<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/NCT02259426</url>
  </required_header>
  <id_info>
    <org_study_id>DAPPI-1</org_study_id>
    <nct_id>NCT02259426</nct_id>
  </id_info>
  <brief_title>Dihydroartemisinin-piperaquine With Low Dose Primaquine to Reduce Malaria Transmission</brief_title>
  <acronym>DAPPI</acronym>
  <official_title>A Double Blind Randomized Controlled Trial of Dihydroartemisinin-piperaquine Alone and in Combination With Single Dose Primaquine to Reduce Post-treatment Malaria Transmission.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>London School of Hygiene and Tropical Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>International Centre of Insect Physiology and Ecology (ICIPE)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>London School of Hygiene and Tropical Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primaquine (PQ) is currently the only available drug that can clear the mature transmission&#xD;
      stages of P. falciparum parasites. PQ was previously shown to clear gametocytes that persist&#xD;
      after artemisinin-combination therapy. A major caveat to the use of primaquine in mass&#xD;
      adminsitrations for the reduction of malaria transmission is that metabolism of the drug in&#xD;
      individuals with glucose-6 phosphate dehydrogenase (G6PD) deficiency can lead to transient&#xD;
      haemolysis. The haemolytic side effect of PQ is dose-related. Haemolysis is more commonly&#xD;
      observed after prolonged PQ treatment but has also been observed in African populations&#xD;
      following a single dose of PQ. This haemolysis was self-limiting, largely restricted to G6PD&#xD;
      deficient individuals and did not lead to clinical symptoms. Nevertheless, any drug-induced&#xD;
      haemolysis is reason for concern and the World Health Organization has therefore reduced the&#xD;
      recommended dose of single low dose primaquine from 0.75mg/kg to 0.25mg/kg. This dosage is&#xD;
      deemed safe without prior G6PD or Hb screening. However, there is limited direct evidence on&#xD;
      the extent to which this dosage of PQ prevents malaria transmission to mosquitoes.&#xD;
&#xD;
      In the current study, the investigators will assess the efficacy of DP in combination with&#xD;
      low-dose PQ to prevent onward malaria transmission. The investigators will perform the&#xD;
      investigators study in individuals aged 5-15 years who are carry microscopically detectable&#xD;
      densities of P. falciparum gametocytes. This age group is chosen because asexual parasite&#xD;
      carriage and gametocyte carriage are common in this age group. All enrolled individuals will&#xD;
      receive a full three-day course of DP, and will be randomized to receive a dose of primaquine&#xD;
      or placebo with their third dose. Efficacy will be determined based on gametocyte carriage&#xD;
      during follow-up, measured by molecular methods. For all individuals, the effect of treatment&#xD;
      on infectivity to mosquitoes will be assessed by membrane feeding assays at two time points.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">December 2015</completion_date>
  <primary_completion_date type="Actual">September 2015</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Gametocyte prevalence on day 7 after initiation of treatment</measure>
    <time_frame>day 7 of follow-up</time_frame>
    <description>Gametocyte prevalence on day 7 after initiation of treatment is measured by molecular methods.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Transmission to Anopheles gambiae mosquitoes</measure>
    <time_frame>Day 3 and 7 during follow-up</time_frame>
    <description>Mosquito membrane feeding assays will be used to determine the proportion of infected mosquitoes and the oocyst burden in infected mosquitoes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Haematological recovery</measure>
    <time_frame>14 days during follow-up</time_frame>
    <description>Haemoglobin concentration will be determined at enrolment and on days 2, 3, 7 and 14 during follow-up. Haemoglobin concentration will be presented as grams per decilitre and as concentration relative to enrollment value.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gametocyte sex-ratio</measure>
    <time_frame>14 days of follow-up</time_frame>
    <description>The ratio of male:female gametocytes will be determined at enrolment and on days 2, 3, 7 and 14 during follow-up by qRT-PCR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gametocyte carriage during follow-up</measure>
    <time_frame>14 days during follow-up</time_frame>
    <description>Gametocyte prevalence at enrolment and on days 2, 3, 7 (primary outcome measure), and 14 during follow-up. The duration of gametocyte carriage in days will be estimated.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">120</enrollment>
  <condition>Malaria</condition>
  <condition>Asymptomatic Malaria</condition>
  <condition>Plasmodium Falciparum</condition>
  <arm_group>
    <arm_group_label>Dihydroartemisínin-piperaquine (Artekin)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Dihydroartemisínin-piperaquine combination alone</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dihydroartemisinin-piperaquine, Primaquine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dihydroartemisinin-piperaquine with single-dose 0.25mg/kg Primaquine</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dihydroartemisinin-piperaquine combination (Artekin)</intervention_name>
