<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/NCT04445103</url>
  </required_header>
  <id_info>
    <org_study_id>68999970512</org_study_id>
    <nct_id>NCT04445103</nct_id>
  </id_info>
  <brief_title>The Malaria Heart Disease Study</brief_title>
  <official_title>The Malaria Heart Disease Study: A Novel Pathway to Subclinical Heart Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Gentofte, Copenhagen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Federal University of Acre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Sao Paulo</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Independent Research Fund Denmark</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Gentofte, Copenhagen</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>
      The Malaria Heart Disease Study is a prospective longitudinal cohort study of a random sample&#xD;
      of approximately 1200 individuals from the state of Acre in Brazil. The overall hypothesis is&#xD;
      that patients who have (i) previously suffered from a malaria infection or (ii) patients with&#xD;
      ongoing symptomatic malaria will benefit from having an echocardiogram and blood tests&#xD;
      performed as a screening tool to diagnose early cardiac impairment and prevent future&#xD;
      cardiovascular disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this study is to investigate the relationship between exposure to malaria and&#xD;
      the risk of developing subclinical and manifest cardiovascular disease. The study is&#xD;
      conducted in the high endemic malaria zone pertaining to the city of Cruzeiro do Sul, located&#xD;
      in the state of Acre, Brazil. The city is considered a part of the Amazon basin.&#xD;
&#xD;
      By invitation of a random sample of patients with a history of malaria, controls with no&#xD;
      history of malaria, and symptomatic patients with ongoing malaria infection, the aim is to&#xD;
      elucidate potential pathways linking malaria to cardiovascular disease.&#xD;
&#xD;
      Aim 1: Determine whether prior exposure to malaria is associated with myocardial dysfunction.&#xD;
      The investigators hypothesize that adults with a history of treated malaria (cases) will have&#xD;
      worse left ventricular (LV) diastolic function and systolic strain compared to age- and&#xD;
      sex-matched controls without a history of malaria infection. The investigators will recruit&#xD;
      500 cases and 500 controls from Cruzeiro-do-Sul, Brazil. State-of-the-art ultrasonographic&#xD;
      examinations will be used to asses novel imaging metrics of cardiac function.&#xD;
&#xD;
      Aim 2: Define the extent to which proinflammatory factors (such as Ang-2, CRP, VEGF) are&#xD;
      associated with cardiac dysfunction in subjects with a history of malaria. The investigators&#xD;
      hypothesize that proinflammatory biomarkers will be higher in cases compared to controls, and&#xD;
      that higher concentrations of inflammatory markers will associate with worse LV diastolic&#xD;
      function and strain. The investigators will measure inflammatory biomarkers, determine the&#xD;
      association with cardiac dysfunction, and test whether history of malaria modifies this&#xD;
      association.&#xD;
&#xD;
      Aim 3: Determine if echocardiographic parameters of systolic and diastolic function and&#xD;
      cardiac biomarkers are significantly elevated in patients with symptomatic malaria (N=200).&#xD;
&#xD;
      Upon conclusion of this study, the investigators will better understand the relationship of&#xD;
      malaria with subclinical cardiac dysfunction. This will allow development of the scientific&#xD;
      foundation and necessary infrastructure to expand this project to a longitudinal study to&#xD;
      prospectively assess associations with relevant clinical outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Due to the COVID-19 pandemic it was not possible to complete the study inclusion as originally&#xD;
    anticipated.&#xD;
  </why_stopped>
  <start_date type="Actual">June 21, 2020</start_date>
  <completion_date type="Actual">January 25, 2021</completion_date>
  <primary_completion_date type="Actual">January 25, 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>Echocardiography</measure>
    <time_frame>2020-2023</time_frame>
    <description>Alterations in systolic and diastolic function assessed by conventional and speckle tracking echocardiography</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers</measure>
    <time_frame>2020-2023</time_frame>
    <description>Elevated cardiac biomarkers</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Endothelial dysfunction</measure>
    <time_frame>2020-2023</time_frame>
    <description>Elevated markers of endothelial dysfunction</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inflammation</measure>
