<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/NCT04441372</url>
  </required_header>
  <id_info>
    <org_study_id>MSF0001</org_study_id>
    <nct_id>NCT04441372</nct_id>
  </id_info>
  <brief_title>Prognostication of Oxygen Requirement in Non-severe SARS-CoV-2 Infection</brief_title>
  <acronym>PRIORITISE</acronym>
  <official_title>Prognostication of Oxygen Requirement in Non-severe SARS-CoV-2 Infection</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medecins Sans Frontieres, Spain</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Mahidol Oxford Tropical Medicine Research Unit</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>International Centre for Diarrhoeal Disease Research, Bangladesh</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Foundation for Innovative New Diagnostics, Switzerland</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Medecins Sans Frontieres, Spain</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Note that this is a study that is co-sponsored by Medecins Sans Frontieres, Spain, and the&#xD;
      University of Oxford.&#xD;
&#xD;
      The primary objective of this study is to identify clinical and biochemical prognostic&#xD;
      markers in adults with virologically confirmed COVID-19 who do not require oxygen&#xD;
      supplementation, with a focus on: aiding safe discharge from a healthcare facility (i.e. a&#xD;
      high NPV); near-term impact on COVID-19 interventions in resource-limited settings (i.e.&#xD;
      simple clinico-demographic variables and biochemical markers for which near-patient / POCTs&#xD;
      are commercially available or in late-stage development).&#xD;
&#xD;
      The secondary objective of this study is to evaluate the field-based performance of&#xD;
      near-patient lateral flow assays for suPAR and IL-6 in adults with non-severe SARS-CoV-2&#xD;
      infection&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background&#xD;
&#xD;
      At the time of writing the novel betacoronavirus SARS-CoV-2 has infected more than 11 million&#xD;
      individuals and killed more than 500,000. The most recent epidemiological surveillance curve&#xD;
      shows that the number of new infections continues to rise, with over 230,000 new cases&#xD;
      reported in the last 24 hours.&#xD;
&#xD;
      Whilst the absolute number of deaths attributable to COVID-19 is substantial, effectively&#xD;
      managing high patient volumes is also a major challenge facing health systems, particularly&#xD;
      in under-resourced settings. With an estimated case-fatality rate amongst symptomatic&#xD;
      patients of between 1-2%, it is vitally important that health workers are able to accurately&#xD;
      identify the majority of patients at low risk for progression to severe disease. These&#xD;
      patients can be safely discharged away from the health facility ensuring the available&#xD;
      resources are allocated to patients most likely to benefit. If low-risk patients cannot be&#xD;
      readily identified, there is a real risk that health facilities in these regions will be&#xD;
      overrun, with consequent substantial avoidable mortality.&#xD;
&#xD;
      COVID-19 has already started to hit extremely vulnerable populations in refugee camps and&#xD;
      conflict areas. In Bangladesh, cases within the Rohingya refugee megacamps have already been&#xD;
      reported, and local transmission is ongoing. Such contexts already suffer from a lack of&#xD;
      medical facilities and even a moderate number of COVID-19 cases will overburden existing, and&#xD;
      proposed, capacity. Having the ability to prognosticate the need for supplemental oxygen (the&#xD;
      main treatment available in these settings) through measurement of parameters available at&#xD;
      the time of arrival at a healthcare facility would strengthen the capability to identify&#xD;
      those patients presenting with moderate symptoms that can be safely discharged away from the&#xD;
      facility. Based on recent estimates, only 20% of all symptomatic patients with COVID-19&#xD;
      develop a requirement for supplemental oxygen.&#xD;
&#xD;
      Although existing prognostic scores have yielded disappointing results in patients with&#xD;
      SARS-CoV-2 infection a number of demographic, clinical and laboratory parameters are&#xD;
      associated with a more severe disease course and worse patient outcomes. However, to our&#xD;
      knowledge, few studies have examined the performance of prognostic markers in patients who do&#xD;
      not require supplemental oxygen at presentation. Only one of these studies included&#xD;
      outpatient or ambulatory care settings and none were conducted in resource-limited settings.&#xD;
      Hence, whether measurement of these parameters can inform the decision to safely discharge a&#xD;
      patient away from a health facility is as yet unclear.&#xD;
&#xD;
      Main research question&#xD;
&#xD;
      In adults presenting to care with non-severe COVID-19, can subsequent need for oxygen be&#xD;
