm_group_label>1.1 Outpatient SARS-CoV-2 Positive, ACEI/ARB vs non-ACEI/ARB</arm_group_label>
    <arm_group_label>2.1 COVID-19 Hospitalized, ACEI/ARB vs non-ACEI/ARB</arm_group_label>
    <other_name>doxazosin</other_name>
    <other_name>prazosin</other_name>
    <other_name>terazosin</other_name>
    <other_name>acebutolol</other_name>
    <other_name>nebivolol</other_name>
    <other_name>atenolol</other_name>
    <other_name>betaxolol</other_name>
    <other_name>bisoprolol</other_name>
    <other_name>metoprolol</other_name>
    <other_name>pindolol</other_name>
    <other_name>penbutolol</other_name>
    <other_name>carvedilol</other_name>
    <other_name>labetalol</other_name>
    <other_name>nadolol</other_name>
    <other_name>propranolol</other_name>
    <other_name>timolol</other_name>
    <other_name>amlodipine</other_name>
    <other_name>felodipine</other_name>
    <other_name>isradipine</other_name>
    <other_name>nifedipine</other_name>
    <other_name>nicardipine</other_name>
    <other_name>nisoldipine</other_name>
    <other_name>diltiazem</other_name>
    <other_name>verapamil</other_name>
    <other_name>clonidine</other_name>
    <other_name>guanfacine</other_name>
    <other_name>guanabenz</other_name>
    <other_name>methyldopa</other_name>
    <other_name>reserpine</other_name>
    <other_name>hydralazine</other_name>
    <other_name>minoxidil</other_name>
    <other_name>aliskiren</other_name>
    <other_name>spironolactone</other_name>
    <other_name>eplerenone</other_name>
    <other_name>bumetanide</other_name>
    <other_name>furosemide</other_name>
    <other_name>ethacrynic acid</other_name>
    <other_name>torsemide</other_name>
    <other_name>amiloride</other_name>
    <other_name>triamterene</other_name>
    <other_name>bendroflumethiazide</other_name>
    <other_name>chlorothiazide</other_name>
    <other_name>chlorthalidone</other_name>
    <other_name>hydrochlorothiazide</other_name>
    <other_name>indapamide</other_name>
    <other_name>metolazone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ACEI</intervention_name>
    <description>Veterans will be categorized as exposed to an ACEI if they have one or more pharmacy fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an oral ARB in the 90 days (± 14 days) prior to each Veteran's index date.</description>
    <arm_group_label>1.2 Outpatient SARS-CoV-2 Positive, ACEI vs. ARB</arm_group_label>
    <arm_group_label>2.2 COVID-19 Hospitalized, ACEI vs. ARB</arm_group_label>
    <other_name>benazepril</other_name>
    <other_name>captopril</other_name>
    <other_name>enalapril</other_name>
    <other_name>fosinopril</other_name>
    <other_name>lisinopril</other_name>
    <other_name>moexipril</other_name>
    <other_name>perindopril</other_name>
    <other_name>quinapril</other_name>
    <other_name>ramipril</other_name>
    <other_name>trandolapril</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ARB</intervention_name>
    <description>Veterans will be categorized as exposed to an ARB if they have one or more pharmacy fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date. Sacubitril/valsartan (Brand name: Entresto®) will be excluded from ARB exposures.</description>
    <arm_group_label>1.2 Outpatient SARS-CoV-2 Positive, ACEI vs. ARB</arm_group_label>
    <arm_group_label>2.2 COVID-19 Hospitalized, ACEI vs. ARB</arm_group_label>
    <other_name>azilsartan</other_name>
    <other_name>candesartan</other_name>
    <other_name>eprosartan</other_name>
    <other_name>irbesartan</other_name>
    <other_name>losartan</other_name>
    <other_name>olmesartan</other_name>
    <other_name>telmisartan</other_name>
    <other_name>valsartan</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Aim 1: Positive test for SARS-CoV-2 in the outpatient setting, diagnosed with hypertension&#xD;
        prior to the index date, and be treated with an antihypertensive in the 90 days prior to&#xD;