    <time_frame>2020-2023</time_frame>
    <description>Elevated proinflammatory markers</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">597</enrollment>
  <condition>Plasmodium Falciparum</condition>
  <condition>Plasmodium Vivax</condition>
  <condition>Heart Diseases</condition>
  <condition>Cardiovascular Diseases</condition>
  <arm_group>
    <arm_group_label>History of malaria</arm_group_label>
    <description>Individuals with a history of malaria infection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Controls</arm_group_label>
    <description>Individuals without a history of malaria infection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Symptomatic malaria</arm_group_label>
    <description>Patients with symptomatic malaria infection (complicated and uncomplicated)</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Assessment of cardiac function</intervention_name>
    <description>Echocardiographic examination and assessment of cardiac biomakers</description>
    <arm_group_label>Controls</arm_group_label>
    <arm_group_label>History of malaria</arm_group_label>
    <arm_group_label>Symptomatic malaria</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        The study population conforms to three study groups: i) History of malaria infection ii)&#xD;
        Controls and iii) Symptomatic malaria infection&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Group 1 (History of malaria) Inclusion: Patients with a record of malaria &gt;=18 years old&#xD;
        will be invited at random Exclusion: Persons not able to cooperate and persons unwilling or&#xD;
        unable to understand and sign &quot;informed consent&quot;, persons who are hospitalized due to&#xD;
        severe malaria&#xD;
&#xD;
        Group 2 (Controls) Inclusion: Patients with no record of malaria &gt;=18 years old will be&#xD;
        invited at random Exclusion: Persons not able to cooperate and persons unwilling or unable&#xD;
        to understand and sign &quot;informed consent&quot;&#xD;
&#xD;
        Group 3 (Symptomatic malaria) Inclusion: Patients &gt;=18 years old diagnosed in&#xD;
        outpatient/inpatient clinic with malaria infection by thick and thin blood smear and/or&#xD;
        rapid diagnostic test. Enrollment of both severe (complicated) and uncomplicated malaria&#xD;
        cases as defined by the WHO criteria. Exclusion: Persons not able to cooperate and persons&#xD;
        unwilling or unable to understand and sign &quot;informed consent&quot;, suspected or verified&#xD;
        concomitant protozoal infections&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philip Brainin, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Federal University of Acre</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Odilson Silvestre, MD, PhD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Federal University of Acre</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Tor Biering-Sørensen, MD, PhD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Gentofte University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Philip Brainin</name>
      <address>
        <city>Cruzeiro do Sul</city>
        <state>Acre</state>
        <zip>69980000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <link>
    <url>https://www.malariaheart.com/</url>
    <description>Official study website</description>
  </link>
  <results_reference>
    <citation>Wegener A, Lima KO, Holm AE, Gomes LC, Matos LO, Vieira IVM, Souza RM, Marinho CRF, Vestergaard LS, Biering-Sorensen T, Silvestre OM, Brainin P. Cardiopulmonary alterations by ultrasound in a patient with uncomplicated mixed malaria infection: a case report from the Amazon Basin. Malar J. 2021 Jul 28;20(1):330. doi: 10.1186/s12936-021-03861-5.</citation>
    <PMID>34321001</PMID>
  </results_reference>
  <results_reference>
    <citation>Holm AE, Gomes LC, Lima KO, Wegener A, Matos LO, Vieira IVM, Kaagaard MD, Pareek M, de Souza RM, Marinho CRF, Biering-Sorensen T, Silvestre OM, Brainin P. Tropical diseases and risk of hypertension in the Amazon Basin: a cross-sectional study. J Hum Hypertens. 2022 Dec;36(12):1121-1127. doi: 10.1038/s41371-021-00633-1. Epub 2021 Nov 13.</citation>
    <PMID>34775497</PMID>
  </results_reference>
  <results_reference>
    <citation>Wegener A, Kaagaard MD, Gomes LC, Holm AE, Matos LO, Lima KO, Vieira IVM, de Souza RM, Olsen FJ, Marinho CRF, Biering-Sorensen T, Silvestre OM, Brainin P. Reference values for left ventricular dimensions, systolic and diastolic function: a study from the Amazon Basin of Brazil. Int J Cardiovasc Imaging. 2021 Nov 22. doi: 10.1007/s10554-021-02475-x. Online ahead of print.</citation>
    <PMID>34807316</PMID>
  </results_reference>
  <results_reference>
