<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/NCT03797989</url>
  </required_header>
  <id_info>
    <org_study_id>VAC069</org_study_id>
    <nct_id>NCT03797989</nct_id>
  </id_info>
  <brief_title>VAC069: A Study of Blood-stage Controlled Human P. Vivax Infection</brief_title>
  <official_title>VAC069: A Clinical Study to Assess the Safety and Feasibility of Controlled Blood-stage Plasmodium Vivax Human Malaria Infection Through Experimental Inoculation of Cryopreserved Infected Erythrocytes in Healthy Malaria-naïve UK Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Oxford</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Oxford</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This is a clinical study to assess the safety and feasibility of Plasmodium vivax (P. vivax)&#xD;
      controlled blood-stage human malaria infection (CHMI), by inoculation using a newly created&#xD;
      source of P. vivax malaria-infected blood.&#xD;
&#xD;
      25 healthy malaria-naïve UK volunteers, aged 18 - 50, will be recruited through the five&#xD;
      phases of the study at the CCVTM, Oxford. Volunteers will undergo primary, secondary and&#xD;
      tertiary P. vivax blood-stage challenges, which will be induced by injection of P. vivax&#xD;
      infected blood. After the first challenge, the optimal dose for blood-stage CHMI will be&#xD;
      selected and used for the second and third challenges. Through each challenge period,&#xD;
      volunteers will have blood taken at regular intervals to measure the parasite growth,&#xD;
      quantify the sexual parasite forms and assess the immune response to P. vivax infection.&#xD;
      Transmission of P. vivax from volunteers to the Anopheline mosquito vectors will also be&#xD;
      assessed.&#xD;
&#xD;
      In each challenge, following diagnosis, volunteers will be treated with a standard&#xD;
      antimalarial course of oral artemether-lumefantrine (Riamet), given over 60 hours. Volunteers&#xD;
      who take part in this study will be involved in the trial for approximately 2 years,&#xD;
      receiving each of the three challenges at intervals of approximately 5 (and up to 9) months.&#xD;
      Volunteers will be followed for 3 months after their last challenge.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study aims primarily to assess the safety and feasibility of controlled blood-stage&#xD;
      human P. vivax malaria infection. This will be the first time that this source of P. vivax&#xD;
      infected blood will be utilised and the first P. vivax bloodstage CHMI in Europe. If&#xD;
      demonstrated to be safe, it is intended that this parasitised blood bank be used in future&#xD;
      CHMI studies to evaluate candidate vaccines.&#xD;
&#xD;
      This study will also assess parasite growth, including quantifying the sexual-stage parasites&#xD;
      in the blood, as well as the transmission of P. vivax from volunteers to the Anopheline&#xD;
      mosquito vectors and the immune responses in primary, secondary and tertiary P. vivax&#xD;
      blood-stage challenge, as further secondary aims. Natural immunity to P. vivax is acquired&#xD;
      over time, following repeated exposure. Repeated blood-stage challenge would improve&#xD;
      understanding of how the human immune response to P. vivax infected is acquired, and how&#xD;
      parasite growth changes in a second or third exposure. Repeated challenges can also be used&#xD;
      to test if potential vaccine candidates can protect against repeated malaria infection. If&#xD;
      proven to be safe and feasible in this study, this will provide a basis for conducting P.&#xD;
      vivax blood-stage re-challenge studies for evaluation of new vaccine candidates.&#xD;
&#xD;
      The study is funded through The Wellcome Trust and MultiViVax, a European Commission Horizon&#xD;
      2020 funded project.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 10, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2022</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety of primary P. vivax blood-stage CHMI as measured by (S)AE occurrences</measure>
    <time_frame>36 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>The optimal inoculation dose to take forward to future P. vivax CHMI studies</measure>
    <time_frame>3 months</time_frame>
    <description>Choosing the optimal inoculation dose to take forward to future P. vivax CHMI studies will be decided based on the following algorithm:&#xD;
Ideal choice = the first group (2/2 volunteers) to reach diagnosis criteria (within 21 days). N.B. If both volunteers in Group 1 develop infection AND both volunteers in Group 2 (or 3) reliably develop infection within 5 days of Group 1 (and within the 21-day window) then the lowest dose group should be chosen.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Feasibility of primary P. vivax blood-stage CHMI as measured by successful infection (development of detectable persistent parasitaemia by thick film and qPCR +/- clinical symptoms)</measure>
    <time_frame>36 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety of secondary and tertiary P. vivax controlled blood-stage CHMI as measured by (S)AE occurrences</measure>
    <time_frame>36 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune response to primary, secondary and tertiary P. vivax pre-treatment</measure>
    <time_frame>36 months</time_frame>
    <description>As measured by antibody, B cell and T cell responses through experimental injection of P. vivax infected erythrocytes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gametocytaemia</measure>