        the index date.&#xD;
&#xD;
        Aim 2: Hospitalized for COVID-19, diagnosed with hypertension prior to the index date, and&#xD;
        be treated with an antihypertensive in the 90 days prior to the index date.&#xD;
&#xD;
        ACEI/ARB vs. non-ACEI/ARB analyses (aims 1.1 and 2.1): Do not have compelling indications&#xD;
        that would warrant preferential treatment with an ACEI or an ARB (i.e., diabetes, stroke,&#xD;
        chronic kidney disease, heart failure with reduced ejection fraction, or coronary heart&#xD;
        disease).&#xD;
&#xD;
        ACEI vs. ARB analyses (aims 1.2 and 2.2): Not concomitantly treated with an ACEI and an ARB&#xD;
        in the 90 days prior to the index date, and must be treated with at least an ACEI or an ARB&#xD;
        in the 90 days prior to the index date.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Positive SARS-CoV-2 test in the outpatient setting (Aim 1) or hospitalized for&#xD;
             COVID-19 (Aim 2)&#xD;
&#xD;
          -  Meet continuous enrollment criteria (≥1 inpatient or any outpatient encounter in each&#xD;
             of the two, six-month periods during the 365 days prior to the index date)&#xD;
&#xD;
          -  Do not have data inconsistencies (test patients, not Veterans, multiple death dates in&#xD;
             data, or not alive on index date)&#xD;
&#xD;
          -  Diagnosed with hypertension at any point prior to the index date&#xD;
&#xD;
          -  Had at least one prescription dispensed for an antihypertensive medication in the 90&#xD;
             days prior to the index date&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Aim 1.1 and 2.1 (ACEI/ARB vs. non-ACEI/ARB comparison): diagnosed with a compelling&#xD;
             indication for ACEI/ARB at any point prior to the index date (i.e., diabetes, stroke,&#xD;
             chronic kidney disease, heart failure with reduced ejection fraction, or coronary&#xD;
             heart disease)&#xD;
&#xD;
          -  Aim 1.2 and 2.2 (ACE vs. ARB comparison): prescription fills for both an ACEI and an&#xD;
             ARB in the 90 days prior to the index date; no prescription fill for an ACEI or an ARB&#xD;
             in the 90 days prior to the index date&#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>Adam P Bress, PharmD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Utah</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Derington CG, Cohen JB, Mohanty AF, Greene TH, Cook J, Ying J, Wei G, Herrick JS, Stevens VW, Jones BE, Wang L, Zheutlin AR, South AM, Hanff TC, Smith SM, Cooper-DeHoff RM, King JB, Alexander GC, Berlowitz DR, Ahmad FS, Penrod MJ, Hess R, Conroy MB, Fang JC, Rubin MA, Beddhu S, Cheung AK, Xian W, Weintraub WS, Bress AP. Angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use and COVID-19-related outcomes among US Veterans. PLoS One. 2021 Apr 23;16(4):e0248080. doi: 10.1371/journal.pone.0248080. eCollection 2021. Erratum In: PLoS One. 2021 May 13;16(5):e0251897.</citation>
    <PMID>33891615</PMID>
  </results_reference>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>July 6, 2020</study_first_submitted>
  <study_first_submitted_qc>July 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 13, 2020</study_first_posted>
  <last_update_submitted>April 26, 2021</last_update_submitted>
  <last_update_submitted_qc>April 26, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 28, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Utah</investigator_affiliation>
    <investigator_full_name>Adam Bress</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>angiotensin-converting enzyme inhibitor</keyword>
  <keyword>angiotensin receptor antagonist</keyword>
  <keyword>Veterans</keyword>
  <keyword>antihypertensive medications</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Losartan</mesh_term>
    <mesh_term>Timolol</mesh_term>