    <citation>Kaagaard MD, Matos LO, Holm AE, Gomes LC, Wegener A, Lima KO, Vieira IVM, de Souza RM, Marinho CRF, Hviid L, Vestergaard LS, Dominguez H, Biering-Sorensen T, Silvestre OM, Brainin P. Frequency of Electrocardiographic Alterations and Pericardial Effusion in Patients With Uncomplicated Malaria. Am J Cardiol. 2022 Feb 15;165:116-123. doi: 10.1016/j.amjcard.2021.11.009. Epub 2021 Dec 12.</citation>
    <PMID>34906368</PMID>
  </results_reference>
  <results_reference>
    <citation>Wegener A, Holm AE, Gomes LC, Lima KO, Kaagaard MD, Matos LO, Vieira IVM, de Souza RM, Marinho CRF, Nascimento BR, Biering-Sorensen T, Silvestre OM, Brainin P. Prevalence of rheumatic heart disease in adults from the Brazilian Amazon Basin. Int J Cardiol. 2022 Apr 1;352:115-122. doi: 10.1016/j.ijcard.2022.01.026. Epub 2022 Jan 20.</citation>
    <PMID>35065154</PMID>
  </results_reference>
  <results_reference>
    <citation>Wegener A, Holm AE, Gomes LC, Lima KO, Matos LO, Vieira IVM, Kaagaard MD, de Souza RM, Hviid L, Guimaraes Lacerda MV, Vestergaard LS, Farias Marinho CR, Platz E, Biering-Sorensen T, Silvestre OM, Brainin P. Prevalence and Dynamic Changes in Lung Ultrasound Findings among Adults with Uncomplicated Malaria and Controls in the Amazon Basin, Brazil. Am J Trop Med Hyg. 2022 Apr 11;106(6):1637-45. doi: 10.4269/ajtmh.21-1107. Online ahead of print.</citation>
    <PMID>35405640</PMID>
  </results_reference>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>June 21, 2020</study_first_submitted>
  <study_first_submitted_qc>June 21, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 24, 2020</study_first_posted>
  <last_update_submitted>July 16, 2022</last_update_submitted>
  <last_update_submitted_qc>July 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 19, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital, Gentofte, Copenhagen</investigator_affiliation>
    <investigator_full_name>Philip Brainin</investigator_full_name>
    <investigator_title>Philip Brainin, MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Echocardiography</keyword>
  <keyword>Endothelial dysfunction</keyword>
  <keyword>Cardiovascular inflammation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Malaria</mesh_term>
    <mesh_term>Cardiovascular Diseases</mesh_term>
    <mesh_term>Heart Diseases</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/NCT04445103
org study id: 68999970512
nct id: NCT04445103
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The Malaria Heart Disease Study is a prospective longitudinal cohort study of a random sample
      of approximately 1200 individuals from the state of Acre in Brazil. The overall hypothesis is
      that patients who have (i) previously suffered from a malaria infection or (ii) patients with
      ongoing symptomatic malaria will benefit from having an echocardiogram and blood tests
      performed as a screening tool to diagnose early cardiac impairment and prevent future
      cardiovascular disease.
The purpose of this study is to investigate the relationship between exposure to malaria and
      the risk of developing subclinical and manifest cardiovascular disease. The study is
      conducted in the high endemic malaria zone pertaining to the city of Cruzeiro do Sul, located
      in the state of Acre, Brazil. The city is considered a part of the Amazon basin.

      By invitation of a random sample of patients with a history of malaria, controls with no
      history of malaria, and symptomatic patients with ongoing malaria infection, the aim is to
      elucidate potential pathways linking malaria to cardiovascular disease.

      Aim 1: Determine whether prior exposure to malaria is associated with myocardial dysfunction.
      The investigators hypothesize that adults with a history of treated malaria (cases) will have
      worse left ventricular (LV) diastolic function and systolic strain compared to age- and
      sex-matched controls without a history of malaria infection. The investigators will recruit
      500 cases and 500 controls from Cruzeiro-do-Sul, Brazil. State-of-the-art ultrasonographic
      examinations will be used to asses novel imaging metrics of cardiac function.

      Aim 2: Define the extent to which proinflammatory factors (such as Ang-2, CRP, VEGF) are
      associated with cardiac dysfunction in subjects with a history of malaria. The investigators
      hypothesize that proinflammatory biomarkers will be higher in cases compared to controls, and
      that higher concentrations of inflammatory markers will associate with worse LV diastolic
      function and strain. The investigators will measure inflammatory biomarkers, determine the
      association with cardiac dysfunction, and test whether history of malaria modifies this
      association.

      Aim 3: Determine if echocardiographic parameters of systolic and diastolic function and
      cardiac biomarkers are significantly elevated in patients with symptomatic malaria (N=200).