      predicted from parameters measured at the time of arrival at a healthcare facility?&#xD;
&#xD;
      This study will evaluate several clinical and biochemical biomarkers that have been&#xD;
      identified as possible predictors of deterioration in patients with COVID-19. The primary&#xD;
      objective is to develop a prognostic tool combining up to four markers (including a maximum&#xD;
      of two biochemical markers) with a high negative predictive value (NPV) for subsequent&#xD;
      supplemental oxygen requirement (WHO Grade ≥ 5). Clinical biomarkers will be limited to&#xD;
      simple clinico-demographic variables (for example, age, sex and duration of symptoms) in&#xD;
      order to ensure the tool remains as simple as possible. Biochemical biomarkers for which&#xD;
      point-of-care (POC) and/or near-patient tests are either already commercially available or in&#xD;
      late-stage development have been prioritised, in order to maximise the chance of translation&#xD;
      on to the field within a time period that is useful for the current global pandemic response.&#xD;
&#xD;
      The requirement for supplemental oxygen has been selected as the primary outcome: it is a&#xD;
      relatively objective endpoint (based either on the measurement of peripheral oxygen&#xD;
      saturation [sO2 ≤ 93%] or a respiratory rate &gt; 30 breaths per minute or a clinical decision&#xD;
      to give supplemental oxygen) and from a practical perspective is the main evidence-based&#xD;
      therapeutic intervention available in such settings, but in very limited supply in the&#xD;
      majority of low- and middle-income countries (LMICs).&#xD;
&#xD;
      We have identified near-patient tests for one of the priority biochemical biomarkers that&#xD;
      have not yet been field-evaluated in LMICs (suPAR). We will evaluate the performance of this&#xD;
      test under field conditions. We have selected this test for evaluation because unlike the&#xD;
      other potential markers for which near-patient tests also exist, there is a relative paucity&#xD;
      of field experience in tropical settings. As all biochemical markers will be measured using a&#xD;
      validated multi-analyte quantitative immunoassay (using the Ella platform), this study will&#xD;
      provide an opportunity to evaluate the field performance of these tests. If either of the&#xD;
      markers is found to be useful prognosticators for patients with non-severe SARS-CoV-2&#xD;
      infection, this may facilitate a more rapid translation of the results of this study into&#xD;
      practice.&#xD;
&#xD;
      Assumptions, limitations, and generalisability&#xD;
&#xD;
      The main assumption that underlies this work is that a validated, rapid, low-cost&#xD;
      antigen-based test for SARS-CoV-2 will become available in the near future. There is reason&#xD;
      to believe that this will be the case.Availability of such a test would allow the prognostic&#xD;
      tool developed in this study to be applied to the appropriate patient population at the point&#xD;
      of arrival at a health facility. Whilst the absence of such a test would undoubtedly limit&#xD;
      the utility of the tool, it is likely that when local incidence of patients presenting with&#xD;
      confirmed SARS-CoV-2 infection exceeds a threshold, use of the tool could be justified based&#xD;
      upon a clinical case definition alone. Furthermore, in order to mitigate this risk, we plan&#xD;
      to use the data collected in this study (specifically the baseline and outcome data collected&#xD;
      from participants who are subsequently confirmed to be SARS-CoV-2 negative by RT-PCR) to&#xD;
      inform exploratory simulation analyses, with the aim of customizing of the tool for use in&#xD;
      different prevalence settings, thereby extending utility to different phases of the pandemic.&#xD;
&#xD;
      An additional limitation of this study is that due to its single-site nature we will not be&#xD;
      able to explore whether the performance of the prognostic markers is impacted by different&#xD;
      host populations, or perform an external geographic validation of the prognostic model. To&#xD;
      mitigate this risk we have designed a pragmatic study that could be implemented in other&#xD;
      sites. We are actively exploring options for conducting the study at other sites if&#xD;
      sufficient additional funding can be identified. We will inform and seek approval from all&#xD;
      relevant regulatory bodies (international and local) prior to the inclusion of any additional&#xD;
      study sites.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">October 1, 2020</start_date>
  <completion_date type="Anticipated">December 1, 2021</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2021</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>14 Days</target_duration>
  <primary_outcome>
    <measure>Clinical and biochemical prognostic markers</measure>
    <time_frame>14 days</time_frame>
