Tracking Resistance to Artemisinin (TRAC)
Condition: Falciparum Malaria
MeSH terms: Malaria; Malaria, Falciparum
Study type: Interventional
Phase: Phase 4

Summary: 
      Because the artemisinins are the most potent antimalarial drugs, the reduction in parasite
      numbers is rapid. Therefore, early measures of reducing parasite counts are needed. This
      study will look at conventional markers of parasite reduction e.g. parasite clearance time,
      parasite reduction ratio, and the time to achieve a fall of 50%, 90% and 99% of the
      pre-treatment parasitaemia.

      Defining artemisinin resistance requires the use of artesunate (AS) alone because it is now
      appreciated that the partner drug in a combination treatment has a significant impact on the
      rate of parasite clearance. This study will dose patients for 3 days with AS alone (or longer
      until parasites clear) and measure the parasite count frequently in order to be able to
      define an accurate regression line of a graph of the natural logarithm of the parasite count
      (Y axis) versus time (X axis). This will be followed by a full course of an artemisinin
      combination therapy (ACT). Two different dose regimens of artesunate will be compared at all
      sites except those in western Cambodia, as unpublished observations from the Thai-Myanmar
      border suggest the standard lower daily dose of 2mg/kg may enable the earlier detection of
      low level resistance than a 4mg/kg daily dose.
    

Detailed description: 
      Background:

      Artemisinins are the cornerstone of current antimalarial treatment. Evidence of reduced
      susceptibility to artemisinins in Western Cambodia was first presented in January 2007 and
      confirmed in a subsequent detailed pharmacokinetic-pharmacodynamic study conducted by our
      group. Artemisinin resistance was manifest by a marked slowing of parasite clearance. The
      spread of highly artemisinin resistant falciparum malaria would have devastating consequences
      for malaria control and elimination. The response to artemisinin resistance in P. falciparum
      depends critically upon answering one pivotal question: how far has it spread? This research
      proposal focuses on filling critical gaps in knowledge that are essential to planning an
      effective response.

      Objectives/Hypothesis/Questions:

      This is a multi-centre study with the primary objective of comparing the P. falciparum
      parasite clearance compared to a reference parasite clearance rate obtained from historical
      data in artemisinin sensitive falciparum malaria.

      The aim of this large scale study is to determine if artemisinin resistance has spread and if
      so, how far it has spread.

      Research design:

      This is a multi-centre, open-label randomised trial to assess the clearance rates of
      peripheral blood P. falciparum parasitaemias in patients with acute uncomplicated falciparum
      malaria treated with two different doses of artesunate.

      The study will recruit patients with acute uncomplicated P. falciparum malaria. The total
      number of patients for this study is expected to be 1800.

      Patients will be randomised 1:1 to receive either:

        -  AS2: Artesunate 2 mg/kg/day for 3 days OR

        -  AS4: Artesunate 4 mg/kg/day for 3 days

        -  followed by a full course of Artesunate- mefloquine (MAS3) Patients will be hospitalised
           for at least the 1st three days. During hospitalisation, patients will have malaria
           parasite count done at 0, 4, 6, 8, 12, then every 6 hours until parasite clearance. The
           weekly follow up is until day 14 (on Day 7 and Day 14).

      Value and significance of the research The study aims to address a simple but crucial
      question regarding artemisinin resistance for which currently there is no answer: has
      artemisinin resistant Plasmodium falciparum spread from Western Cambodia? The results will
      determine how to approach the subsequent efforts; strengthening of strategies for eliminating
      the resistant parasites in Western Cambodia if the resistance is confined to this area, or
      for containment and malaria control if the resistant parasites have already spread.

      Potential outcomes Within one year we expect to produce a map of the geographical extent,
      prevalence and severity of artemisinin resistance.
    

Intervention name(s): Artesunate 2; Artesunate 4
Intervention type(s): Drug; Drug
Intervention description(s): Artesunate 2 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine; Artesunate 4 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine
Intervention MeSH terms: Artesunate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Uncomplicated P. falciparum malaria