    <time_frame>36 months</time_frame>
    <description>As measured by qPCR in primary, secondary and tertiary P. vivax blood-stage CHMI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feasibility of secondary and tertiary P. vivax controlled blood-stage CHMI as measured by successful infection (development of detectable persistent parasitaemia by thick film and qPCR +/- clinical symptoms)</measure>
    <time_frame>36 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transmissibility of gametocytes from the infected volunteer to Anopheline mosquito vector, which will be assesed by Direct Membrane Feeding Assays (DMFA)</measure>
    <time_frame>36 months</time_frame>
  </secondary_outcome>
  <number_of_arms>16</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>Malaria, Vivax</condition>
  <arm_group>
    <arm_group_label>Phase A: Group 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each volunteer will receive one vial of P. vivax infected inoculum (parasitised red blood cells) at the first blood-stage controlled human malaria infection (CHMI). The optimal dose will be determined following the first CHMI and the selected dose will be administered to all volunteers (Groups 1-3) at both the second and third CHMI.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase A: Group 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each volunteer will receive a fifth of a vial (1:5 dilution) of P. vivax infected inoculum (parasitised red blood cells) at the first blood-stage controlled human malaria infection (CHMI). The optimal dose will be determined following the first CHMI and the selected dose will be administered to all volunteers (Groups 1-3) at both the second and third CHMI.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase A: Group 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each volunteer will receive one twentieth of a vial (1:20 dilution) of P. vivax infected inoculum (parasitised red blood cells) at the first blood-stage controlled human malaria infection (CHMI). The optimal dose will be determined following the first CHMI and the selected dose will be administered to all volunteers (Groups 1-3) at both the second and third CHMI.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase B: Group 4</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The six volunteers from Groups 1, 2 and 3 in will undergo secondary challenge using the optimal inoculum, as determined in Phase A of the study. They will constitute 'Group 4' in Phase B. This will occur approximately eight months (and up to nine months) later after their primary challenge.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase B: Group 6</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three new malaria naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls to Group 4.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase C: Group 5</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The six volunteers from Group 4 in Phase B will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 5 in Phase C. This will occur approximately sixteen months (and up to twenty months) later after their secondary challenge.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase C: Group 7</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The three volunteers from Group 6 who underwent primary challenge in Phase B undergo secondary challenge, again using the optimal inoculum as determined in Phase A, and will now form Group 7 in Phase C. This will occur approximately six months (and up to nine months) later after their primary challenge.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase C: Group 9</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Four to eight new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Groups 5 and 7.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase D: Group 8</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The three volunteers from Group 7 in Phase C will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 8 in Phase D. This will occur approximately five months (and up to ten months) after their secondary challenge.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase D: Group 10</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The four to eight volunteers from Group 9 in Phase C will undergo secondary challenge, using the optimal inoculum as determined in Phase A, and form Group 10 in Phase D. This will occur approximately six months (and up to nine months) later after their primary challenge.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase D: Group 12</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Four to eight new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Groups 8 and 10.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase E: Group 11</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The four to eight volunteers from Group 10 in Phase D will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 11 in Phase E. This will occur approximately five months (and up to ten months) after their secondary challenge.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase E: Group 13</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The four to eight volunteers from Group 12 in Phase D will undergo secondary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 13 in Phase E. This will occur approximately five months (and up to ten months) after their secondary challenge.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase E: Group 15</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Two new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Groups 11 and 13.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase F: Group 14</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The four to eight volunteers from Group 13 in Phase E will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 14 in Phase F. This will occur approximately five months (and up to ten months) after their secondary challenge.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase F: Group 16</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Two new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Group 14.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>P. vivax infected inoculum (parasitised red blood cells)</intervention_name>