    <description>Identify clinical and biochemical prognostic markers in adults with non-severe COVID-19. This is assessed through the ability of the markers to predict progression to subsequent supplemental oxygen requirement - sensitivity, specificity, NPV, PPV and AUROC, and discrimination (c-index) and calibration (plots of observed probabilities against predicted probabilities) of a prognostic model combining up to four markers.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluate field-based performance of POC</measure>
    <time_frame>14 days</time_frame>
    <description>To evaluate the field-based performance of near-patient lateral flow assays for suPAR in adults with non-severe SARS-CoV-2 infection. This is assessed through looking at correlation of the near-patient lateral flow assays and the instrumented multi-analyte immunoassaygold standard.</description>
  </secondary_outcome>
  <enrollment type="Anticipated">600</enrollment>
  <condition>SARS-CoV2</condition>
  <condition>COVID</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood will be taken for biomarker assessment from all participants and may include pathogen&#xD;
      identification&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The study will be conducted at two study sites in India: AIIMS Patna and CMC Vellore. Both&#xD;
        sites are recognised by the government and Health Clusters as COVID-19 management&#xD;
        facilities. Other study sites may be added over time.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
        The participant may enter the study if ALL of the following apply:&#xD;
&#xD;
          1. Aged ≥ 18 years, and willing and able to give informed consent and comply with study&#xD;
             procedures;&#xD;
&#xD;
          2. RT-PCR or antigen test positive for SARS-CoV-2 during current illness&#xD;
&#xD;
          3. Systemic manifestation of SARS-CoV-2 infection defined as:&#xD;
&#xD;
        Breathing difficulty&#xD;
&#xD;
        OR&#xD;
&#xD;
        History of fever during current illness AND chest pain OR abdominal pain OR loose stool OR&#xD;
        severe myalgia&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
        The participant may not enter the study if ANY of the following apply:&#xD;
&#xD;
          1. Requires supplemental oxygen or mechanical ventilation (invasive / non-invasive) at&#xD;
             presentation;&#xD;
&#xD;
          2. Laboratory confirmed SARS-CoV-2 infection (virological or serological) during a&#xD;
             previous illness episode.&#xD;
&#xD;
          3. Documented history of Vaccination for SARS-Cov-2&#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>Arjun Chandna, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cambodia Oxford Medical Research Unit</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sakib Burza, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medecins Sans Frontieres, Spain</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mikhael Yosia, MD</last_name>
    <phone>+6281378778784</phone>
    <email>msfe-jakarta-med@barcelona.msf.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Arjun Chandna, MD</last_name>
    <phone>+85585712586</phone>
    <email>arjun@tropmedres.ac</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Foundation for Scientific and Technological Development in Health (FIOTEC)</name>
      <address>
        <city>Rio De Janeiro</city>
        <zip>4036</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Andre Siqueiria</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>All India Institute of Medical Sciences Patna (AIIMS)</name>
      <address>
        <city>Patna</city>
        <state>Bihar</state>
        <zip>801507</zip>
        <country>India</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Christian Medical College, Vellore</name>
      <address>
        <city>Vellore</city>
        <state>Tamil Nadu</state>
        <zip>632004</zip>
        <country>India</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location_countries>
    <country>Brazil</country>
    <country>India</country>
  </location_countries>
  <removed_countries>
    <country>Bangladesh</country>
  </removed_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>June 17, 2020</study_first_submitted>
  <study_first_submitted_qc>June 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 22, 2020</study_first_posted>
  <last_update_submitted>September 30, 2021</last_update_submitted>
  <last_update_submitted_qc>September 30, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 1, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>SARS-CoV-2</keyword>
  <keyword>COVID-19</keyword>
  <keyword>Prognosis</keyword>
  <keyword>Oxygen</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>July 4, 2023</submitted>
  </pending_results>
  <!-- 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/NCT04441372
org study id: MSF0001
nct id: NCT04441372
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Note that this is a study that is co-sponsored by Medecins Sans Frontieres, Spain, and the
      University of Oxford.

