<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/NCT01662700</url>
  </required_header>
  <id_info>
    <org_study_id>FTM1202</org_study_id>
    <nct_id>NCT01662700</nct_id>
  </id_info>
  <brief_title>Comparison of Two Antimalarial Drugs Regimens in Patient With Plasmodium Vivax Malaria in Thailand</brief_title>
  <official_title>An Open Label Randomized Comparison of Two Antimalarial Drugs Regimens in Patient With Plasmodium Vivax Malaria in Thailand</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mahidol University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Mahidol University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In Thailand, the proportion of P.vivax infection has now been increasing and is equal to&#xD;
      Plasmodium falciparum since 1998. The incidence of P.vivax has recently been reported as 20&#xD;
      per 1000 population per year. Unlike Plasmodium falciparum, P.vivax infection rarely develops&#xD;
      into complicated malaria and death is unusual. However, P.vivax has a dormant stage (the&#xD;
      hypnozoite) that persists in the human liver and may cause relapse weeks, months, or even&#xD;
      years later. Therefore, P.vivax infection is considered to have greater impact on morbidity&#xD;
      than mortality, resulting in significant social and economic burden. Moreover, it is very&#xD;
      difficult to control P.vivax transmission, because gametocytes appear almost simultaneously&#xD;
      with schizonts.&#xD;
&#xD;
      Radical treatment of the infection, therefore, normally consists of a blood schizontocidal&#xD;
      course of chloroquine and a course primaquine for the elimination of the hypnozoites as&#xD;
      anti-relapse therapy. In Thailand, chloroquine and primaquine have remained the mainstay&#xD;
      chemotherapeutics for the treatment of P.vivax for more than 60 years and resistance has not&#xD;
      yet been reported . The relapse rates at day 28 are about 50% without primaquine therapy and&#xD;
      about 20% with standard primaquine therapy. Relapse has not been observed among patients&#xD;
      receiving high dose primaquine therapy (30 mg daily for 14 days).&#xD;
&#xD;
      Since January 2007, the evidence of reduced susceptibility of Plasmodium falciparum to&#xD;
      artemisinins in Western Cambodia at Thai-Cambodia border was first presented and confirmed in&#xD;
      a subsequent detailed pharmacokinetic-pharmacodynamic study. Nevertheless, a trend of gradual&#xD;
      decline of in vitro sensitivity to chloroquine has been documented in some areas of the&#xD;
      country, particularly Thai-Myanmar border. There has been no clinical-parasitological&#xD;
      evidence of chloroquine resistant P.vivax in Thai-Cambodia border, Thailand.&#xD;
&#xD;
      The objectives of the present study are to assess in vivo efficacy of first line regimen of&#xD;
      chloroquine given with primaquine, and in vitro susceptibility of P.vivax isolates in areas&#xD;
      along Thai-Cambodia border, Thailand.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Plasmodium vivax affects 70-80 million cases of malaria worldwide annually, is the major&#xD;
      cause of human malaria in parts of Pacific region and South America. In Thailand, the&#xD;
      proportion of P.vivax infection has increased and it is now equal to Plasmodium falciparum&#xD;
      since 1998. The incidence of P.vivax has recently been reported as 20 per 1000 population per&#xD;
      year. Unlike Plasmodium falciparum, P.vivax infection rarely develops into complicated&#xD;
      malaria and death is unusual. However, P.vivax has a dormant stage (the hypnozoite) that&#xD;
      persists in the human liver and may cause relapse weeks, months, or even years later.&#xD;
      Therefore, P.vivax infection is considered to have greater impact on morbidity than&#xD;
      mortality, resulting in significant social and economic burden. Moreover, it is very&#xD;
      difficult to control P.vivax transmission, because gametocytes appear almost simultaneously&#xD;
      with schizonts.&#xD;
&#xD;
      Radical treatment of the infection, therefore, normally consists of a blood schizontocidal&#xD;
      course of chloroquine and a course primaquine for the elimination of the hypnozoites as&#xD;
