<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/NCT02199951</url>
  </required_header>
  <id_info>
    <org_study_id>INESS 02/2012</org_study_id>
    <secondary_id>GRANT ID#. 48363.01</secondary_id>
    <nct_id>NCT02199951</nct_id>
  </id_info>
  <brief_title>Introduction of Eurartesim® in Burkina Faso, Mozambique, Ghana and Tanzania</brief_title>
  <official_title>Observational Study to Evaluate the Clinical Safety After Introduction of the Fixed Dose Artemisinin-based Combination Therapy Eurartesim® (Dihydroartemisinin/Piperaquine [Dha/Pqp]) in Public Health Districts in Sub-Saharan Africa.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>INDEPTH Network</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Health, Ghana</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ifakara Health Research and Development Centre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ministry of Health, Burkina Faso</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Centro de Investigacao em Saude de Manhica</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>INDEPTH Network</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      WHO recommends the use of artemisinin-based combination therapies (ACTs) in the treatment of&#xD;
      uncomplicated malaria to stem falciparum malaria drug resistance. New ACTs are entering the&#xD;
      African market and will be used by the public health care system. The collection of safety&#xD;
      data and risk evaluation through observational data are critical in order to assess&#xD;
      risk/benefit profile of each ACT through its life cycle and providing information on the best&#xD;
      use. Additionally there is need to assess the impact of the introduction of a new ACT in the&#xD;
      evolution of its efficacy and malaria morbidity and mortality. Dihydroartemisinin/Piperaquine&#xD;
      (DHA/PQP) is a new ACT approved by European Medical Agency and a number of African countries.&#xD;
      This is a phase IV observational evaluation of the clinical safety of the fixed-dose DHA/PQP&#xD;
      (Eurartesim®) in public health facilities within selected Health and Demographic Surveillance&#xD;
      Centres in Burkina Faso (Nouna), Mozambique (Manhica), Ghana (Dodowa, Kintampo, Navrongo),&#xD;
      Tanzania (Rufiji) and other African countries to be added. Eurartesim® will be used as&#xD;
      first-line treatment of uncomplicated malaria an objective to evaluate the safety of&#xD;
      Eurartesim® when used under usual conditions in 10,000 patients. Patients &gt; 6 months and 5 kg&#xD;
      except pregnant women will be enrolled and Eurartesim® administered as a single daily dose&#xD;
      regimen over 3 days. Patients will be contacted at Day 5 (± 2 days) after treatment, to&#xD;
      assess recovery and any adverse events.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study will be performed in public health facilities in up to 7 selected HDSS centres (Health&#xD;
      and Demographic Surveillance sites) within the HDSS in Burkina Faso (1), Mozambique (1),&#xD;
      Ghana (3), and Tanzania (2), where Eurartesim® will be used as first-line treatment of&#xD;
      uncomplicated malaria episodes.&#xD;
&#xD;
      Primary:&#xD;
&#xD;
      Evaluate the safety of Eurartesim® when used under usual conditions in 10,000 patients with&#xD;
      signs and symptoms of uncomplicated malaria confirmed by a parasitological diagnosis&#xD;
      (Microscopy/Rapid Diagnostic Test) or, when this test is not available, by WHO diagnostic&#xD;
      criteria.&#xD;
&#xD;
      Main Secondary:&#xD;
&#xD;
      Intensive assessment of a nested subset of 1,000 patients to evaluate the effect of the&#xD;
      administration of Eurartesim® on blood biochemistry, full blood count, WBC differential count&#xD;
      and QTc intervals. QTc interval and piperaquine concentration relationship will also be&#xD;
      investigated in selected centers.&#xD;
&#xD;
      Other Secondaries:&#xD;
&#xD;
      Although it is expected that the vast majority of patients will be infected with P.&#xD;
      falciparum, comparisons of the clinical tolerability of Plasmodium falciparum infected&#xD;
      patients versus patients infected with other Plasmodia, as confirmed by the thick blood smear&#xD;
      results, will be carried-out in the nested subset of 1,000 patients.&#xD;
