<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/NCT03304691</url>
  </required_header>
  <id_info>
    <org_study_id>999917165</org_study_id>
    <secondary_id>17-I-N165</secondary_id>
    <nct_id>NCT03304691</nct_id>
  </id_info>
  <brief_title>Molecular Basis of Erythrocyte Invasion by Plasmodium Vivax Into Duffy-Negative Erythrocytes in Mali</brief_title>
  <official_title>The Molecular Basis of Erythrocyte Invasion by Plasmodium Vivax Into Duffy-Negative Erythrocytes in Mali</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</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>
      Background:&#xD;
&#xD;
      Malaria is caused by parasites carried by some mosquitos. When the mosquitos bite people, the&#xD;
      parasites can infect them. One of these parasites is Plasmodium vivax (P. vivax). Some&#xD;
      children have P. vivax in their blood. They did not have malaria symptoms, but some also had&#xD;
      a blood problem called anemia. This can make people feel tired or weak. This could have been&#xD;
      caused by P. vivax. Researchers want to know how P. vivax infects these children, and if it&#xD;
      affects their health.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To collect blood, stool, and urine monthly from children to look for infections with P.&#xD;
      vivax, worms, and other parasites.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      Children between 6 months and 10 years old&#xD;
&#xD;
      Design:&#xD;
&#xD;
      For screening, the study will be explained to the participant s parents or guardians, who&#xD;
      will provide consent.&#xD;
&#xD;
      Participants will have a visit once a month for about 3 months, from November to January, and&#xD;
      then for about 6 months from June to November 2018. Visits include:&#xD;
&#xD;
      Questions about their health&#xD;
&#xD;
      Medical history&#xD;
&#xD;
      Physical exam&#xD;
&#xD;
      Blood draw by pricking the finger tip&#xD;
&#xD;
      Urine and stool collection. They may collect these at home and bring them back.&#xD;
&#xD;
      If participants have P. vivax in their blood, them may need to come back to the clinic within&#xD;
      3 days. They will have blood taken from their arm using a needle.&#xD;
&#xD;
      If participants feel ill during the study, they can go to the clinic for an exam and blood&#xD;
      tests.&#xD;
&#xD;
      If participants develop malaria while on the study, they will be treated.&#xD;
&#xD;
      Participants samples will be stored for future research studies.&#xD;
&#xD;
      ...&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Plasmodium vivax was thought not to be a problem in Duffy blood group negative Africans.&#xD;
      However, recent research has found that P. vivax infection occurs not only in areas where&#xD;
      Duffy-positive and -negative people live side-by-side, but also in areas where populations&#xD;
      are predominantly Duffy-negative, such as Bandiagara, Mali. In this region, our research&#xD;
      group recently observed 25 P. vivax infections in children, all of whom were Duffy-negative.&#xD;
      Furthermore, some preliminary data suggest that, despite having extremely low parasitemia and&#xD;
      no malarial symptoms (no fever, muscle aches, or chills), the children of Bandiagara with P.&#xD;
      vivax may have a drop in hemoglobin.&#xD;
&#xD;
      The present study involves two substudies to detect P. vivax infections in children and&#xD;
      adults of two predominantly Duffy-negative Malian populations where P. vivax infections have&#xD;
      previously been identified. The cohort study will be conducted in the Bandiagara region. We&#xD;
      will conduct physical exams and collect blood, urine, and stool samples at baseline and&#xD;
      monthly (urine samples will be collected only at baseline) for about 10 months. Our goal is&#xD;
      to detect and characterize P. vivax infections, focusing on molecularly characterizing how P.&#xD;
      vivax invades erythrocytes in Duffy-negative individuals. Specifically, we want to identify&#xD;
      the parasite ligands involved in this invasion. We will use RNA sequencing (RNAseq) of P.&#xD;
      vivax in blood samples of infected subjects to define the level of expression of parasite&#xD;
      invasion ligands. From the parasite DNA found in blood samples, we will determine whether&#xD;
      there is gene expansion of the parasite ligand Duffy binding protein (PvDBP) (the number of&#xD;
      copies of PvDBP in each genome), and identify the sequence of PvDBP to determine whether it&#xD;
      can bind an erythrocyte receptor other than the Duffy blood group antigen (i.e.,&#xD;
      Duffy-negative erythrocytes). An additional focus will be whether P. vivax leads to anemia in&#xD;
      the Duffy-negative children.&#xD;
&#xD;
      In addition, we will conduct a cross-sectional study to investigate the prevalence of P.&#xD;
      vivax in the general population in Yirimadio, a periurban setting of Bamako, which is the&#xD;
      sole place in Mali besides Bandiagara where P. vivax infections have been reported in&#xD;
      Duffy-negative individuals. This will be achieved by undertaking a cross-sectional survey.&#xD;
      Subjects will provide blood for blood smear and filter paper analyses to identify the&#xD;
      presence of P. vivax infection at 3 different time points.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 30, 2021</start_date>
  <completion_date type="Anticipated">April 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">April 30, 2023</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>Identify the P. vivax ligands for infection of Duffy blood group negative Africans by RNA sequencing (RNAseq) of blood from P. vivax cases.</measure>
    <time_frame>Monthly surveillance visits throughout length of the study</time_frame>
    <description>Identify the P. vivax ligands for infection of Duffy blood group negative Africans by RNA sequencing (RNAseq) of blood from P. vivax cases.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Determine the prevalence of P. vivax in Yirimadio in Duffy negative population</measure>