      Upon conclusion of this study, the investigators will better understand the relationship of
      malaria with subclinical cardiac dysfunction. This will allow development of the scientific
      foundation and necessary infrastructure to expand this project to a longitudinal study to
      prospectively assess associations with relevant clinical outcomes.
observational model: Cohort
time perspective: Prospective
measure: Echocardiography
time frame: 2020-2023
description: Alterations in systolic and diastolic function assessed by conventional and speckle tracking echocardiography
measure: Biomarkers
time frame: 2020-2023
description: Elevated cardiac biomarkers
measure: Endothelial dysfunction
time frame: 2020-2023
description: Elevated markers of endothelial dysfunction
measure: Inflammation
time frame: 2020-2023
description: Elevated proinflammatory markers
arm group label: History of malaria
description: Individuals with a history of malaria infection
arm group label: Controls
description: Individuals without a history of malaria infection
arm group label: Symptomatic malaria
description: Patients with symptomatic malaria infection (complicated and uncomplicated)
intervention type: Diagnostic Test
intervention name: Assessment of cardiac function
description: Echocardiographic examination and assessment of cardiac biomakers
arm group label: Controls
arm group label: History of malaria
arm group label: Symptomatic malaria
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Philip Brainin, MD, PhD
role: Principal Investigator
affiliation: Federal University of Acre
last name: Odilson Silvestre, MD, PhD, MPH
role: Principal Investigator
affiliation: Federal University of Acre
last name: Tor Biering-Sørensen, MD, PhD, MPH
role: Principal Investigator
affiliation: Gentofte University Hospital
facility: 
country: Brazil
url: https://www.malariaheart.com/
description: Official study website
citation: Wegener A, Lima KO, Holm AE, Gomes LC, Matos LO, Vieira IVM, Souza RM, Marinho CRF, Vestergaard LS, Biering-Sorensen T, Silvestre OM, Brainin P. Cardiopulmonary alterations by ultrasound in a patient with uncomplicated mixed malaria infection: a case report from the Amazon Basin. Malar J. 2021 Jul 28;20(1):330. doi: 10.1186/s12936-021-03861-5.
PMID: 34321001
citation: Holm AE, Gomes LC, Lima KO, Wegener A, Matos LO, Vieira IVM, Kaagaard MD, Pareek M, de Souza RM, Marinho CRF, Biering-Sorensen T, Silvestre OM, Brainin P. Tropical diseases and risk of hypertension in the Amazon Basin: a cross-sectional study. J Hum Hypertens. 2022 Dec;36(12):1121-1127. doi: 10.1038/s41371-021-00633-1. Epub 2021 Nov 13.
PMID: 34775497
citation: Wegener A, Kaagaard MD, Gomes LC, Holm AE, Matos LO, Lima KO, Vieira IVM, de Souza RM, Olsen FJ, Marinho CRF, Biering-Sorensen T, Silvestre OM, Brainin P. Reference values for left ventricular dimensions, systolic and diastolic function: a study from the Amazon Basin of Brazil. Int J Cardiovasc Imaging. 2021 Nov 22. doi: 10.1007/s10554-021-02475-x. Online ahead of print.
PMID: 34807316
citation: Kaagaard MD, Matos LO, Holm AE, Gomes LC, Wegener A, Lima KO, Vieira IVM, de Souza RM, Marinho CRF, Hviid L, Vestergaard LS, Dominguez H, Biering-Sorensen T, Silvestre OM, Brainin P. Frequency of Electrocardiographic Alterations and Pericardial Effusion in Patients With Uncomplicated Malaria. Am J Cardiol. 2022 Feb 15;165:116-123. doi: 10.1016/j.amjcard.2021.11.009. Epub 2021 Dec 12.
PMID: 34906368
citation: Wegener A, Holm AE, Gomes LC, Lima KO, Kaagaard MD, Matos LO, Vieira IVM, de Souza RM, Marinho CRF, Nascimento BR, Biering-Sorensen T, Silvestre OM, Brainin P. Prevalence of rheumatic heart disease in adults from the Brazilian Amazon Basin. Int J Cardiol. 2022 Apr 1;352:115-122. doi: 10.1016/j.ijcard.2022.01.026. Epub 2022 Jan 20.
PMID: 35065154
citation: Wegener A, Holm AE, Gomes LC, Lima KO, Matos LO, Vieira IVM, Kaagaard MD, de Souza RM, Hviid L, Guimaraes Lacerda MV, Vestergaard LS, Farias Marinho CR, Platz E, Biering-Sorensen T, Silvestre OM, Brainin P. Prevalence and Dynamic Changes in Lung Ultrasound Findings among Adults with Uncomplicated Malaria and Controls in the Amazon Basin, Brazil. Am J Trop Med Hyg. 2022 Apr 11;106(6):1637-45. doi: 10.4269/ajtmh.21-1107. Online ahead of print.
PMID: 35405640
responsible party type: Principal Investigator
investigator affiliation: University Hospital, Gentofte, Copenhagen
investigator full name: Philip Brainin
investigator title: Philip Brainin, MD, PhD
mesh term: Malaria
mesh term: Cardiovascular Diseases
mesh term: Heart Diseases
sharing ipd: Undecided