&#xD;
      Assessment of the relationship between the occurrence of Adverse Events and the&#xD;
      administration of concomitant medications will also be evaluated in the subset of 1,000&#xD;
      patients.&#xD;
&#xD;
      All patients visiting Health facilities in the HDSS areas and for whom a diagnosis of&#xD;
      uncomplicated malaria (according to the WHO criteria) is suspected or confirmed by a&#xD;
      parasitological diagnosis (Microscopy/Rapid Diagnostic Test) and who have signed informed&#xD;
      consent/assent (a parent/guardian for children below 18 years old) will be included in the&#xD;
      study. In the subset of 1,000 patients, the presence of Plasmodia of any species will be&#xD;
      confirmed microscopically.&#xD;
&#xD;
      A thick blood smear will be prepared for further microscopic diagnosis in all the patients.&#xD;
      Eurartesim® tablets will be prescribed to the patients (or to the parents/guardians, if the&#xD;
      patients are children) meeting the protocol inclusion criteria before the results of the&#xD;
      thick blood smear are known.&#xD;
&#xD;
      The patients will be contacted at Day 5 (± 2 days), in order to capture recovery status and&#xD;
      all the experienced adverse events. A visit by the community health agent will be scheduled&#xD;
      on all the cases in which the information collected during the telephone contact should be&#xD;
      considered incomplete or unreliable ones. Special procedures will be followed in case of&#xD;
      serious and/or severe adverse events and events classified of special interest (see specific&#xD;
      section).&#xD;
&#xD;
      The subset of 1,000 patients will be intensively followed-up. These patients will have&#xD;
      haematology (Hb and full blood counts (RBC, WBC and differential count)) and standard&#xD;
      biochemistry (BUN, Creatinine, ALT/AST, Bilirubine, electrolytes (K+ and Cl-)) undertaken at&#xD;
      Day 1 (before drug administration), Day 3 (3-4 hours after the last dose of treatment), and&#xD;
      Day 7. If the results are abnormal and clinically relevant, the blood examination will be&#xD;
      repeated until normalization. In all the 1000 patients, a plasma sample will be collected on&#xD;
      Day 1 (before drug administration), twice on Day 3 (i.e. before and 3-4 hours after the last&#xD;
      drug administration) as well as on Day 7 to assess plasma PQ concentration. From such blood&#xD;
      drawings and before centrifugation, three drops of whole blood will be spotted on filter&#xD;
      papers. These filter papers will be utilized to determine whole blood piperaquine&#xD;
      concentration with the Dry Blood Spot methodology (if a validated analytical method for such&#xD;
      determination will be settled up at the time of the study course). ECGs will be undertaken on&#xD;
      Day 1 (before drug administration), twice on Day 3 (i.e. before and 3-4 hours after the last&#xD;
      drug administration) as well as on Day 7 (ECG on Day 1 and Day 3 after last drug&#xD;
      administration will be collected in triplicate); safety information will be collected at all&#xD;
      these visits.&#xD;
&#xD;
      If the QTcF (QT corrected by Fridericia's formula) value assessed on Day 3 before last dose&#xD;
      is above 500 ms, Eurartesim® should be withheld until QTcF returns below 480 ms within 6&#xD;
      hours. Thereafter, the Eurartesim® cycle may be completed under frequent QTc monitoring based&#xD;
      on medical judgment. If the QTcF does not return below 480 ms within 6 hours, another&#xD;
      antimalarial therapy should be considered.&#xD;
&#xD;
      The occurrence of any adverse events will be solicited from the subset of 1,000 patients on&#xD;
      Days 3 and 7 following administration of Eurartesim® as well as in any additional visits.&#xD;
&#xD;
      All patients in the study with a cardiac event of special interest (see below) will have an&#xD;
      ECG performed.&#xD;
&#xD;
      Patients will be asked to report to the health facility or to the HDSS if any adverse event&#xD;
      occurs after Day 5 (± 2 days) contact and within 28 days after the start of Eurartesim®&#xD;
      intake.&#xD;
&#xD;
      Female patients will be encouraged to communicate to the study team if they get pregnant&#xD;