    <time_frame>Beginning, peak, and end of transmission season</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identify the vector populations in and around the study area that may transmit malaria, including during the dry season, as well as the infection rates in these populations.</measure>
    <time_frame>Monthly surveillance visits throughout length of the study</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Study the association between P. vivax parasitemia and anemia in Duffy-negative Africans.</measure>
    <time_frame>Monthly surveillance visits throughout length of the study</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine by stool examinations the presence of hypnozoites in the liver that fail to cause blood infections.</measure>
    <time_frame>Monthly surveillance visits throughout length of the study</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine the number of clones of P. vivax circulating in the community by DNA sequencing of polymorphic parasite proteins.</measure>
    <time_frame>Monthly surveillance visits throughout length of the study</time_frame>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">900</enrollment>
  <condition>Malaria</condition>
  <arm_group>
    <arm_group_label>Bandiagara, Mali</arm_group_label>
    <description>Children of both sexes between 6 months and 10 years of age.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Yirimadio, Bamako, Mali</arm_group_label>
    <description>Children and adults of both sexes 6 months and older.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Subjects will be selected to enroll based on community permission and sensitization&#xD;
        strategies for both the Bandiagara and Yirimadio sites.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
        For inclusion in the cohort substudy, a child must meet the following criteria:&#xD;
&#xD;
          1. Is greater than or equal to 6 months and less than or equal to 10 years of age&#xD;
&#xD;
          2. Residing in Bandiagara for at least 6 months prior to screening&#xD;
&#xD;
          3. Will be available to attend visits during this study&#xD;
&#xD;
          4. Agrees to provide urine and stool samples during this study&#xD;
&#xD;
          5. Agrees to allow storage of samples for future research.&#xD;
&#xD;
        For inclusion in the cross-sectional substudy, an individual must meet the following&#xD;
        criteria:&#xD;
&#xD;
          1. Aged greater than or equal to 6 months;&#xD;
&#xD;
          2. Residing in Yirimadio for at least 6 months prior to screening.&#xD;
&#xD;
        EXCLUISION CRITERIA:&#xD;
&#xD;
        The following criterion is exclusionary in either substudy:&#xD;
&#xD;
        1) Has any underlying conditions that, in the judgement of the clinical investigators,&#xD;
        could increase the risk to the subject.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Louis H Miller, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Allergy and Infectious Diseases (NIAID)</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Karthigayan Gunalan</last_name>
    <phone>(240) 747-7893</phone>
    <email>karthigayan.gunalan@nih.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Louis H Miller, M.D.</last_name>
    <phone>(240) 472-0736</phone>
    <email>lmiller@niaid.nih.gov</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Yirimadio Community Health Center</name>
      <address>
        <city>Bamako</city>
        <country>Mali</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Drissa Coulibaly, M.D.</last_name>
      <phone>+22320228109</phone>
      <email>coulibalyd@icermali.org</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Bandiagara Malaria Program (BMP) Clinic</name>
      <address>
        <city>Bandiagara</city>
        <country>Mali</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Drissa Coulibaly, M.D.</last_name>
      <phone>(223) 222-8109</phone>
      <email>coulibalyd@icermali.org</email>
    </contact>
  </location>
  <location_countries>
    <country>Mali</country>
  </location_countries>
  <reference>
    <citation>Gunalan K, Niangaly A, Thera MA, Doumbo OK, Miller LH. Plasmodium vivax Infections of Duffy-Negative Erythrocytes: Historically Undetected or a Recent Adaptation? Trends Parasitol. 2018 May;34(5):420-429. doi: 10.1016/j.pt.2018.02.006. Epub 2018 Mar 9.</citation>
    <PMID>29530446</PMID>
  </reference>
  <reference>
    <citation>Gunalan K, Sa JM, Moraes Barros RR, Anzick SL, Caleon RL, Mershon JP, Kanakabandi K, Paneru M, Virtaneva K, Martens C, Barnwell JW, Ribeiro JM, Miller LH. Transcriptome profiling of Plasmodium vivax in Saimiri monkeys identifies potential ligands for invasion. Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7053-7061. doi: 10.1073/pnas.1818485116. Epub 2019 Mar 14.</citation>
    <PMID>30872477</PMID>
  </reference>
  <reference>
    <citation>Niangaly A, Karthigayan Gunalan, Amed Ouattara, Coulibaly D, Sa JM, Adams M, Travassos MA, Ferrero J, Laurens MB, Kone AK, Thera MA, Plowe CV, Miller LH, Doumbo OK. Plasmodium vivax Infections over 3 Years in Duffy Blood Group Negative Malians in Bandiagara, Mali. Am J Trop Med Hyg. 2017 Sep;97(3):744-752. doi: 10.4269/ajtmh.17-0254. Epub 2017 Jul 27.</citation>
    <PMID>28749772</PMID>
  </reference>
  <verification_date>February 15, 2023</verification_date>
  <study_first_submitted>October 6, 2017</study_first_submitted>
  <study_first_submitted_qc>October 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 9, 2017</study_first_posted>
  <last_update_submitted>February 16, 2023</last_update_submitted>
  <last_update_submitted_qc>February 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 17, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Malaria</keyword>
  <keyword>Parasitemia</keyword>
  <keyword>Anemia</keyword>
  <keyword>Ligand</keyword>
  <keyword>Anopheles gambiae</keyword>
  <keyword>Natural History</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Malaria</mesh_term>
  </condition_browse>
  <!-- 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/NCT03304691
org study id: 999917165
secondary id: 17-I-N165
nct id: NCT03304691
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Background:

      Malaria is caused by parasites carried by some mosquitos. When the mosquitos bite people, the
      parasites can infect them. One of these parasites is Plasmodium vivax (P. vivax). Some
      children have P. vivax in their blood. They did not have malaria symptoms, but some also had
      a blood problem called anemia. This can make people feel tired or weak. This could have been
      caused by P. vivax. Researchers want to know how P. vivax infects these children, and if it
      affects their health.

      Objective:

      To collect blood, stool, and urine monthly from children to look for infections with P.
      vivax, worms, and other parasites.

      Eligibility:

      Children between 6 months and 10 years old

      Design:

      For screening, the study will be explained to the participant s parents or guardians, who
      will provide consent.

      Participants will have a visit once a month for about 3 months, from November to January, and
      then for about 6 months from June to November 2018. Visits include:

      Questions about their health

      Medical history

      Physical exam

      Blood draw by pricking the finger tip

      Urine and stool collection. They may collect these at home and bring them back.

      If participants have P. vivax in their blood, them may need to come back to the clinic within
      3 days. They will have blood taken from their arm using a needle.

      If participants feel ill during the study, they can go to the clinic for an exam and blood
      tests.

      If participants develop malaria while on the study, they will be treated.

      Participants samples will be stored for future research studies.

      ...
Plasmodium vivax was thought not to be a problem in Duffy blood group negative Africans.
      However, recent research has found that P. vivax infection occurs not only in areas where
      Duffy-positive and -negative people live side-by-side, but also in areas where populations
      are predominantly Duffy-negative, such as Bandiagara, Mali. In this region, our research
      group recently observed 25 P. vivax infections in children, all of whom were Duffy-negative.
      Furthermore, some preliminary data suggest that, despite having extremely low parasitemia and
      no malarial symptoms (no fever, muscle aches, or chills), the children of Bandiagara with P.
      vivax may have a drop in hemoglobin.