      antirelapse therapy. However, chloroquine-resistant P.vivax (CRPv) has been emer-ging in&#xD;
      different parts of the world. The first report of chloroquine resistant Plasmodium vivax was&#xD;
      in 2 Australian soldiers returning from Papua New Guinea in Indonesia and is now spreading&#xD;
      over Asia and the Pacific region. In Thailand, chloroquine and primaquine have remained the&#xD;
      mainstay chemotherapeutics for the treatment of P.vivax for more than 60 years and resistance&#xD;
      has not yet been reported. Occasional failure of the standard primaquine therapy (15 mg daily&#xD;
      for 14 days) to prevent relapse has been observed. However, primaquine resistance has not&#xD;
      been confirmed. In Thailand, the relapse rates at day 28 are about 50% without primaquine&#xD;
      therapy, and about 20% with standard primaquine therapy. Relapse has not been observed among&#xD;
      patients receiving high dose primaquine therapy (30 mg daily for 14 days).&#xD;
&#xD;
      A number of factors are reportedly associated with relapse, or the reappearance of P.vivax,&#xD;
      including inadequate primaquine dosage, high parasitaemia at diagnosis, and short duration of&#xD;
      symptoms prior to diagnosis, presence of gametocytes on admission, age, and gender. Because&#xD;
      the radical cure of P.vivax hypnozoites requires 14 days of primaquine therapy, adherence to&#xD;
      the drug regimen may greatly affect the prevention of relapse. Unfortunately, the effect of&#xD;
      patient adherence on 14 day primaquine treatment, and its relation to preventing parasite&#xD;
      reappearance, is not well-document.&#xD;
&#xD;
      Since January 2007, the evidence of reduced susceptibility of Plasmodium falciparum to&#xD;
      artemisinins in Western Cambodia at Thai_Cambodia border was first presented and confirmed in&#xD;
      a subsequent detailed pharmacokinetic-pharmacodynamic study. Nevertheless, a trend of gradual&#xD;
      decline of in vitro sensitivity to chloroquine has been documented in some areas of the&#xD;
      country, particularly Thai-Myanmar border. There has been no clinical-parasitological&#xD;
      evidence of chloroquine resistant P.vivax in Thai-Cambodia border, Thailand.&#xD;
&#xD;
      The objectives of the present study are to assess in vivo efficacy of first line regimen of&#xD;
      chloroquine given with primaquine, and in vitro susceptibility of P.vivax isolates in areas&#xD;
      along Thai-Cambodia border, Thailand.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>October 2012</start_date>
  <completion_date type="Anticipated">December 2014</completion_date>
  <primary_completion_date type="Anticipated">December 2014</primary_completion_date>
  <phase>Phase 4</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Parasite Clearance Rate</measure>
    <time_frame>7 days</time_frame>
    <description>Parasite clearance rate as defined by the slope of the linear portion of the natural logarithm parasite clearance curve</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Relapse rate of P. vivax</measure>
    <time_frame>3 months</time_frame>
    <description>Incidence of relapse in P.vivax infection</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Parasite clearance time</measure>
    <time_frame>7 days</time_frame>
    <description>Parasite clearance time assessed by microscopy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parasite density time</measure>
    <time_frame>7 days</time_frame>
    <description>Time of parasite count to fall to 50%, 90% and 99% of initial parasite density</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fever clearance time</measure>
    <time_frame>7 days</time_frame>
    <description>Fever clearance time (i.e. the time taken for temperature to fall below 37 degrees celsius and remain there for at least 24 hrs)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with gametocytemia</measure>
    <time_frame>7 days</time_frame>
    <description>Proportion of patients with gametocytemia before, during and after treatment, assessed at admission, on day 3 stratified by presence of gametocytes at enrolment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In vitro antimalarial drug susceptibility</measure>
    <time_frame>7 days</time_frame>