      within a period of two months after the start of the Eurartesim® treatment. In these cases,&#xD;
      information on the evolution of the pregnancy will be collected at 3, 6, 9 months and after&#xD;
      the delivery (6 and 14 weeks). Information on the drugs taken during the pregnancy as well as&#xD;
      AEs/SAEs/AESIs and the health status of the newborn/s will be collected.&#xD;
&#xD;
      Patients will be instructed to take Eurartesim® with a dose regimen of one administration&#xD;
      every 24 hours over a period of three days, i.e. at Day 1, then after 24 hours (Day 2) and&#xD;
      after 48 hours (Day 3) from the first administration.&#xD;
&#xD;
      The dose will be based on patient body weight. Two strengths of Eurartesim® will be provided&#xD;
      to facilitate the dosing in children and adults: 20/160mg and 40/320mg of DHA and PQP&#xD;
      respectively.&#xD;
&#xD;
      The patients will be instructed to take Eurartesim® with water, at least three hours before&#xD;
      or three hours after food intake (i.e. three hours after the previous food intake with no&#xD;
      food intake for the following three hours after Eurartesim® administration).&#xD;
&#xD;
      To facilitate drug administration in small children, tablets will be crushed on a spoon and&#xD;
      given with water. If vomiting occurs within 30 min from drug administration, dose will be&#xD;
      re-administered. If vomiting occurs within 30 to 60 min, half a dose have to be&#xD;
      re-administered. Re-dosing should not be attempted more than once.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>September 2013</start_date>
  <completion_date type="Anticipated">December 2014</completion_date>
  <primary_completion_date type="Anticipated">August 2014</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>Adverse events</measure>
    <time_frame>28 Days</time_frame>
    <description>• Clinical safety will be determined by analysis of the number of adverse events (frequency, intensity, action taken, outcome) captured during their follow up contacts on Day 5 (±2 days) after starting the treatment with Eurartesim® as well as those identified in the referring hospitals or through adverse events spontaneously reported by the patient detected at the health facility within 28 days after the first medication intake.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse events of special interest</measure>
    <time_frame>28 Days</time_frame>
    <description>In case of an AESI confirmed by the study doctor, the sponsor shall be informed within 24 hours, even if the event does not satisfy any condition of seriousness. Notification will occur through the use of an ad hoc AESI form. AESIs can be related to:&#xD;
Cardio-toxicity i.e. prolonged QT&#xD;
Neurotoxicity/seizures&#xD;
Cutaneous reactions/phototoxicity</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Peak plasma concentration (Cmax) on Day 3 and plasma concentrations before last dose on day 3 and day 7)</measure>
    <time_frame>7 Days</time_frame>
    <description>In predefined centres having the capability to store plasma samples, all the 1000 subset will also perform a blood drawing for PQ plasma concentration at Day 1 (before drug administration), twice at Day 3 (before and 3-4 after the last drug administration) as well as on Day 7.</description>
  </other_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">10000</enrollment>
  <condition>Malaria</condition>
  <arm_group>
    <arm_group_label>Dihydroartemisinin and piperaquine</arm_group_label>
    <description>The patients will take Eurartesim® (DHA/PQP) with a dose regimen of one administration every 24 hours over a period of three days, i.e. at Day 1, then after 24 hours (Day 2) and after 48 hours (Day 3) from the first administration. The dose will be based on body weight. Two strengths of Eurartesim® will be provided for dosing in children and adults: 20/160mg and 40/320mg of DHA and PQP respectively. Body weight (kg) Daily dose (mg) Number of tablets per dose 20/160mg DHA/PQ 40/320mg DHA/PQ 5 to &lt;7 10 mg DHA and 80 mg PQP ½ tablet 7 to &lt;13 20 mg DHA and 160 mg PQP 1 tablet 13 to &lt; 24 40 mg DHA and 320 mg PQP 1 tablet 24 to &lt; 36 80 mg DHA and 640 mg PQP 2 tablets 36 to &lt; 75 120 mg DHA and 960 mg PQP 3 tablets 75 to &lt; 100 160 mg DHA and 1280 mg PQP 4 tablets &gt; 100.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dihydroartemisinin and piperaquine</intervention_name>