    <mesh_term>Propranolol</mesh_term>
    <mesh_term>Metoprolol</mesh_term>
    <mesh_term>Atenolol</mesh_term>
    <mesh_term>Verapamil</mesh_term>
    <mesh_term>Felodipine</mesh_term>
    <mesh_term>Nadolol</mesh_term>
    <mesh_term>Acebutolol</mesh_term>
    <mesh_term>Amlodipine</mesh_term>
    <mesh_term>Valsartan</mesh_term>
    <mesh_term>Hydrochlorothiazide</mesh_term>
    <mesh_term>Telmisartan</mesh_term>
    <mesh_term>Clonidine</mesh_term>
    <mesh_term>Carvedilol</mesh_term>
    <mesh_term>Candesartan</mesh_term>
    <mesh_term>Candesartan cilexetil</mesh_term>
    <mesh_term>Ramipril</mesh_term>
    <mesh_term>Olmesartan</mesh_term>
    <mesh_term>Olmesartan Medoxomil</mesh_term>
    <mesh_term>Enalapril</mesh_term>
    <mesh_term>Enalaprilat</mesh_term>
    <mesh_term>Lisinopril</mesh_term>
    <mesh_term>Irbesartan</mesh_term>
    <mesh_term>Eplerenone</mesh_term>
    <mesh_term>Nebivolol</mesh_term>
    <mesh_term>Chlorthalidone</mesh_term>
    <mesh_term>Bisoprolol</mesh_term>
    <mesh_term>Perindopril</mesh_term>
    <mesh_term>Diltiazem</mesh_term>
    <mesh_term>Minoxidil</mesh_term>
    <mesh_term>Guanfacine</mesh_term>
    <mesh_term>Prazosin</mesh_term>
    <mesh_term>Doxazosin</mesh_term>
    <mesh_term>Benazepril</mesh_term>
    <mesh_term>Captopril</mesh_term>
    <mesh_term>Labetalol</mesh_term>
    <mesh_term>Hydralazine</mesh_term>
    <mesh_term>Indapamide</mesh_term>
    <mesh_term>Nicardipine</mesh_term>
    <mesh_term>Quinapril</mesh_term>
    <mesh_term>Metolazone</mesh_term>
    <mesh_term>Torsemide</mesh_term>
    <mesh_term>Trandolapril</mesh_term>
    <mesh_term>Methyldopa</mesh_term>
    <mesh_term>Fosinopril</mesh_term>
    <mesh_term>Isradipine</mesh_term>
    <mesh_term>Pindolol</mesh_term>
    <mesh_term>Eprosartan</mesh_term>
    <mesh_term>Moexipril</mesh_term>
    <mesh_term>Betaxolol</mesh_term>
    <mesh_term>Bendroflumethiazide</mesh_term>
    <mesh_term>Chlorothiazide</mesh_term>
    <mesh_term>Reserpine</mesh_term>
    <mesh_term>Guanabenz</mesh_term>
    <mesh_term>Nisoldipine</mesh_term>
    <mesh_term>Penbutolol</mesh_term>
    <mesh_term>Nifedipine</mesh_term>
    <mesh_term>Amiloride</mesh_term>
    <mesh_term>Triamterene</mesh_term>
    <mesh_term>Furosemide</mesh_term>
    <mesh_term>Spironolactone</mesh_term>
    <mesh_term>Bumetanide</mesh_term>
    <mesh_term>Ethacrynic Acid</mesh_term>
    <mesh_term>Terazosin</mesh_term>
    <mesh_term>Azilsartan medoxomil</mesh_term>
    <mesh_term>Angiotensin-Converting Enzyme Inhibitors</mesh_term>
  </intervention_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>June 17, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/31/NCT04467931/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/NCT04467931
org study id: 00132408
nct id: NCT04467931
lead sponsor: 
collaborator: 
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has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for
      COVID-19, enters type II pneumocytes using angiotensin-converting enzyme 2 (ACE2). It is
      unclear whether ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) increase,
      decrease, or have no significant effect on ACE2 expression or activity. Therefore, ACEI and
      ARB may be harmful, beneficial, or have no impact on Coronavirus Disease 2019 severity and
      mortality. The Specific Aims of this observational study are: (1) Among SARS-CoV-2-positive
      outpatients, compare all-cause hospitalization and mortality rates between: 1.1 Current users
      of a range of doses of ACEI/ARB- vs. non- ACEI/ARB-based regimens, and 1.2 Current users of a
      range of doses of ACEI- vs. ARB-based regimens, and (2) Among those hospitalized for
      COVID-19, compare all-cause mortality between: 2.1 Current users of a range of doses of
      ACEI/ARB- vs. non- ACEI/ARB-based regimens, and 2.2 Current users of a range of doses of
      ACEI- vs. ARB-based regimens.