    <description>IC0, IC90, IC99 of Plasmodium vivax responses to antimalarial drugs ( ex vivo)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Acute Uncomplicated Malaria With P.Vivax Infection</condition>
  <arm_group>
    <arm_group_label>AS2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Artesunate 2 mg/kg/day for 5 days Combine with&#xD;
Primaquine 15 mg is given daily for 14 days.&#xD;
Or primaquine 45 mg is given once a week for 8 weeks in G6PD deficiency patients.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Chloroquine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>CH25: Chloroquine 25 mg/kg: 15 mg base/kg on the first days (D0), followed by 5 mg base/kg daily on the second and third day (day1-2) (total 25 mg base/ kg).&#xD;
Combine with&#xD;
Primaquine 15 mg is given daily for 14 days.&#xD;
Or primaquine 45 mg is given once a week for 8 weeks in G6PD deficiency patients.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Artesunate</intervention_name>
    <arm_group_label>AS2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chloroquine</intervention_name>
    <arm_group_label>Chloroquine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female, aged from 18 years to 65 years old who can come to the study hospital&#xD;
             for follow up in case of re-infection&#xD;
&#xD;
          -  Acute uncomplicated malaria with P.vivax infection, confirmed by positive blood smear&#xD;
             with asexual forms of P. vivax with parasitaemia &gt; 1,000 parasites/microliters&#xD;
&#xD;
          -  Fever defined as temperature &gt; 37.5 degree celsius or a history of fever within the&#xD;
             last 24 hours&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
          -  Willingness and ability of the patients/guardians to comply with the study protocol&#xD;
             for the duration of the study&#xD;
&#xD;
          -  Communicate with Thai language&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Mixed infection with other plasmodium species&#xD;
&#xD;
          -  For females: pregnancy, breast feeding&#xD;
&#xD;
          -  History of allergy or known contraindication to chloroquine, artesunate or primaquine&#xD;
&#xD;
          -  Any criteria of severe / complicated malaria (WHO 2010)&#xD;
&#xD;
          -  Presence of febrile condition caused by disease other than malaria.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Kraburi Hospital</name>
      <address>
        <city>Ranong</city>
        <country>Thailand</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Thongchai Keeratihatayagorn, MD</last_name>
      <phone>+6681 8952244</phone>
    </contact>
    <contact_backup>
      <last_name>Prakaykaew Charunwatthana, MD</last_name>
      <phone>+6681-844 9678</phone>
      <email>jib@tropmedres.ac</email>
    </contact_backup>
    <investigator>
      <last_name>Thongchai Keeratihatayagorn, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Khunhan Hospital</name>
      <address>
        <city>Srisaket</city>
        <country>Thailand</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ratchadaporn Runchareon, MD</last_name>
      <phone>+6681-790-9275</phone>
    </contact>
    <contact_backup>
      <last_name>Prakaykaew Charunwatthana, MD</last_name>
      <phone>+6681-844 9678</phone>
      <email>jib@tropmedres.ac</email>
    </contact_backup>
    <investigator>
      <last_name>Ratchadaporn Runchareon, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Phusing Hospital</name>
      <address>
        <city>Srisaket</city>
        <country>Thailand</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kitipumi Chutasmit, MD</last_name>
      <phone>+6687 9654139</phone>
    </contact>
    <contact_backup>
      <last_name>Prakaykaew Charunwatthan, MD</last_name>
      <phone>+6681-844 9678</phone>
      <email>jib@tropmedres.ac</email>
    </contact_backup>
    <investigator>
      <last_name>Kitipumi Chutasmit, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Kap Choeng Hospital</name>
      <address>
        <city>Surin</city>
        <country>Thailand</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Satawat Sinprasitkul, MD</last_name>
      <phone>+6681 7601087</phone>
    </contact>
    <contact_backup>
      <last_name>Prakaykaew Charunwatthana, MD</last_name>
      <phone>+6681-844 9678</phone>
      <email>jib@tropmedres.ac</email>