    <arm_group_label>Dihydroartemisinin-piperaquine, Primaquine</arm_group_label>
    <arm_group_label>Dihydroartemisínin-piperaquine (Artekin)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Primaquine</intervention_name>
    <description>Single-dose 0.25mg/kg</description>
    <arm_group_label>Dihydroartemisinin-piperaquine, Primaquine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Microscopically detectable P. falciparum gametocyte carriage&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 5 years or &gt; 15 years&#xD;
&#xD;
          -  Non-falciparum malaria co-infection&#xD;
&#xD;
          -  Malaria parasite density ≥ 200,000 parasites/µL&#xD;
&#xD;
          -  Clinical symptoms indicating severe malaria&#xD;
&#xD;
          -  Axillary temperature ≥ 39°C&#xD;
&#xD;
          -  Body Mass Index (BMI) below 16 or above 32 kg/m2&#xD;
&#xD;
          -  Haemoglobin concentration below 9.5 g/dL&#xD;
&#xD;
          -  Anti-malarials taken in last 2 days&#xD;
&#xD;
          -  For women: Pregnancy (assessed by clinical examination and urine pregnancy test) or&#xD;
             lactation&#xD;
&#xD;
          -  Known hypersensitivity to DP or PQ&#xD;
&#xD;
          -  History and/or symptoms indicating chronic illness&#xD;
&#xD;
          -  Current use of tuberculosis or anti-retroviral medication&#xD;
&#xD;
          -  Unable to give written informed consent&#xD;
&#xD;
          -  Unwillingness to participate in two membrane feeding assays&#xD;
&#xD;
          -  Travel history to Angola, Cameroon, Chad, Central African Republic, Congo, DR Congo, -&#xD;
             Equatorial Guinea, Ethiopia, Gabon, Nigeria and Sudan&#xD;
&#xD;
          -  Family history of congenital prolongation of the QTc interval or sudden death or with&#xD;
             any other clinical condition known to prolong the QTc interval such as history of&#xD;
             symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe&#xD;
             cardiac disease&#xD;
&#xD;
          -  Taking drugs that are known to influence cardiac function and to prolong QTc interval,&#xD;
             such as class IA and III: neuroleptics, antidepressant agents, certain antibiotics&#xD;
             including some agents of the following classes - macrolides, fluoroquinolones,&#xD;
             imidazole, and triazole antifungal agents, certain non-sedating antihistaminics&#xD;
             (terfenadine, astemizole) and cisapride&#xD;
&#xD;
          -  Known disturbances of electrolyte balance, e.g. hypokalaemia or hypomagnesaemia&#xD;
&#xD;
          -  Taking drugs which may be metabolized by cytochrome enzyme CYP2D6 (e.g., flecainide,&#xD;
             metoprolol, imipramine, amitriptyline, clomipramine)&#xD;
&#xD;
          -  Blood transfusion within last 90 days&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>15 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Teun Bousema, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Radboud university medical center, London School of hygiene and tropical medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Patrick Sawa, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>ICIPE</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>ICIPE</name>
      <address>
        <city>Mbita</city>
        <state>Nyanza</state>
        <zip>30-40305</zip>
        <country>Kenya</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Kenya</country>
  </location_countries>
  <verification_date>January 2016</verification_date>
  <study_first_submitted>September 29, 2014</study_first_submitted>
  <study_first_submitted_qc>October 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 8, 2014</study_first_posted>
  <last_update_submitted>January 13, 2016</last_update_submitted>
  <last_update_submitted_qc>January 13, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 14, 2016</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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Piperaquine</mesh_term>
    <mesh_term>Primaquine</mesh_term>
    <mesh_term>Artenimol</mesh_term>
  </intervention_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/NCT02259426
org study id: DAPPI-1
nct id: NCT02259426
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
Primaquine (PQ) is currently the only available drug that can clear the mature transmission
      stages of P. falciparum parasites. PQ was previously shown to clear gametocytes that persist
      after artemisinin-combination therapy. A major caveat to the use of primaquine in mass
      adminsitrations for the reduction of malaria transmission is that metabolism of the drug in
      individuals with glucose-6 phosphate dehydrogenase (G6PD) deficiency can lead to transient
      haemolysis. The haemolytic side effect of PQ is dose-related. Haemolysis is more commonly
      observed after prolonged PQ treatment but has also been observed in African populations
      following a single dose of PQ. This haemolysis was self-limiting, largely restricted to G6PD
      deficient individuals and did not lead to clinical symptoms. Nevertheless, any drug-induced
      haemolysis is reason for concern and the World Health Organization has therefore reduced the
      recommended dose of single low dose primaquine from 0.75mg/kg to 0.25mg/kg. This dosage is
      deemed safe without prior G6PD or Hb screening. However, there is limited direct evidence on
      the extent to which this dosage of PQ prevents malaria transmission to mosquitoes.