The Coronavirus Disease 2019 (COVID-19) pandemic has killed >129,000 Americans as of June 30,
      2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for
      COVID-19, enters type II pneumocytes using angiotensin-converting enzyme 2 (ACE2). ACE
      inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase ACE2 expression.
      Theoretically, if ACEI/ARB use increases ACE2 expression in the lungs, ACEI/ARBs could
      promote SARS-CoV-2 entry into type II pneumocytes and worsen COVID-19 infection. In contrast,
      other evidence suggests that ACEI/ARBs may mitigate virus-induced inflammatory responses in
      the lungs by upregulating ACE2-mediated generation of the vasodilator and anti-inflammatory
      protein angiotensin-(1-7), thereby preventing tissue damage. Few data exist on the direction
      or magnitude of the association between ACEI/ARB use and COVID-19 severity, and whether these
      associations differ between ACEIs and ARBs. Because ACEI/ARBs are among the most commonly
      used prescription medications, it is critical to determine if ACEI/ARB users have a
      differential risk of more severe COVID-19 infection compared to non-users. The objective of
      this study is to reduce morbidity and mortality of the COVID-19 pandemic by generating timely
      evidence on the direction and magnitude of the association between ACEI/ARB use and COVID-19
      severity and mortality.
observational model: Cohort
time perspective: Retrospective
measure: All-Cause-Hospitalization or All-Cause Mortality
time frame: Through study completion (October 21, 2020).
description: For outpatient Veterans with a positive SARS-CoV-2 test (Aims 1.1 and 1.2), the primary outcome is a composite of time to all-cause hospitalization or all-cause mortality.
measure: All-Cause Mortality
time frame: Through study completion (October 21, 2020).
description: For Veterans hospitalized with COVID-19 (Aims 2.1 and 2.2), the primary outcome is time to all-cause mortality.
measure: ICU admission
time frame: Through study completion (October 21, 2020).
description: For aims 1 and 2, a secondary outcome will be time to intensive care unit (ICU) admission.
measure: Mechanical ventilation
time frame: Through study completion (October 21, 2020).
description: For aim 2, a secondary outcome will be time to mechanical ventilation.
measure: Dialysis
time frame: Through study completion (October 21, 2020).
description: For aim 2, a secondary outcome will be time to in-hospital dialysis.
measure: Negative control outcomes (Gastrointestinal bleed or urinary tract infection)
time frame: Through study completion (October 21, 2020).
description: Time to first occurrence of gastrointestinal bleed or urinary tract infection. This will be a negative control outcome.
arm group label: 1.1 Outpatient SARS-CoV-2 Positive, ACEI/ARB vs non-ACEI/ARB
description: Among Veterans with treated hypertension and without compelling indications who test positive for SARS-CoV-2, compare all-cause hospitalization and all-cause mortality rates between current users of a range of doses of ACEI/ARB- vs. non-ACEI/ARB-based regimens.
arm group label: 1.2 Outpatient SARS-CoV-2 Positive, ACEI vs. ARB
description: Among Veterans with treated hypertension who test positive for SARS-CoV-2, compare all-cause hospitalization and all-cause mortality rates between current users of a range of doses of ACEI- vs. ARB-based regimens.