    </contact_backup>
    <investigator>
      <last_name>Satawat Sinprasitkul, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Worawun Kopkitngam, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Thailand</country>
  </location_countries>
  <verification_date>January 2013</verification_date>
  <study_first_submitted>August 8, 2012</study_first_submitted>
  <study_first_submitted_qc>August 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 10, 2012</study_first_posted>
  <last_update_submitted>January 24, 2013</last_update_submitted>
  <last_update_submitted_qc>January 24, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 25, 2013</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>P. vivax infection</keyword>
  <keyword>Artesunate</keyword>
  <keyword>Chloroquine</keyword>
  <keyword>Primaquine</keyword>
  <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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Artesunate</mesh_term>
    <mesh_term>Chloroquine</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/NCT01662700
org study id: FTM1202
nct id: NCT01662700
lead sponsor: 
has dmc: No
In Thailand, the proportion of P.vivax infection has now been increasing and is equal to
      Plasmodium falciparum since 1998. The incidence of P.vivax has recently been reported as 20
      per 1000 population per year. Unlike Plasmodium falciparum, P.vivax infection rarely develops
      into complicated malaria and death is unusual. However, P.vivax has a dormant stage (the
      hypnozoite) that persists in the human liver and may cause relapse weeks, months, or even
      years later. Therefore, P.vivax infection is considered to have greater impact on morbidity
      than mortality, resulting in significant social and economic burden. Moreover, it is very
      difficult to control P.vivax transmission, because gametocytes appear almost simultaneously
      with schizonts.

      Radical treatment of the infection, therefore, normally consists of a blood schizontocidal
      course of chloroquine and a course primaquine for the elimination of the hypnozoites as
      anti-relapse therapy. In Thailand, chloroquine and primaquine have remained the mainstay
      chemotherapeutics for the treatment of P.vivax for more than 60 years and resistance has not
      yet been reported . The relapse rates at day 28 are about 50% without primaquine therapy and
      about 20% with standard primaquine therapy. Relapse has not been observed among patients
      receiving high dose primaquine therapy (30 mg daily for 14 days).

      Since January 2007, the evidence of reduced susceptibility of Plasmodium falciparum to
      artemisinins in Western Cambodia at Thai-Cambodia border was first presented and confirmed in
      a subsequent detailed pharmacokinetic-pharmacodynamic study. Nevertheless, a trend of gradual
      decline of in vitro sensitivity to chloroquine has been documented in some areas of the
      country, particularly Thai-Myanmar border. There has been no clinical-parasitological
      evidence of chloroquine resistant P.vivax in Thai-Cambodia border, Thailand.

      The objectives of the present study are to assess in vivo efficacy of first line regimen of
      chloroquine given with primaquine, and in vitro susceptibility of P.vivax isolates in areas
      along Thai-Cambodia border, Thailand.
Plasmodium vivax affects 70-80 million cases of malaria worldwide annually, is the major
      cause of human malaria in parts of Pacific region and South America. In Thailand, the
      proportion of P.vivax infection has increased and it is now equal to Plasmodium falciparum
      since 1998. The incidence of P.vivax has recently been reported as 20 per 1000 population per
      year. Unlike Plasmodium falciparum, P.vivax infection rarely develops into complicated
      malaria and death is unusual. However, P.vivax has a dormant stage (the hypnozoite) that
      persists in the human liver and may cause relapse weeks, months, or even years later.
      Therefore, P.vivax infection is considered to have greater impact on morbidity than
      mortality, resulting in significant social and economic burden. Moreover, it is very
      difficult to control P.vivax transmission, because gametocytes appear almost simultaneously
      with schizonts.