    <description>Antimalarial</description>
    <arm_group_label>Dihydroartemisinin and piperaquine</arm_group_label>
    <other_name>Eurartesim</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with uncomplicated malaria except pregnant women&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Uncomplicated malaria (Plasmodia of any species) diagnosed as per national policies&#xD;
             and in line with WHO recommendations (a history of fever in the previous 24 h and/or&#xD;
             the presence of anaemia, for which pallor of the palms appears to be the most reliable&#xD;
             sign in young children). Confirmation of malaria by a parasitological diagnosis with&#xD;
             RDT is encouraged but its absence does not prevent patients from being enrolled.&#xD;
&#xD;
               -  Age ≥ 6 months and weight ≥ 5 kg.&#xD;
&#xD;
               -  Capability of taking an oral medication.&#xD;
&#xD;
               -  Ability and willingness to participate based on signed informed consent (a parent&#xD;
                  or a guardian has to sign for children below 18 years old), or on verbal consent&#xD;
                  given in front of a witness signing the informed consent, and access to health&#xD;
                  facility. The patient is to comply with all scheduled follow-up visits.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  • Known allergy to artemisinin or to piperaquine.&#xD;
&#xD;
               -  Known pregnancy.&#xD;
&#xD;
               -  Lactating women should be excluded if other anti-malarial treatments are&#xD;
                  available&#xD;
&#xD;
               -  Complicated malaria.&#xD;
&#xD;
               -  Taking medicinal products that are known to prolong the QTc interval. These&#xD;
                  include (but are not limited to):&#xD;
&#xD;
               -  Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide,&#xD;
                  procainamide, quinidine, hydroquinidine, sotalol).&#xD;
&#xD;
               -  Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine,&#xD;
                  haloperidol, mesoridazine, pimozide, or thioridazine), antidepressive agents.&#xD;
&#xD;
               -  Certain antimicrobial agents, including agents of the following classes:&#xD;
&#xD;
          -  macrolides (e.g. erythromycin, clarithromycin),&#xD;
&#xD;
          -  fluoroquinolones (e.g. moxifloxacin, sparfloxacin),&#xD;
&#xD;
          -  imidazole and triazole antifungal agents,&#xD;
&#xD;
          -  and also pentamidine and saquinavir.&#xD;
&#xD;
               -  Certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine).&#xD;
&#xD;
               -  Cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl,&#xD;
                  methadone, vinca alkaloids, arsenic trioxide.&#xD;
&#xD;
               -  Have taken a DHA/PQP dose in the previous four weeks.&#xD;
&#xD;
               -  Family history of sudden unexplained death, or personal or family history of&#xD;
                  predisposing cardiac conditions for arrhythmia/QT prolongation (including&#xD;
                  congenital long QT syndrome, arrhythmia, QTc interval greater than 450&#xD;
                  milliseconds with either Bazett or Fridericia correction).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Fred N Binka, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>INDEPTH Network</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Bernhards R Ogutu, MD, PhD</last_name>
    <phone>+254 733 966 065</phone>
    <email>berrnhards.ogutu@indepth-network.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Rita Baiden, MD</last_name>
    <phone>+233 208 098 000</phone>
    <email>rita.baiden@indepth-network.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Nouna Research Centre</name>
      <address>
        <city>Nouna</city>
        <country>Burkina Faso</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Guillaume COMPAORE, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Nanoro Health Research Centre</name>
      <address>
        <city>Ouagadougou</city>
        <country>Burkina Faso</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Innocent Valea, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>INDEPTH Network</name>
      <address>
        <city>Accra</city>