    <description>In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.</description>
    <arm_group_label>Phase A: Group 1</arm_group_label>
    <arm_group_label>Phase A: Group 2</arm_group_label>
    <arm_group_label>Phase A: Group 3</arm_group_label>
    <arm_group_label>Phase B: Group 4</arm_group_label>
    <arm_group_label>Phase B: Group 6</arm_group_label>
    <arm_group_label>Phase C: Group 5</arm_group_label>
    <arm_group_label>Phase C: Group 7</arm_group_label>
    <arm_group_label>Phase C: Group 9</arm_group_label>
    <arm_group_label>Phase D: Group 10</arm_group_label>
    <arm_group_label>Phase D: Group 12</arm_group_label>
    <arm_group_label>Phase D: Group 8</arm_group_label>
    <arm_group_label>Phase E: Group 11</arm_group_label>
    <arm_group_label>Phase E: Group 13</arm_group_label>
    <arm_group_label>Phase E: Group 15</arm_group_label>
    <arm_group_label>Phase F: Group 14</arm_group_label>
    <arm_group_label>Phase F: Group 16</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy adult aged 18 to 50 years.&#xD;
&#xD;
          -  Red blood cells positive for the Duffy antigen/chemokine receptor (DARC).&#xD;
&#xD;
          -  Normal serum levels of Glucose-6-phosphate dehydrogenase (G6PDH).&#xD;
&#xD;
          -  Negative haemoglobinopathy screen&#xD;
&#xD;
          -  Able and willing (in the Investigator's opinion) to comply with all study&#xD;
             requirements.&#xD;
&#xD;
          -  Willing to allow the Investigators to discuss the volunteer's medical history with&#xD;
             their General Practitioner.&#xD;
&#xD;
          -  Women only: Must practice continuous effective contraception for the duration of the&#xD;
             clinic visits (first 3 months post-CHMI).&#xD;
&#xD;
          -  Agreement to permanently refrain from blood donation&#xD;
&#xD;
          -  Written informed consent to participate in the trial.&#xD;
&#xD;
          -  Reachable (24/7) by mobile phone during the period between CHMI and completion of all&#xD;
             antimalarial treatment.&#xD;
&#xD;
          -  Willing to take a curative anti-malarial regimen following CHMI.&#xD;
&#xD;
          -  Willing to reside in Oxford for the duration of the study, until antimalarials have&#xD;
             been completed.&#xD;
&#xD;
          -  Answer all questions on the informed consent quiz correctly.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of clinical malaria (any species).&#xD;
&#xD;
          -  Travel to a clearly malaria endemic locality during the study period or within the&#xD;
             preceding six months.&#xD;
&#xD;
          -  Use of systemic antibiotics with known antimalarial activity within 30 days of CHMI&#xD;
             (e.g.trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin,&#xD;
             erythromycin, fluoroquinolones and azithromycin).&#xD;
&#xD;
          -  Haemoglobin &lt;120 g/L for a female volunteer or &lt;130 g/L for a male volunteer prior to&#xD;
             primary CHMI. (However, for enrolment into secondary and tertiary CHMIs slightly lower&#xD;
             haemoglobin values (≤0.5 g/L) will be permitted at the discretion of the Investigator,&#xD;
             to account for the blood volume donated during the previous CHMI).&#xD;
&#xD;
          -  Receipt of immunoglobulins within the three months prior to enrolment.&#xD;
&#xD;
          -  Receipt of blood transfusion at any time in the past.&#xD;
&#xD;
          -  Peripheral venous access unlikely to allow twice daily blood testing (as determined by&#xD;
             the Investigator).&#xD;
&#xD;
          -  Receipt of an investigational product in the 30 days preceding enrolment, or planned&#xD;
             receipt during the study period.&#xD;
&#xD;
          -  Prior receipt of an investigational vaccine likely to impact on interpretation of the&#xD;
             trial data or the P. vivax parasite as assessed by the Investigator.&#xD;
&#xD;
          -  Planned receipt of a COVID-19 vaccine between 2 weeks before the day of CHMI until&#xD;
             completion of antimalarial treatment&#xD;
&#xD;
          -  Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV&#xD;
             infection; asplenia; recurrent, severe infections and chronic (more than 14 days)&#xD;
             immunosuppressant medication within the past 6 months (inhaled and topical steroids&#xD;
             are allowed).&#xD;
&#xD;
          -  History of allergic disease or reactions likely to be exacerbated by malaria&#xD;
             infection.&#xD;
&#xD;
          -  Pregnancy, lactation or intention to become pregnant during the study.&#xD;
&#xD;
          -  Use of medications known to cause prolongation of the QT interval and existing&#xD;
             contraindication to the use of Malarone.&#xD;