      In the current study, the investigators will assess the efficacy of DP in combination with
      low-dose PQ to prevent onward malaria transmission. The investigators will perform the
      investigators study in individuals aged 5-15 years who are carry microscopically detectable
      densities of P. falciparum gametocytes. This age group is chosen because asexual parasite
      carriage and gametocyte carriage are common in this age group. All enrolled individuals will
      receive a full three-day course of DP, and will be randomized to receive a dose of primaquine
      or placebo with their third dose. Efficacy will be determined based on gametocyte carriage
      during follow-up, measured by molecular methods. For all individuals, the effect of treatment
      on infectivity to mosquitoes will be assessed by membrane feeding assays at two time points.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Gametocyte prevalence on day 7 after initiation of treatment
time frame: day 7 of follow-up
description: Gametocyte prevalence on day 7 after initiation of treatment is measured by molecular methods.
measure: Transmission to Anopheles gambiae mosquitoes
time frame: Day 3 and 7 during follow-up
description: Mosquito membrane feeding assays will be used to determine the proportion of infected mosquitoes and the oocyst burden in infected mosquitoes.
measure: Haematological recovery
time frame: 14 days during follow-up
description: Haemoglobin concentration will be determined at enrolment and on days 2, 3, 7 and 14 during follow-up. Haemoglobin concentration will be presented as grams per decilitre and as concentration relative to enrollment value.
measure: Gametocyte sex-ratio
time frame: 14 days of follow-up
description: The ratio of male:female gametocytes will be determined at enrolment and on days 2, 3, 7 and 14 during follow-up by qRT-PCR.
measure: Gametocyte carriage during follow-up
time frame: 14 days during follow-up
description: Gametocyte prevalence at enrolment and on days 2, 3, 7 (primary outcome measure), and 14 during follow-up. The duration of gametocyte carriage in days will be estimated.
arm group label: Dihydroartemisínin-piperaquine (Artekin)
arm group type: Active Comparator
description: Dihydroartemisínin-piperaquine combination alone
arm group label: Dihydroartemisinin-piperaquine, Primaquine
arm group type: Experimental
description: Dihydroartemisinin-piperaquine with single-dose 0.25mg/kg Primaquine
intervention type: Drug
intervention name: Dihydroartemisinin-piperaquine combination (Artekin)
arm group label: Dihydroartemisinin-piperaquine, Primaquine
arm group label: Dihydroartemisínin-piperaquine (Artekin)
intervention type: Drug
intervention name: Primaquine
description: Single-dose 0.25mg/kg
arm group label: Dihydroartemisinin-piperaquine, Primaquine
criteria: 
gender: All
minimum age: 5 Years
maximum age: 15 Years
healthy volunteers: No
last name: Teun Bousema, PhD
role: Principal Investigator
affiliation: Radboud university medical center, London School of hygiene and tropical medicine
last name: Patrick Sawa, MD
role: Principal Investigator
affiliation: ICIPE
facility: 
country: Kenya
responsible party type: Sponsor
mesh term: Malaria
mesh term: Piperaquine
mesh term: Primaquine
mesh term: Artenimol