<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/NCT04422015</url>
  </required_header>
  <id_info>
    <org_study_id>1R01AI150521</org_study_id>
    <nct_id>NCT04422015</nct_id>
  </id_info>
  <brief_title>Biological Mechanisms in Afebrile P. Falciparum Malaria</brief_title>
  <acronym>AsintMal</acronym>
  <official_title>Unravelling Disease Tolerance and Host Resistance in Afebrile P. Falciparum Infections: a Prospective Study in Mozambican Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Alfredo Mayor</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Centro de Investigação em Saúde de Manhiça</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Barcelona Institute for Global Health</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This project aims to disentangle the role of host immune resistance and disease tolerance in&#xD;
      afebrile malaria infections, with the goal of guiding context-adapted tactics to target this&#xD;
      hidden reservoir, as well as to develop new approaches to clear malaria infection and reduce&#xD;
      its severity through host-directed therapies.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Asymptomatic Plasmodium falciparum (Pf) infections debilitate the health of affected&#xD;
      population while representing a hidden source of parasite transmission that can compromise&#xD;
      elimination efforts. The lack of consensus on the best strategy to deal with this&#xD;
      asymptomatic reservoir is partly due to the poor knowledge on the biological mechanisms&#xD;
      underlying these subclinical infections. Preliminary results in Mozambique show that afebrile&#xD;
      adults with a Pf infection detected by rapid diagnostic tests can progress to fever (10%),&#xD;
      clear the infection (20%) and stabilize at low-density (50%) or high-density (20%)&#xD;
      parasitemias. The study hypothesis is that these four main trajectories are driven by&#xD;
      antibodies against Pf variant antigens, codified by the var gene family and expressed on the&#xD;
      surface of infected erythrocytes, which would clear the infection unless the parasites&#xD;
      develop immune evasion mechanisms, and by tolerance factors that minimize parasite-induced&#xD;
      pathology and sustains host homeostasis.With the overarching goal of identifying key&#xD;
      biological factors sustaining afebrile malaria infections, this project will establish a&#xD;
      cohort of afebrile Mozambican adults followed during one month to identify subjects who can&#xD;
      reduce pathogen load and eventually clear the infection, those who maintain infections at&#xD;
      high-density and afebrile levels (tolerant), and those who fail to establish disease&#xD;
      tolerance and progress to fever. Circulating and overall parasite biomass will be quantified,&#xD;
      and new infections will be identified during follow-up using next-generation sequencing.&#xD;
      Clinical samples from individuals with low and high parasite densities will be used to test&#xD;
      whether parasitological trajectories of afebrile Pf infections correlate with host antibody&#xD;
      immunity against erythrocyte surface antigens and the transcription of Pf var genes involved&#xD;
      in cytoadhesion and immune evasion. Cytometry by time of flight and global mass spectrometry&#xD;
      will be applied on clinical samples from afebrile individuals with high parasite densities&#xD;
      (tolerant) and those progressing to fever (non-tolerant) to identify leukocyte populations&#xD;
      and metabolic pathways involved in the regulation of inflammation, tissue damage and&#xD;
      normoglycemia that support host-parasite relationships at afebrile levels. The expected&#xD;
      outcome of this project is the identification of key molecular drivers of afebrile Pf&#xD;
      infections for a better understanding of the relevance of these infections in different&#xD;
      transmission setting which may require context-specific control approaches, as well as for&#xD;
      the development of new tools to achieve sterilizing immunity and enhance disease tolerance.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 1, 2020</start_date>
  <completion_date type="Actual">March 31, 2021</completion_date>
  <primary_completion_date type="Actual">March 31, 2021</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>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of individuals developing fever</measure>
    <time_frame>1 month</time_frame>
    <description>Development of axilary temperature higher or equal than 37.5ºC</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of individuals clearing the infection</measure>
    <time_frame>1 month</time_frame>
    <description>Clearance of parasite infection as detected by qPCR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of individuals maintaining infections without fever</measure>
    <time_frame>1 month</time_frame>
    <description>Confirmed P. falciparum ifection at day 28 by qPCR</description>
  </secondary_outcome>
  <enrollment type="Actual">475</enrollment>
  <condition>Falciparum Malaria</condition>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>No intervention</intervention_name>
    <description>No intervention</description>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Healthy individuals (temperature below 37.5ºC) with a P. falciprum infection confirmed by&#xD;
        RDT and microscopy&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years and ≤60 years&#xD;
&#xD;
          -  A positive RDT and microscopy for P. falciparum&#xD;
&#xD;
          -  Axillary temperature &lt; 37.5ºC without history of fever during the last 24h&#xD;
&#xD;
          -  No danger signals for severe malaria (Impaired consciousness, respiratory distress,&#xD;
             multiple convulsions, prostration, shock, abnormal bleeding, jaundice)&#xD;
&#xD;
          -  Ability and willingness to comply with the study protocol for the duration of the&#xD;