        <zip>KD 213</zip>
        <country>Ghana</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bernhards R Ogutu, MD</last_name>
      <phone>+254 733 966 065</phone>
      <email>bernhards.ogutu@indepth-network.org</email>
    </contact>
    <contact_backup>
      <last_name>Rita Baiden, MD</last_name>
      <phone>+233 302 519394</phone>
      <email>rita.baiden@indepth-network.org</email>
    </contact_backup>
    <investigator>
      <last_name>Fred N Binka, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Dodowa Health ReseaRCH Centre</name>
      <address>
        <city>Accra</city>
        <country>Ghana</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Alex Adjei, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Kintampo Health Research Centre</name>
      <address>
        <city>Kintampo</city>
        <country>Ghana</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Asante P Kwaku, MD, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Mnahica Health Research Centre</name>
      <address>
        <city>Maputo</city>
        <country>Mozambique</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Esperance Sevene, MD, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Rufigi Research Centre</name>
      <address>
        <city>Rufiji</city>
        <country>Tanzania</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Abdunoor K Mulokozi</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Burkina Faso</country>
    <country>Ghana</country>
    <country>Mozambique</country>
    <country>Tanzania</country>
  </location_countries>
  <link>
    <url>http://www.indepth-network.org</url>
    <description>INESS</description>
  </link>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>May 1, 2013</study_first_submitted>
  <study_first_submitted_qc>July 24, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 25, 2014</study_first_posted>
  <last_update_submitted>July 24, 2014</last_update_submitted>
  <last_update_submitted_qc>July 24, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 25, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Uncomplicated Malaria</keyword>
  <keyword>dihydroartemisinin</keyword>
  <keyword>piperaquine</keyword>
  <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>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/NCT02199951
org study id: INESS 02/2012
secondary id: GRANT ID#. 48363.01
nct id: NCT02199951
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
WHO recommends the use of artemisinin-based combination therapies (ACTs) in the treatment of
      uncomplicated malaria to stem falciparum malaria drug resistance. New ACTs are entering the
      African market and will be used by the public health care system. The collection of safety
      data and risk evaluation through observational data are critical in order to assess
      risk/benefit profile of each ACT through its life cycle and providing information on the best
      use. Additionally there is need to assess the impact of the introduction of a new ACT in the
      evolution of its efficacy and malaria morbidity and mortality. Dihydroartemisinin/Piperaquine
      (DHA/PQP) is a new ACT approved by European Medical Agency and a number of African countries.
      This is a phase IV observational evaluation of the clinical safety of the fixed-dose DHA/PQP
      (Eurartesim®) in public health facilities within selected Health and Demographic Surveillance
      Centres in Burkina Faso (Nouna), Mozambique (Manhica), Ghana (Dodowa, Kintampo, Navrongo),
      Tanzania (Rufiji) and other African countries to be added. Eurartesim® will be used as
      first-line treatment of uncomplicated malaria an objective to evaluate the safety of
      Eurartesim® when used under usual conditions in 10,000 patients. Patients > 6 months and 5 kg
      except pregnant women will be enrolled and Eurartesim® administered as a single daily dose
      regimen over 3 days. Patients will be contacted at Day 5 (± 2 days) after treatment, to
      assess recovery and any adverse events.
Study will be performed in public health facilities in up to 7 selected HDSS centres (Health
      and Demographic Surveillance sites) within the HDSS in Burkina Faso (1), Mozambique (1),
      Ghana (3), and Tanzania (2), where Eurartesim® will be used as first-line treatment of
      uncomplicated malaria episodes.