      The present study involves two substudies to detect P. vivax infections in children and
      adults of two predominantly Duffy-negative Malian populations where P. vivax infections have
      previously been identified. The cohort study will be conducted in the Bandiagara region. We
      will conduct physical exams and collect blood, urine, and stool samples at baseline and
      monthly (urine samples will be collected only at baseline) for about 10 months. Our goal is
      to detect and characterize P. vivax infections, focusing on molecularly characterizing how P.
      vivax invades erythrocytes in Duffy-negative individuals. Specifically, we want to identify
      the parasite ligands involved in this invasion. We will use RNA sequencing (RNAseq) of P.
      vivax in blood samples of infected subjects to define the level of expression of parasite
      invasion ligands. From the parasite DNA found in blood samples, we will determine whether
      there is gene expansion of the parasite ligand Duffy binding protein (PvDBP) (the number of
      copies of PvDBP in each genome), and identify the sequence of PvDBP to determine whether it
      can bind an erythrocyte receptor other than the Duffy blood group antigen (i.e.,
      Duffy-negative erythrocytes). An additional focus will be whether P. vivax leads to anemia in
      the Duffy-negative children.

      In addition, we will conduct a cross-sectional study to investigate the prevalence of P.
      vivax in the general population in Yirimadio, a periurban setting of Bamako, which is the
      sole place in Mali besides Bandiagara where P. vivax infections have been reported in
      Duffy-negative individuals. This will be achieved by undertaking a cross-sectional survey.
      Subjects will provide blood for blood smear and filter paper analyses to identify the
      presence of P. vivax infection at 3 different time points.
observational model: Cohort
time perspective: Prospective
measure: Identify the P. vivax ligands for infection of Duffy blood group negative Africans by RNA sequencing (RNAseq) of blood from P. vivax cases.
time frame: Monthly surveillance visits throughout length of the study
description: Identify the P. vivax ligands for infection of Duffy blood group negative Africans by RNA sequencing (RNAseq) of blood from P. vivax cases.
measure: Determine the prevalence of P. vivax in Yirimadio in Duffy negative population
time frame: Beginning, peak, and end of transmission season
measure: Identify the vector populations in and around the study area that may transmit malaria, including during the dry season, as well as the infection rates in these populations.
time frame: Monthly surveillance visits throughout length of the study
measure: Study the association between P. vivax parasitemia and anemia in Duffy-negative Africans.
time frame: Monthly surveillance visits throughout length of the study
measure: Determine by stool examinations the presence of hypnozoites in the liver that fail to cause blood infections.
time frame: Monthly surveillance visits throughout length of the study
measure: Determine the number of clones of P. vivax circulating in the community by DNA sequencing of polymorphic parasite proteins.
time frame: Monthly surveillance visits throughout length of the study
arm group label: Bandiagara, Mali
description: Children of both sexes between 6 months and 10 years of age.
arm group label: Yirimadio, Bamako, Mali
description: Children and adults of both sexes 6 months and older.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 6 Months
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Louis H Miller, M.D.
role: Principal Investigator
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
last name: Karthigayan Gunalan
phone: (240) 747-7893
email: karthigayan.gunalan@nih.gov
last name: Louis H Miller, M.D.
phone: (240) 472-0736
email: lmiller@niaid.nih.gov
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Mali
citation: Gunalan K, Niangaly A, Thera MA, Doumbo OK, Miller LH. Plasmodium vivax Infections of Duffy-Negative Erythrocytes: Historically Undetected or a Recent Adaptation? Trends Parasitol. 2018 May;34(5):420-429. doi: 10.1016/j.pt.2018.02.006. Epub 2018 Mar 9.
PMID: 29530446
citation: Gunalan K, Sa JM, Moraes Barros RR, Anzick SL, Caleon RL, Mershon JP, Kanakabandi K, Paneru M, Virtaneva K, Martens C, Barnwell JW, Ribeiro JM, Miller LH. Transcriptome profiling of Plasmodium vivax in Saimiri monkeys identifies potential ligands for invasion. Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7053-7061. doi: 10.1073/pnas.1818485116. Epub 2019 Mar 14.
PMID: 30872477
citation: Niangaly A, Karthigayan Gunalan, Amed Ouattara, Coulibaly D, Sa JM, Adams M, Travassos MA, Ferrero J, Laurens MB, Kone AK, Thera MA, Plowe CV, Miller LH, Doumbo OK. Plasmodium vivax Infections over 3 Years in Duffy Blood Group Negative Malians in Bandiagara, Mali. Am J Trop Med Hyg. 2017 Sep;97(3):744-752. doi: 10.4269/ajtmh.17-0254. Epub 2017 Jul 27.
PMID: 28749772
responsible party type: Sponsor
mesh term: Malaria