arm group label: 2.1 COVID-19 Hospitalized, ACEI/ARB vs non-ACEI/ARB
description: Among Veterans with treated hypertension and without compelling indications who are hospitalized for COVID-19, compare all-cause mortality rates between current users of a range of doses of ACEI/ARB- vs. non-ACEI/ARB-based regimens.
arm group label: 2.2 COVID-19 Hospitalized, ACEI vs. ARB
description: Among Veterans with treated hypertension who are hospitalized for COVID-19, compare all-cause mortality rates between current users of a range of doses of ACEI- vs. ARB-based regimens.
intervention type: Drug
intervention name: ACEI/ARB
description: Veterans will be categorized as exposed to ACEI/ARB if they have one or more pharmacy fills for an oral ACEI or an ARB in the 90 days (± 14 days) prior to each Veteran's index date. Sacubitril/valsartan (Brand name: Entresto®) will be excluded from ARB exposures.
arm group label: 1.1 Outpatient SARS-CoV-2 Positive, ACEI/ARB vs non-ACEI/ARB
arm group label: 2.1 COVID-19 Hospitalized, ACEI/ARB vs non-ACEI/ARB
other name: benazepril
other name: captopril
other name: enalapril
other name: fosinopril
other name: lisinopril
other name: moexipril
other name: perindopril
other name: quinapril
other name: ramipril
other name: trandolapril
other name: azilsartan
other name: candesartan
other name: eprosartan
other name: irbesartan
other name: losartan
other name: olmesartan
other name: telmisartan
other name: valsartan
intervention type: Drug
intervention name: Non-ACEI/ARB
description: Veterans will be categorized as exposed to a non-ACEI/ARB if they have one or more pharmacy fills for an oral non-ACEI or ARB medication in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an ACEI/ARB medication in the 90 days (± 14 days) prior to each Veteran's index date. Specific drug classes include: aldosterone receptor antagonist, beta-blocker, calcium channel blocker, centrally-acting drug, direct arterial vasodilator, direct renin inhibitor, thiazide diuretic, loop diuretic, and potassium sparing diuretic.
arm group label: 1.1 Outpatient SARS-CoV-2 Positive, ACEI/ARB vs non-ACEI/ARB
arm group label: 2.1 COVID-19 Hospitalized, ACEI/ARB vs non-ACEI/ARB
other name: doxazosin
other name: prazosin
other name: terazosin
other name: acebutolol
other name: nebivolol
other name: atenolol
other name: betaxolol
other name: bisoprolol
other name: metoprolol
other name: pindolol
other name: penbutolol
other name: carvedilol
other name: labetalol
other name: nadolol
other name: propranolol
other name: timolol
other name: amlodipine
other name: felodipine
other name: isradipine
other name: nifedipine
other name: nicardipine
other name: nisoldipine
other name: diltiazem
other name: verapamil
other name: clonidine
other name: guanfacine
other name: guanabenz
other name: methyldopa
other name: reserpine
other name: hydralazine
other name: minoxidil
other name: aliskiren
other name: spironolactone
other name: eplerenone
other name: bumetanide
other name: furosemide
other name: ethacrynic acid
other name: torsemide
other name: amiloride
other name: triamterene
other name: bendroflumethiazide
other name: chlorothiazide
other name: chlorthalidone
other name: hydrochlorothiazide
other name: indapamide
other name: metolazone
intervention type: Drug
intervention name: ACEI
description: Veterans will be categorized as exposed to an ACEI if they have one or more pharmacy fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an oral ARB in the 90 days (± 14 days) prior to each Veteran's index date.