      Radical treatment of the infection, therefore, normally consists of a blood schizontocidal
      course of chloroquine and a course primaquine for the elimination of the hypnozoites as
      antirelapse therapy. However, chloroquine-resistant P.vivax (CRPv) has been emer-ging in
      different parts of the world. The first report of chloroquine resistant Plasmodium vivax was
      in 2 Australian soldiers returning from Papua New Guinea in Indonesia and is now spreading
      over Asia and the Pacific region. In Thailand, chloroquine and primaquine have remained the
      mainstay chemotherapeutics for the treatment of P.vivax for more than 60 years and resistance
      has not yet been reported. Occasional failure of the standard primaquine therapy (15 mg daily
      for 14 days) to prevent relapse has been observed. However, primaquine resistance has not
      been confirmed. In Thailand, the relapse rates at day 28 are about 50% without primaquine
      therapy, and about 20% with standard primaquine therapy. Relapse has not been observed among
      patients receiving high dose primaquine therapy (30 mg daily for 14 days).

      A number of factors are reportedly associated with relapse, or the reappearance of P.vivax,
      including inadequate primaquine dosage, high parasitaemia at diagnosis, and short duration of
      symptoms prior to diagnosis, presence of gametocytes on admission, age, and gender. Because
      the radical cure of P.vivax hypnozoites requires 14 days of primaquine therapy, adherence to
      the drug regimen may greatly affect the prevention of relapse. Unfortunately, the effect of
      patient adherence on 14 day primaquine treatment, and its relation to preventing parasite
      reappearance, is not well-document.

      Since January 2007, the evidence of reduced susceptibility of Plasmodium falciparum to
      artemisinins in Western Cambodia at Thai_Cambodia border was first presented and confirmed in
      a subsequent detailed pharmacokinetic-pharmacodynamic study. Nevertheless, a trend of gradual
      decline of in vitro sensitivity to chloroquine has been documented in some areas of the
      country, particularly Thai-Myanmar border. There has been no clinical-parasitological
      evidence of chloroquine resistant P.vivax in Thai-Cambodia border, Thailand.

      The objectives of the present study are to assess in vivo efficacy of first line regimen of
      chloroquine given with primaquine, and in vitro susceptibility of P.vivax isolates in areas
      along Thai-Cambodia border, Thailand.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Parasite Clearance Rate
time frame: 7 days
description: Parasite clearance rate as defined by the slope of the linear portion of the natural logarithm parasite clearance curve
measure: Relapse rate of P. vivax
time frame: 3 months
description: Incidence of relapse in P.vivax infection
measure: Parasite clearance time
time frame: 7 days
description: Parasite clearance time assessed by microscopy
measure: Parasite density time
time frame: 7 days
description: Time of parasite count to fall to 50%, 90% and 99% of initial parasite density
measure: Fever clearance time
time frame: 7 days
description: Fever clearance time (i.e. the time taken for temperature to fall below 37 degrees celsius and remain there for at least 24 hrs)
measure: Proportion of patients with gametocytemia
time frame: 7 days
description: Proportion of patients with gametocytemia before, during and after treatment, assessed at admission, on day 3 stratified by presence of gametocytes at enrolment
measure: In vitro antimalarial drug susceptibility
time frame: 7 days
description: IC0, IC90, IC99 of Plasmodium vivax responses to antimalarial drugs ( ex vivo)
arm group label: AS2
arm group type: Experimental
description: Artesunate 2 mg/kg/day for 5 days Combine with
Primaquine 15 mg is given daily for 14 days.
Or primaquine 45 mg is given once a week for 8 weeks in G6PD deficiency patients.
arm group label: Chloroquine
arm group type: Active Comparator
description: CH25: Chloroquine 25 mg/kg: 15 mg base/kg on the first days (D0), followed by 5 mg base/kg daily on the second and third day (day1-2) (total 25 mg base/ kg).
Combine with
Primaquine 15 mg is given daily for 14 days.
Or primaquine 45 mg is given once a week for 8 weeks in G6PD deficiency patients.
intervention type: Drug
intervention name: Artesunate
arm group label: AS2
intervention type: Drug
intervention name: Chloroquine
arm group label: Chloroquine
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
country: Thailand
responsible party type: Sponsor
mesh term: Malaria
mesh term: Malaria, Vivax
mesh term: Artesunate
mesh term: Chloroquine