      The primary objective of this study is to identify clinical and biochemical prognostic
      markers in adults with virologically confirmed COVID-19 who do not require oxygen
      supplementation, with a focus on: aiding safe discharge from a healthcare facility (i.e. a
      high NPV); near-term impact on COVID-19 interventions in resource-limited settings (i.e.
      simple clinico-demographic variables and biochemical markers for which near-patient / POCTs
      are commercially available or in late-stage development).

      The secondary objective of this study is to evaluate the field-based performance of
      near-patient lateral flow assays for suPAR and IL-6 in adults with non-severe SARS-CoV-2
      infection
Background

      At the time of writing the novel betacoronavirus SARS-CoV-2 has infected more than 11 million
      individuals and killed more than 500,000. The most recent epidemiological surveillance curve
      shows that the number of new infections continues to rise, with over 230,000 new cases
      reported in the last 24 hours.

      Whilst the absolute number of deaths attributable to COVID-19 is substantial, effectively
      managing high patient volumes is also a major challenge facing health systems, particularly
      in under-resourced settings. With an estimated case-fatality rate amongst symptomatic
      patients of between 1-2%, it is vitally important that health workers are able to accurately
      identify the majority of patients at low risk for progression to severe disease. These
      patients can be safely discharged away from the health facility ensuring the available
      resources are allocated to patients most likely to benefit. If low-risk patients cannot be
      readily identified, there is a real risk that health facilities in these regions will be
      overrun, with consequent substantial avoidable mortality.

      COVID-19 has already started to hit extremely vulnerable populations in refugee camps and
      conflict areas. In Bangladesh, cases within the Rohingya refugee megacamps have already been
      reported, and local transmission is ongoing. Such contexts already suffer from a lack of
      medical facilities and even a moderate number of COVID-19 cases will overburden existing, and
      proposed, capacity. Having the ability to prognosticate the need for supplemental oxygen (the
      main treatment available in these settings) through measurement of parameters available at
      the time of arrival at a healthcare facility would strengthen the capability to identify
      those patients presenting with moderate symptoms that can be safely discharged away from the
      facility. Based on recent estimates, only 20% of all symptomatic patients with COVID-19
      develop a requirement for supplemental oxygen.

      Although existing prognostic scores have yielded disappointing results in patients with
      SARS-CoV-2 infection a number of demographic, clinical and laboratory parameters are
      associated with a more severe disease course and worse patient outcomes. However, to our
      knowledge, few studies have examined the performance of prognostic markers in patients who do
      not require supplemental oxygen at presentation. Only one of these studies included
      outpatient or ambulatory care settings and none were conducted in resource-limited settings.
      Hence, whether measurement of these parameters can inform the decision to safely discharge a
      patient away from a health facility is as yet unclear.

      Main research question

      In adults presenting to care with non-severe COVID-19, can subsequent need for oxygen be
      predicted from parameters measured at the time of arrival at a healthcare facility?

      This study will evaluate several clinical and biochemical biomarkers that have been
      identified as possible predictors of deterioration in patients with COVID-19. The primary
      objective is to develop a prognostic tool combining up to four markers (including a maximum
      of two biochemical markers) with a high negative predictive value (NPV) for subsequent
      supplemental oxygen requirement (WHO Grade ≥ 5). Clinical biomarkers will be limited to
      simple clinico-demographic variables (for example, age, sex and duration of symptoms) in
      order to ensure the tool remains as simple as possible. Biochemical biomarkers for which
      point-of-care (POC) and/or near-patient tests are either already commercially available or in
      late-stage development have been prioritised, in order to maximise the chance of translation
      on to the field within a time period that is useful for the current global pandemic response.