&#xD;
          -  Use of medications known to have a potentially clinically significant interaction with&#xD;
             Riamet and Malarone.&#xD;
&#xD;
          -  Any clinical condition known to prolong the QT interval.&#xD;
&#xD;
          -  History of cardiac arrhythmia, including clinically relevant bradycardia.&#xD;
&#xD;
          -  Disturbances of electrolyte balance, e.g. hypokalaemia or hypomagnesaemia.&#xD;
&#xD;
          -  Family history of congenital QT prolongation or sudden death.&#xD;
&#xD;
          -  Contraindications to the use of both of the proposed anti-malarial medications Riamet&#xD;
             and Malarone.&#xD;
&#xD;
          -  History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in&#xD;
             situ).&#xD;
&#xD;
          -  History of serious psychiatric condition that may affect participation in the study.&#xD;
&#xD;
          -  Any other serious chronic illness requiring hospital specialist supervision.&#xD;
&#xD;
          -  Suspected or known current alcohol abuse as defined by an alcohol intake of greater&#xD;
             than 25 standard UK units every week.&#xD;
&#xD;
          -  Suspected or known injecting drug abuse in the 5 years preceding enrolment.&#xD;
&#xD;
          -  Hepatitis B surface antigen (HBsAg) detected in serum.&#xD;
&#xD;
          -  Seropositive for hepatitis C virus (antibodies to HCV) at screening or at C-7 (unless&#xD;
             has taken part in a prior hepatitis C vaccine study with confirmed negative HCV&#xD;
             antibodies prior to participation in that study, and negative HCV RNA PCR at screening&#xD;
             for this study).&#xD;
&#xD;
          -  Positive family history in both 1st AND 2nd degree relatives &lt; 50 years old for&#xD;
             cardiac disease.&#xD;
&#xD;
          -  Volunteers unable to be closely followed for social, geographic or psychological&#xD;
             reasons.&#xD;
&#xD;
          -  Any clinically significant abnormal finding on biochemistry or haematology blood&#xD;
             tests, urinalysis or clinical examination. In the event of abnormal test results,&#xD;
             confirmatory repeat tests will be requested.&#xD;
&#xD;
          -  Any other significant disease, disorder, or finding which may significantly increase&#xD;
             the risk to the volunteer because of participation in the study, affect the ability of&#xD;
             the volunteer to participate in the study or impair interpretation of the study data.&#xD;
&#xD;
          -  Inability of the study team to contact the volunteer's GP to confirm medical history&#xD;
             and safety to participate.&#xD;
&#xD;
          -  Additional exclusion criteria for Groups 6-13: Body weight &lt;50Kg, as measured at&#xD;
             screening&#xD;
&#xD;
        Exclusion criteria on day of CHMI:&#xD;
&#xD;
          -  Acute disease, defined as moderate or severe illness with or without fever.&#xD;
&#xD;
          -  Current COVID-19 infection, defined as ongoing symptoms with positive COVID-19 PCR&#xD;
             swab test taken during current illness or positive COVID-19 PCR swab test within&#xD;
             preceding 14 days without symptoms.&#xD;
&#xD;
          -  Pregnancy.&#xD;
&#xD;
          -  Potential volunteers who are due to have a COVID-19 vaccine in the period between 2&#xD;
             weeks before the day of malaria challenge and expected time of completion of malaria&#xD;
             treatment will not be enrolled (estimate up to 3 weeks after day of challenge based on&#xD;
             experience in this study to date). If a volunteer receives an appointment for COVID-19&#xD;
             vaccination after they have undergone malaria challenge but before reaching malaria&#xD;
             diagnosis criteria, they will be advised to delay their COVID-19 vaccination until&#xD;
             after reaching malaria diagnostic criteria and completion of antimalarial treatment.&#xD;
             If a participant does not wish to delay their COVID-19 vaccination, they will be&#xD;
             treated with antimalarial treatment at that time point and withdrawn from the study&#xD;
             but will be encouraged to complete follow-up for safety.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Angela M Minassian, MBBS MA DPhil MRCP FRCPath</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Oxford</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centre for Clinical Vaccinology &amp; Tropical Medicine</name>
      <address>
        <city>Oxford</city>
        <state>Oxfordshire</state>
        <zip>OX3 7LE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>November 29, 2018</study_first_submitted>
  <study_first_submitted_qc>January 4, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 9, 2019</study_first_posted>
  <last_update_submitted>August 16, 2022</last_update_submitted>
  <last_update_submitted_qc>August 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 17, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Malaria</mesh_term>
    <mesh_term>Malaria, Vivax</mesh_term>
  </condition_browse>
  <pending_results>
    <submitted>March 1, 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/NCT03797989
org study id: VAC069
nct id: NCT03797989
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a clinical study to assess the safety and feasibility of Plasmodium vivax (P. vivax)
      controlled blood-stage human malaria infection (CHMI), by inoculation using a newly created
      source of P. vivax malaria-infected blood.