      Primary:

      Evaluate the safety of Eurartesim® when used under usual conditions in 10,000 patients with
      signs and symptoms of uncomplicated malaria confirmed by a parasitological diagnosis
      (Microscopy/Rapid Diagnostic Test) or, when this test is not available, by WHO diagnostic
      criteria.

      Main Secondary:

      Intensive assessment of a nested subset of 1,000 patients to evaluate the effect of the
      administration of Eurartesim® on blood biochemistry, full blood count, WBC differential count
      and QTc intervals. QTc interval and piperaquine concentration relationship will also be
      investigated in selected centers.

      Other Secondaries:

      Although it is expected that the vast majority of patients will be infected with P.
      falciparum, comparisons of the clinical tolerability of Plasmodium falciparum infected
      patients versus patients infected with other Plasmodia, as confirmed by the thick blood smear
      results, will be carried-out in the nested subset of 1,000 patients.

      Assessment of the relationship between the occurrence of Adverse Events and the
      administration of concomitant medications will also be evaluated in the subset of 1,000
      patients.

      All patients visiting Health facilities in the HDSS areas and for whom a diagnosis of
      uncomplicated malaria (according to the WHO criteria) is suspected or confirmed by a
      parasitological diagnosis (Microscopy/Rapid Diagnostic Test) and who have signed informed
      consent/assent (a parent/guardian for children below 18 years old) will be included in the
      study. In the subset of 1,000 patients, the presence of Plasmodia of any species will be
      confirmed microscopically.

      A thick blood smear will be prepared for further microscopic diagnosis in all the patients.
      Eurartesim® tablets will be prescribed to the patients (or to the parents/guardians, if the
      patients are children) meeting the protocol inclusion criteria before the results of the
      thick blood smear are known.

      The patients will be contacted at Day 5 (± 2 days), in order to capture recovery status and
      all the experienced adverse events. A visit by the community health agent will be scheduled
      on all the cases in which the information collected during the telephone contact should be
      considered incomplete or unreliable ones. Special procedures will be followed in case of
      serious and/or severe adverse events and events classified of special interest (see specific
      section).

      The subset of 1,000 patients will be intensively followed-up. These patients will have
      haematology (Hb and full blood counts (RBC, WBC and differential count)) and standard
      biochemistry (BUN, Creatinine, ALT/AST, Bilirubine, electrolytes (K+ and Cl-)) undertaken at
      Day 1 (before drug administration), Day 3 (3-4 hours after the last dose of treatment), and
      Day 7. If the results are abnormal and clinically relevant, the blood examination will be
      repeated until normalization. In all the 1000 patients, a plasma sample will be collected on
      Day 1 (before drug administration), twice on Day 3 (i.e. before and 3-4 hours after the last
      drug administration) as well as on Day 7 to assess plasma PQ concentration. From such blood
      drawings and before centrifugation, three drops of whole blood will be spotted on filter
      papers. These filter papers will be utilized to determine whole blood piperaquine
      concentration with the Dry Blood Spot methodology (if a validated analytical method for such
      determination will be settled up at the time of the study course). ECGs will be undertaken on
      Day 1 (before drug administration), twice on Day 3 (i.e. before and 3-4 hours after the last
      drug administration) as well as on Day 7 (ECG on Day 1 and Day 3 after last drug
      administration will be collected in triplicate); safety information will be collected at all
      these visits.

      If the QTcF (QT corrected by Fridericia's formula) value assessed on Day 3 before last dose
      is above 500 ms, Eurartesim® should be withheld until QTcF returns below 480 ms within 6
      hours. Thereafter, the Eurartesim® cycle may be completed under frequent QTc monitoring based
      on medical judgment. If the QTcF does not return below 480 ms within 6 hours, another
      antimalarial therapy should be considered.

      The occurrence of any adverse events will be solicited from the subset of 1,000 patients on
      Days 3 and 7 following administration of Eurartesim® as well as in any additional visits.

      All patients in the study with a cardiac event of special interest (see below) will have an
      ECG performed.

      Patients will be asked to report to the health facility or to the HDSS if any adverse event
      occurs after Day 5 (± 2 days) contact and within 28 days after the start of Eurartesim®
      intake.

      Female patients will be encouraged to communicate to the study team if they get pregnant
      within a period of two months after the start of the Eurartesim® treatment. In these cases,
      information on the evolution of the pregnancy will be collected at 3, 6, 9 months and after
      the delivery (6 and 14 weeks). Information on the drugs taken during the pregnancy as well as
      AEs/SAEs/AESIs and the health status of the newborn/s will be collected.

