"Prolonging the Therapeutic Life Span of Artemisinin-based Combination Therapies (ACT) in Bagamoyo District, Tanzania"
Condition: Malaria,Falciparum
MeSH terms: Malaria, Falciparum
Study type: Interventional
Phase: Phase 4

Summary: 
      This clinical trial evaluates the advantage of prolonging the therapeutic life span of
      Artemether-lumefantrine from 3 days to 6 days, and addition of single low dose of Primaquine
      0.25mg/kg. The study will have two arms, one that will receive standard treatment of
      uncomplicated malaria with Artemether-lumefantrine, and the other arm will receive the
      prolonged dose of 6 days together with single low dose primaquine. This approach is expected
      to provide strategies for malaria control in an era of imminent Plasmodium falciparum
      resistance.
    

Detailed description: 
      Despite documented high cure rates of ACT in Tanzania, and Africa elsewhere, clinical trials
      conducted in Tanzania with Swedish International Development cooperation Agency (SIDA) and
      Swedish Research Council support, provide evidence for in vivo selection of lumefantrine
      tolerant/resistant parasites among recurrent infections. Similarly, molecular epidemiology
      studies from Bagamoyo District, Tanzania, have shown temporal selection of lumefantrine
      associated genetic tolerance/resistance markers in the parasite population following wide
      scale use of Artemether-lumefantrine, but without signs of compromised treatment efficacy.

      During the last decade, and despite the documented rapid microscopy determined parasite
      clearance of artemether-lumefantrine in Bagamoyo District, interest has developed in
      understanding the observation of high residual polymerase chain reaction (PCR) determined
      positivity rate on day 3 after supervised artemether-lumefantrine treatment in the magnitude
      of almost 30% in previous assessments from 2015. Using deep sequencing approaches studies
      have recently detected PCR determined delayed parasite clearance curves in P. falciparum
      sub-populations in Bagamoyo District. The clearance times by PCR of these sub-populations
      were similar to artemisinin resistant parasites in Myanmar as assessed by microscopy, but the
      former did, importantly, not harbor any of the described mutations in Kelch13 propeller
      associated with artemisinin resistance. However, these Tanzanian parasite sub-populations
      need to be further studied and characterized since they may provide important clues to the
      understanding of artemisinin survival strategies among the East African P. falciparum
      parasite population.

      Taken together, longitudinal clinical and molecular data described above from Tanzania, East
      Africa, extending from pre-ACT implementation, (before 2006), to a decade of wide scale
      artemether-lumefantrine use in Bagamoyo district, provide evidence for declining
      susceptibility to ACT, both to artemether and lumefantrine, among the P. falciparum
      population. These parasites ("last man standing") that survived 10 years of ACT exposure have
      indeed shown excellent survival instincts and may thus be particularly resistant prone.
      However, if P. falciparum resistance to ACT develops in Africa, this will have devastating
      effects on malaria morbidity and mortality and may swiftly ruin the improvements the global
      malaria community achieved during the past decade with ACT as a key component for success.

      Based on the above the investigators suggest prolonged treatment with ACT and addition of
      transmission blocking treatment using a single low dose of primaquine administered on the
      last day of ACT treatment.
    

Intervention name(s): Artemether-Lumefantrine Tab 20-120mg; Primaquine Phosphate 0.25 mg/kg; Placebo
Intervention type(s): Drug; Drug; Other
Intervention description(s): Artemether-Lumefantrine Tablet 20-120mg; Primaquine Phosphate 0.25 mg/kg; Aqueous solution prepared to mimic the taste of the intervention drug.
Other intervention name(s): ALU; PQ; Placebo for Artemether Lumefantrine + Primaquine Phosphate
Intervention MeSH terms: Lumefantrine; Artemether; Primaquine; Artemether, Lumefantrine Drug Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Artemether-Lumefantrine, Primaquine