             study and to comply with the study visit schedule; and&#xD;
&#xD;
          -  Signed informed consent after explaining the purpose of the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt;18 years or &gt;60 years&#xD;
&#xD;
          -  Axillary temperature ≥37.5ºC&#xD;
&#xD;
          -  Reported pregnancy&#xD;
&#xD;
          -  Presence of any sign/symptom of malaria (Vomiting, diarrhea, weakness, dizziness,&#xD;
             fainting, itching, urticarial)&#xD;
&#xD;
          -  Presence of any other co-existing clinical condition that would not allow the&#xD;
             individual to be considered a &quot;healthy&quot; afebrile carrier&#xD;
&#xD;
          -  Having received antimalarial medication in the preceding 30 days.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Fundação Manhiça/Manhiça Health Research Center</name>
      <address>
        <city>Manhiça</city>
        <zip>1929</zip>
        <country>Mozambique</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Mozambique</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 4, 2020</study_first_submitted>
  <study_first_submitted_qc>June 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>August 29, 2023</last_update_submitted>
  <last_update_submitted_qc>August 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Barcelona Institute for Global Health</investigator_affiliation>
    <investigator_full_name>Alfredo Mayor</investigator_full_name>
    <investigator_title>Associate Research Professor</investigator_title>
  </responsible_party>
  <keyword>afebrile</keyword>
  <keyword>resistance</keyword>
  <keyword>tolerance</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Malaria</mesh_term>
    <mesh_term>Malaria, Falciparum</mesh_term>
  </condition_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/NCT04422015
org study id: 1R01AI150521
nct id: NCT04422015
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
This project aims to disentangle the role of host immune resistance and disease tolerance in
      afebrile malaria infections, with the goal of guiding context-adapted tactics to target this
      hidden reservoir, as well as to develop new approaches to clear malaria infection and reduce
      its severity through host-directed therapies.
Asymptomatic Plasmodium falciparum (Pf) infections debilitate the health of affected
      population while representing a hidden source of parasite transmission that can compromise
      elimination efforts. The lack of consensus on the best strategy to deal with this
      asymptomatic reservoir is partly due to the poor knowledge on the biological mechanisms
      underlying these subclinical infections. Preliminary results in Mozambique show that afebrile
      adults with a Pf infection detected by rapid diagnostic tests can progress to fever (10%),
      clear the infection (20%) and stabilize at low-density (50%) or high-density (20%)
      parasitemias. The study hypothesis is that these four main trajectories are driven by
      antibodies against Pf variant antigens, codified by the var gene family and expressed on the
      surface of infected erythrocytes, which would clear the infection unless the parasites
      develop immune evasion mechanisms, and by tolerance factors that minimize parasite-induced
      pathology and sustains host homeostasis.With the overarching goal of identifying key
      biological factors sustaining afebrile malaria infections, this project will establish a
      cohort of afebrile Mozambican adults followed during one month to identify subjects who can
      reduce pathogen load and eventually clear the infection, those who maintain infections at
      high-density and afebrile levels (tolerant), and those who fail to establish disease
      tolerance and progress to fever. Circulating and overall parasite biomass will be quantified,
      and new infections will be identified during follow-up using next-generation sequencing.
      Clinical samples from individuals with low and high parasite densities will be used to test
      whether parasitological trajectories of afebrile Pf infections correlate with host antibody
      immunity against erythrocyte surface antigens and the transcription of Pf var genes involved
      in cytoadhesion and immune evasion. Cytometry by time of flight and global mass spectrometry
      will be applied on clinical samples from afebrile individuals with high parasite densities
      (tolerant) and those progressing to fever (non-tolerant) to identify leukocyte populations
      and metabolic pathways involved in the regulation of inflammation, tissue damage and
      normoglycemia that support host-parasite relationships at afebrile levels. The expected
      outcome of this project is the identification of key molecular drivers of afebrile Pf
      infections for a better understanding of the relevance of these infections in different
      transmission setting which may require context-specific control approaches, as well as for
      the development of new tools to achieve sterilizing immunity and enhance disease tolerance.
observational model: Cohort
time perspective: Prospective
measure: Proportion of individuals developing fever
time frame: 1 month
description: Development of axilary temperature higher or equal than 37.5ºC
measure: Proportion of individuals clearing the infection
time frame: 1 month
description: Clearance of parasite infection as detected by qPCR
measure: Proportion of individuals maintaining infections without fever
time frame: 1 month
description: Confirmed P. falciparum ifection at day 28 by qPCR
intervention type: Other
intervention name: No intervention
description: No intervention
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Mozambique
responsible party type: Sponsor-Investigator
investigator affiliation: Barcelona Institute for Global Health
investigator full name: Alfredo Mayor
investigator title: Associate Research Professor
mesh term: Malaria
mesh term: Malaria, Falciparum
sharing ipd: Undecided