      25 healthy malaria-naïve UK volunteers, aged 18 - 50, will be recruited through the five
      phases of the study at the CCVTM, Oxford. Volunteers will undergo primary, secondary and
      tertiary P. vivax blood-stage challenges, which will be induced by injection of P. vivax
      infected blood. After the first challenge, the optimal dose for blood-stage CHMI will be
      selected and used for the second and third challenges. Through each challenge period,
      volunteers will have blood taken at regular intervals to measure the parasite growth,
      quantify the sexual parasite forms and assess the immune response to P. vivax infection.
      Transmission of P. vivax from volunteers to the Anopheline mosquito vectors will also be
      assessed.

      In each challenge, following diagnosis, volunteers will be treated with a standard
      antimalarial course of oral artemether-lumefantrine (Riamet), given over 60 hours. Volunteers
      who take part in this study will be involved in the trial for approximately 2 years,
      receiving each of the three challenges at intervals of approximately 5 (and up to 9) months.
      Volunteers will be followed for 3 months after their last challenge.
This study aims primarily to assess the safety and feasibility of controlled blood-stage
      human P. vivax malaria infection. This will be the first time that this source of P. vivax
      infected blood will be utilised and the first P. vivax bloodstage CHMI in Europe. If
      demonstrated to be safe, it is intended that this parasitised blood bank be used in future
      CHMI studies to evaluate candidate vaccines.

      This study will also assess parasite growth, including quantifying the sexual-stage parasites
      in the blood, as well as the transmission of P. vivax from volunteers to the Anopheline
      mosquito vectors and the immune responses in primary, secondary and tertiary P. vivax
      blood-stage challenge, as further secondary aims. Natural immunity to P. vivax is acquired
      over time, following repeated exposure. Repeated blood-stage challenge would improve
      understanding of how the human immune response to P. vivax infected is acquired, and how
      parasite growth changes in a second or third exposure. Repeated challenges can also be used
      to test if potential vaccine candidates can protect against repeated malaria infection. If
      proven to be safe and feasible in this study, this will provide a basis for conducting P.
      vivax blood-stage re-challenge studies for evaluation of new vaccine candidates.

      The study is funded through The Wellcome Trust and MultiViVax, a European Commission Horizon
      2020 funded project.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: None (Open Label)
measure: Safety of primary P. vivax blood-stage CHMI as measured by (S)AE occurrences
time frame: 36 months
measure: The optimal inoculation dose to take forward to future P. vivax CHMI studies
time frame: 3 months
description: Choosing the optimal inoculation dose to take forward to future P. vivax CHMI studies will be decided based on the following algorithm:
Ideal choice = the first group (2/2 volunteers) to reach diagnosis criteria (within 21 days). N.B. If both volunteers in Group 1 develop infection AND both volunteers in Group 2 (or 3) reliably develop infection within 5 days of Group 1 (and within the 21-day window) then the lowest dose group should be chosen.
measure: Feasibility of primary P. vivax blood-stage CHMI as measured by successful infection (development of detectable persistent parasitaemia by thick film and qPCR +/- clinical symptoms)
time frame: 36 months
measure: Safety of secondary and tertiary P. vivax controlled blood-stage CHMI as measured by (S)AE occurrences
time frame: 36 months
measure: Immune response to primary, secondary and tertiary P. vivax pre-treatment
time frame: 36 months
description: As measured by antibody, B cell and T cell responses through experimental injection of P. vivax infected erythrocytes
measure: Gametocytaemia
time frame: 36 months
description: As measured by qPCR in primary, secondary and tertiary P. vivax blood-stage CHMI.
measure: Feasibility of secondary and tertiary P. vivax controlled blood-stage CHMI as measured by successful infection (development of detectable persistent parasitaemia by thick film and qPCR +/- clinical symptoms)
time frame: 36 months
measure: Transmissibility of gametocytes from the infected volunteer to Anopheline mosquito vector, which will be assesed by Direct Membrane Feeding Assays (DMFA)
time frame: 36 months
arm group label: Phase A: Group 1
arm group type: Experimental
description: Each volunteer will receive one vial of P. vivax infected inoculum (parasitised red blood cells) at the first blood-stage controlled human malaria infection (CHMI). The optimal dose will be determined following the first CHMI and the selected dose will be administered to all volunteers (Groups 1-3) at both the second and third CHMI.