arm group label: 1.2 Outpatient SARS-CoV-2 Positive, ACEI vs. ARB
arm group label: 2.2 COVID-19 Hospitalized, ACEI vs. ARB
other name: benazepril
other name: captopril
other name: enalapril
other name: fosinopril
other name: lisinopril
other name: moexipril
other name: perindopril
other name: quinapril
other name: ramipril
other name: trandolapril
intervention type: Drug
intervention name: ARB
description: Veterans will be categorized as exposed to an ARB if they have one or more pharmacy fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date and NO fills for an oral ACEI in the 90 days (± 14 days) prior to each Veteran's index date. Sacubitril/valsartan (Brand name: Entresto®) will be excluded from ARB exposures.
arm group label: 1.2 Outpatient SARS-CoV-2 Positive, ACEI vs. ARB
arm group label: 2.2 COVID-19 Hospitalized, ACEI vs. ARB
other name: azilsartan
other name: candesartan
other name: eprosartan
other name: irbesartan
other name: losartan
other name: olmesartan
other name: telmisartan
other name: valsartan
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Adam P Bress, PharmD, MS
role: Principal Investigator
affiliation: University of Utah
facility: 
country: United States
citation: Derington CG, Cohen JB, Mohanty AF, Greene TH, Cook J, Ying J, Wei G, Herrick JS, Stevens VW, Jones BE, Wang L, Zheutlin AR, South AM, Hanff TC, Smith SM, Cooper-DeHoff RM, King JB, Alexander GC, Berlowitz DR, Ahmad FS, Penrod MJ, Hess R, Conroy MB, Fang JC, Rubin MA, Beddhu S, Cheung AK, Xian W, Weintraub WS, Bress AP. Angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use and COVID-19-related outcomes among US Veterans. PLoS One. 2021 Apr 23;16(4):e0248080. doi: 10.1371/journal.pone.0248080. eCollection 2021. Erratum In: PLoS One. 2021 May 13;16(5):e0251897.
PMID: 33891615
responsible party type: Principal Investigator
investigator affiliation: University of Utah
investigator full name: Adam Bress
investigator title: Associate Professor
mesh term: Hypertension
mesh term: Losartan
mesh term: Timolol
mesh term: Propranolol
mesh term: Metoprolol
mesh term: Atenolol
mesh term: Verapamil
mesh term: Felodipine
mesh term: Nadolol
mesh term: Acebutolol
mesh term: Amlodipine
mesh term: Valsartan
mesh term: Hydrochlorothiazide
mesh term: Telmisartan
mesh term: Clonidine
mesh term: Carvedilol
mesh term: Candesartan
mesh term: Candesartan cilexetil
mesh term: Ramipril
mesh term: Olmesartan
mesh term: Olmesartan Medoxomil
mesh term: Enalapril
mesh term: Enalaprilat
mesh term: Lisinopril
mesh term: Irbesartan
mesh term: Eplerenone
mesh term: Nebivolol
mesh term: Chlorthalidone
mesh term: Bisoprolol
mesh term: Perindopril
mesh term: Diltiazem
mesh term: Minoxidil
mesh term: Guanfacine
mesh term: Prazosin
mesh term: Doxazosin
mesh term: Benazepril
mesh term: Captopril
mesh term: Labetalol
mesh term: Hydralazine
mesh term: Indapamide
mesh term: Nicardipine
mesh term: Quinapril
mesh term: Metolazone
mesh term: Torsemide
mesh term: Trandolapril
mesh term: Methyldopa
mesh term: Fosinopril
mesh term: Isradipine
mesh term: Pindolol
mesh term: Eprosartan
mesh term: Moexipril
mesh term: Betaxolol
mesh term: Bendroflumethiazide
mesh term: Chlorothiazide
mesh term: Reserpine
mesh term: Guanabenz
mesh term: Nisoldipine
mesh term: Penbutolol
mesh term: Nifedipine
mesh term: Amiloride
mesh term: Triamterene
mesh term: Furosemide
mesh term: Spironolactone
mesh term: Bumetanide
mesh term: Ethacrynic Acid
mesh term: Terazosin
mesh term: Azilsartan medoxomil
mesh term: Angiotensin-Converting Enzyme Inhibitors
sharing ipd: No
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