      The requirement for supplemental oxygen has been selected as the primary outcome: it is a
      relatively objective endpoint (based either on the measurement of peripheral oxygen
      saturation [sO2 ≤ 93%] or a respiratory rate > 30 breaths per minute or a clinical decision
      to give supplemental oxygen) and from a practical perspective is the main evidence-based
      therapeutic intervention available in such settings, but in very limited supply in the
      majority of low- and middle-income countries (LMICs).

      We have identified near-patient tests for one of the priority biochemical biomarkers that
      have not yet been field-evaluated in LMICs (suPAR). We will evaluate the performance of this
      test under field conditions. We have selected this test for evaluation because unlike the
      other potential markers for which near-patient tests also exist, there is a relative paucity
      of field experience in tropical settings. As all biochemical markers will be measured using a
      validated multi-analyte quantitative immunoassay (using the Ella platform), this study will
      provide an opportunity to evaluate the field performance of these tests. If either of the
      markers is found to be useful prognosticators for patients with non-severe SARS-CoV-2
      infection, this may facilitate a more rapid translation of the results of this study into
      practice.

      Assumptions, limitations, and generalisability

      The main assumption that underlies this work is that a validated, rapid, low-cost
      antigen-based test for SARS-CoV-2 will become available in the near future. There is reason
      to believe that this will be the case.Availability of such a test would allow the prognostic
      tool developed in this study to be applied to the appropriate patient population at the point
      of arrival at a health facility. Whilst the absence of such a test would undoubtedly limit
      the utility of the tool, it is likely that when local incidence of patients presenting with
      confirmed SARS-CoV-2 infection exceeds a threshold, use of the tool could be justified based
      upon a clinical case definition alone. Furthermore, in order to mitigate this risk, we plan
      to use the data collected in this study (specifically the baseline and outcome data collected
      from participants who are subsequently confirmed to be SARS-CoV-2 negative by RT-PCR) to
      inform exploratory simulation analyses, with the aim of customizing of the tool for use in
      different prevalence settings, thereby extending utility to different phases of the pandemic.

      An additional limitation of this study is that due to its single-site nature we will not be
      able to explore whether the performance of the prognostic markers is impacted by different
      host populations, or perform an external geographic validation of the prognostic model. To
      mitigate this risk we have designed a pragmatic study that could be implemented in other
      sites. We are actively exploring options for conducting the study at other sites if
      sufficient additional funding can be identified. We will inform and seek approval from all
      relevant regulatory bodies (international and local) prior to the inclusion of any additional
      study sites.
observational model: Cohort
time perspective: Prospective
measure: Clinical and biochemical prognostic markers
time frame: 14 days
description: Identify clinical and biochemical prognostic markers in adults with non-severe COVID-19. This is assessed through the ability of the markers to predict progression to subsequent supplemental oxygen requirement - sensitivity, specificity, NPV, PPV and AUROC, and discrimination (c-index) and calibration (plots of observed probabilities against predicted probabilities) of a prognostic model combining up to four markers.
measure: Evaluate field-based performance of POC
time frame: 14 days
description: To evaluate the field-based performance of near-patient lateral flow assays for suPAR in adults with non-severe SARS-CoV-2 infection. This is assessed through looking at correlation of the near-patient lateral flow assays and the instrumented multi-analyte immunoassaygold standard.
Blood will be taken for biomarker assessment from all participants and may include pathogen
      identification
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Arjun Chandna, MD
role: Principal Investigator
affiliation: Cambodia Oxford Medical Research Unit
last name: Sakib Burza, PhD
role: Principal Investigator
affiliation: Medecins Sans Frontieres, Spain
last name: Mikhael Yosia, MD
phone: +6281378778784
email: msfe-jakarta-med@barcelona.msf.org
last name: Arjun Chandna, MD
phone: +85585712586
email: arjun@tropmedres.ac
facility: 
status: Recruiting
contact: 
facility: 
status: Completed
facility: 
status: Completed
country: Brazil
country: India
country: Bangladesh
responsible party type: Sponsor
mesh term: COVID-19
sharing ipd: Undecided
submitted: July 4, 2023