arm group label: Phase A: Group 2
arm group type: Experimental
description: Each volunteer will receive a fifth of a vial (1:5 dilution) of P. vivax infected inoculum (parasitised red blood cells) at the first blood-stage controlled human malaria infection (CHMI). The optimal dose will be determined following the first CHMI and the selected dose will be administered to all volunteers (Groups 1-3) at both the second and third CHMI.
arm group label: Phase A: Group 3
arm group type: Experimental
description: Each volunteer will receive one twentieth of a vial (1:20 dilution) of P. vivax infected inoculum (parasitised red blood cells) at the first blood-stage controlled human malaria infection (CHMI). The optimal dose will be determined following the first CHMI and the selected dose will be administered to all volunteers (Groups 1-3) at both the second and third CHMI.
arm group label: Phase B: Group 4
arm group type: Experimental
description: The six volunteers from Groups 1, 2 and 3 in will undergo secondary challenge using the optimal inoculum, as determined in Phase A of the study. They will constitute 'Group 4' in Phase B. This will occur approximately eight months (and up to nine months) later after their primary challenge.
arm group label: Phase B: Group 6
arm group type: Experimental
description: Three new malaria naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls to Group 4.
arm group label: Phase C: Group 5
arm group type: Experimental
description: The six volunteers from Group 4 in Phase B will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 5 in Phase C. This will occur approximately sixteen months (and up to twenty months) later after their secondary challenge.
arm group label: Phase C: Group 7
arm group type: Experimental
description: The three volunteers from Group 6 who underwent primary challenge in Phase B undergo secondary challenge, again using the optimal inoculum as determined in Phase A, and will now form Group 7 in Phase C. This will occur approximately six months (and up to nine months) later after their primary challenge.
arm group label: Phase C: Group 9
arm group type: Experimental
description: Four to eight new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Groups 5 and 7.
arm group label: Phase D: Group 8
arm group type: Experimental
description: The three volunteers from Group 7 in Phase C will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 8 in Phase D. This will occur approximately five months (and up to ten months) after their secondary challenge.
arm group label: Phase D: Group 10
arm group type: Experimental
description: The four to eight volunteers from Group 9 in Phase C will undergo secondary challenge, using the optimal inoculum as determined in Phase A, and form Group 10 in Phase D. This will occur approximately six months (and up to nine months) later after their primary challenge.
arm group label: Phase D: Group 12
arm group type: Experimental
description: Four to eight new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Groups 8 and 10.
arm group label: Phase E: Group 11
arm group type: Experimental
description: The four to eight volunteers from Group 10 in Phase D will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 11 in Phase E. This will occur approximately five months (and up to ten months) after their secondary challenge.
arm group label: Phase E: Group 13
arm group type: Experimental
description: The four to eight volunteers from Group 12 in Phase D will undergo secondary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 13 in Phase E. This will occur approximately five months (and up to ten months) after their secondary challenge.
arm group label: Phase E: Group 15
arm group type: Experimental
description: Two new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Groups 11 and 13.
arm group label: Phase F: Group 14
arm group type: Experimental
description: The four to eight volunteers from Group 13 in Phase E will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 14 in Phase F. This will occur approximately five months (and up to ten months) after their secondary challenge.
arm group label: Phase F: Group 16
arm group type: Experimental
description: Two new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Group 14.
intervention type: Biological
intervention name: P. vivax infected inoculum (parasitised red blood cells)
description: In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.
arm group label: Phase A: Group 1
arm group label: Phase A: Group 2
arm group label: Phase A: Group 3
arm group label: Phase B: Group 4
arm group label: Phase B: Group 6
arm group label: Phase C: Group 5
arm group label: Phase C: Group 7
arm group label: Phase C: Group 9
arm group label: Phase D: Group 10
arm group label: Phase D: Group 12
arm group label: Phase D: Group 8
arm group label: Phase E: Group 11
arm group label: Phase E: Group 13
arm group label: Phase E: Group 15
arm group label: Phase F: Group 14
arm group label: Phase F: Group 16
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Angela M Minassian, MBBS MA DPhil MRCP FRCPath
role: Principal Investigator
affiliation: University of Oxford
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Malaria
mesh term: Malaria, Vivax
submitted: March 1, 2023