Assessment of Artesunate/Mefloquine in the Peruvian Amazon
Condition: Malaria, Falciparum
MeSH terms: Malaria, Falciparum
Study type: Interventional
Phase: Phase 4

Summary: 
      There is growing evidence of the emergence of P. falciparum resistance to artesunate (a
      derivative of artemisin) in Southeast Asia. The emergence and spread of resistant strains to
      artemisinin would represent an alarming threat to the success of the antimalarial combination
      therapy in the region. The delayed clearance of parasitemia for more than 24 hours has been
      taken as an early sign of resistance, a phenomenon seen at the Thai-Cambodia border.

      The purpose of this research study, is to assess the in vitro and in vivo efficacy of
      combinated artesunate/mefloquine therapy to treatment of uncomplicated Plasmodium falciparum
      malaria in the Peruvian Amazon through the analysis of the rate of clearance of parasitemia
      and other important outcomes.
    

Detailed description: 
      Combination therapy with artemisinin derivatives is the treatment of choice for malaria by P.
      falciparum since 2006, but there is growing evidence of the emergence of P. falciparum
      resistance to artesunate in Southeast Asia. The delayed clearance of parasitemia for more
      than 24 hours has been taken as an early sign of resistance, a phenomenon seen at the
      Thai-Cambodia border. The emergence and spread of resistant strains to artemisinin would
      represent an alarming threat to the success of the antimalarial combination therapy in the
      region.

      This research study, will be conducted in collaboration with the National Institute of Health
      of Peru.

      Objectives:

      Main Objective: To determine the rate of clearance of parasitemia in the first 72 hours after
      administration of artesunate.

      Secondary/exploratory objectives:

        1. to determine the efficacy of the artesunate (AS)/mefloquine (MQ) therapy in participants
           with uncomplicated falciparum malaria in the Peruvian Amazon (sub-study);

        2. to correlate the clinical results from the in vivo study with results of in vitro
           sensitivity and molecular genotyping;

        3. to identify common specific genetic determinants to the resistance of artemisinins in
           parasite populations;

        4. to determine the levels of gametocytes in participants with uncomplicated falciparum
           malaria treated with AS/MQ;

        5. to determine the contribution of host immunity in clinical and parasitological response;

        6. to create a catalog of parasite samples closely correlated with clinical response data
           to perform a longitudinal follow-up of resistance trends;

        7. to determine pharmacokinetic parameters associated with failure of therapy.

      Methodology:

      The study will be conducted in seven health facilities and one hospital in the Department of
      Loreto in the Peruvian Amazon, where 59 volunteers will be enrolled between 5 and 65 years of
      age with confirmed diagnosis of monoinfection by P. falciparum. In addition to the main
      study, we will conduct a sub-study to determine the efficacy of AS/MQ (regime currently used
      in Peru) After signing the informed consent/assent, blood samples will be taken to determine
      parasite density, baseline biochemical tests, genotyping studies, analysis of molecular
      markers and in vitro sensitivity, antibodies against malaria and cytokines. Artesunate will
      be administered according to national guidelines in the first three days, 4 mg/kg/day.
      However, mefloquine administration will be delayed for up to 72 hours to measure the rate of
      clearance of parasitemia with artesunate alone in the first three days. Serial blood samples
      for thick/thin smears will be taken every 4 hours during the first 12 hours and then every 6
      hours until complete the first 72 hours, after the AS administration, during which time the
      study participants will remain in a hospital ward. Monitoring will be undertaken until day 42
      with analysis of thick/thin smears according to WHO guidelines. In case of parasitemia
      recurrence, additional blood samples will be collected for genotyping tests, in vitro
      sensitivity, and analysis of molecular markers of drug resistance and immunology assays. The
      sub-study will be useful to assess the efficacy of the regimen currently in use by the
      Ministry of Health of Peru, in this arm the patients will be given AS 4 mg/kg/day in Days 0,
      1 and 2 and MQ 12.5mg/kg/day in Days 1 and 2. In this arm, the follow up will be done using
      thick smears on Days 1, 2, 3, 7, 14, 21, 28, 35 and 42. Blood samples will be collected on
      Days 0, 42 and the day of recurrence.

      This study will allow the Ministry of Health to know the state of resistance/tolerance to
      artesunate in Peru and take the necessary control measures to ensure that artesunate can be
      used successfully for treatment of falciparum malaria. Importantly, the results of this study
      will be compared to parallelly-designed studies in Kenya (US Army Medical Research Unit
      Kenya-USAMRU K) and Thailand (Army Forces Medical Research Institute of Medical
      Sciences-AFRIMS).

      Relevance: Malaria is one of the main public health problems in Peru, early and efficacious
      treatment in the principal control strategy the appearance of strains that are resistant to
      the regular treatment used in Peru jeopardize the strategies for malaria control in South
      America. This study will allow us to know the current resistance status and to prepare
      corresponding measures.

      Budget: This study will be done as a joined effort between NAMRU-6 and the INS, this will
      cost 201,934.93 Nuevos Soles afforded by Instituto Nacional de Salud and a total cost of
      527,934.93 Nuevos Soles for both participating institutions
    

Intervention name(s): Artesunate; Mefloquine
Intervention type(s): Drug; Drug
Intervention description(s): Orally administration of artesunate 4mg/Kg by three days; Orally administration of mefloquine 15mg/Kg in the fourth day Orally administration of mefloquine 10mg/Kg in the fifth day
Other intervention name(s): Distribuited by AC Farma; Distribuited by AC Farma
Intervention MeSH terms: Artesunate; Mefloquine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: artesunate; mefloquine; falciparum; peruvian amazon