      Patients will be instructed to take Eurartesim® with a dose regimen of one administration
      every 24 hours over a period of three days, i.e. at Day 1, then after 24 hours (Day 2) and
      after 48 hours (Day 3) from the first administration.

      The dose will be based on patient body weight. Two strengths of Eurartesim® will be provided
      to facilitate the dosing in children and adults: 20/160mg and 40/320mg of DHA and PQP
      respectively.

      The patients will be instructed to take Eurartesim® with water, at least three hours before
      or three hours after food intake (i.e. three hours after the previous food intake with no
      food intake for the following three hours after Eurartesim® administration).

      To facilitate drug administration in small children, tablets will be crushed on a spoon and
      given with water. If vomiting occurs within 30 min from drug administration, dose will be
      re-administered. If vomiting occurs within 30 to 60 min, half a dose have to be
      re-administered. Re-dosing should not be attempted more than once.
observational model: Cohort
time perspective: Prospective
measure: Adverse events
time frame: 28 Days
description: • Clinical safety will be determined by analysis of the number of adverse events (frequency, intensity, action taken, outcome) captured during their follow up contacts on Day 5 (±2 days) after starting the treatment with Eurartesim® as well as those identified in the referring hospitals or through adverse events spontaneously reported by the patient detected at the health facility within 28 days after the first medication intake.
measure: Adverse events of special interest
time frame: 28 Days
description: In case of an AESI confirmed by the study doctor, the sponsor shall be informed within 24 hours, even if the event does not satisfy any condition of seriousness. Notification will occur through the use of an ad hoc AESI form. AESIs can be related to:
Cardio-toxicity i.e. prolonged QT
Neurotoxicity/seizures
Cutaneous reactions/phototoxicity
measure: Peak plasma concentration (Cmax) on Day 3 and plasma concentrations before last dose on day 3 and day 7)
time frame: 7 Days
description: In predefined centres having the capability to store plasma samples, all the 1000 subset will also perform a blood drawing for PQ plasma concentration at Day 1 (before drug administration), twice at Day 3 (before and 3-4 after the last drug administration) as well as on Day 7.
arm group label: Dihydroartemisinin and piperaquine
description: The patients will take Eurartesim® (DHA/PQP) with a dose regimen of one administration every 24 hours over a period of three days, i.e. at Day 1, then after 24 hours (Day 2) and after 48 hours (Day 3) from the first administration. The dose will be based on body weight. Two strengths of Eurartesim® will be provided for dosing in children and adults: 20/160mg and 40/320mg of DHA and PQP respectively. Body weight (kg) Daily dose (mg) Number of tablets per dose 20/160mg DHA/PQ 40/320mg DHA/PQ 5 to <7 10 mg DHA and 80 mg PQP ½ tablet 7 to <13 20 mg DHA and 160 mg PQP 1 tablet 13 to < 24 40 mg DHA and 320 mg PQP 1 tablet 24 to < 36 80 mg DHA and 640 mg PQP 2 tablets 36 to < 75 120 mg DHA and 960 mg PQP 3 tablets 75 to < 100 160 mg DHA and 1280 mg PQP 4 tablets > 100.
intervention type: Drug
intervention name: Dihydroartemisinin and piperaquine
description: Antimalarial
arm group label: Dihydroartemisinin and piperaquine
other name: Eurartesim
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 6 Months
maximum age: N/A
healthy volunteers: No
last name: Fred N Binka, MD, PhD
role: Principal Investigator
affiliation: INDEPTH Network
last name: Bernhards R Ogutu, MD, PhD
phone: +254 733 966 065
email: berrnhards.ogutu@indepth-network.org
last name: Rita Baiden, MD
phone: +233 208 098 000
email: rita.baiden@indepth-network.org
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Burkina Faso
country: Ghana
country: Mozambique
country: Tanzania
url: http://www.indepth-network.org
description: INESS
responsible party type: Sponsor
mesh term: Malaria
mesh term: Piperaquine
mesh term: Artenimol