title: A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs.
abstract: BACKGROUND
  Critical to the development of new drugs for treatment of malaria is the capacity to safely evaluate their activity in human subjects. The approach that has been most commonly used is testing in subjects with natural malaria infection, a methodology that may expose symptomatic subjects to the risk of ineffective treatment. Here we describe the development and pilot testing of a system to undertake experimental infection using blood stage Plasmodium falciparum parasites (BSP). The objectives of the study were to assess the feasibility and safety of induced BSP infection as a method for assessment of efficacy of new drug candidates for the treatment of P. falciparum infection.
  
  
  RESULTS
  A prospective, unblinded, Phase IIa trial was undertaken in 19 healthy, malaria-naïve, male adult volunteers who were infected with BSP and followed with careful clinical and laboratory observation, including a sensitive, quantitative malaria PCR assay. Volunteers were randomly allocated to treatment with either of two licensed antimalarial drug combinations, artemether-lumefantrine (A/L) or atovaquone-proguanil (A/P). In the first cohort (n = 6) where volunteers received ∼360 BSP, none reached the target parasitemia of 1,000 before the day designated for antimalarial treatment (day 6). In the second and third cohorts, 13 volunteers received 1,800 BSP, with all reaching the target parasitemia before receiving treatment (A/L, n = 6; A/P, n = 7) The study demonstrated safety in the 19 volunteers tested, and a significant difference in the clearance kinetics of parasitemia between the drugs in the 13 evaluable subjects, with mean parasite reduction ratios of 759 for A/L and 17 for A/P (95% CI 120-4786 and 7-40 respectively; p<0.01).
  
  
  CONCLUSIONS
  This system offers a flexible and safe approach to testing the in vivo activity of novel antimalarials.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01055002.
authors: Queensland Institute for Medical Research, University of Queensland, Brisbane, Australia. j.mccarthy@uq.edu.au
authors: James S
authors: JS
authors: McCarthy
authors: Silvana
authors: S
authors: Sekuloski
authors: Paul M
authors: PM
authors: Griffin
authors: Suzanne
authors: S
authors: Elliott
authors: Nanette
authors: N
authors: Douglas
authors: Chris
authors: C
authors: Peatey
authors: Rebecca
authors: R
authors: Rockett
authors: Peter
authors: P
authors: O'Rourke
authors: Louise
authors: L
authors: Marquart
authors: Cornelius
authors: C
authors: Hermsen
authors: Stephan
authors: S
authors: Duparc
authors: Jörg
authors: J
authors: Möhrle
authors: Katharine R
authors: KR
authors: Trenholme
authors: Andrew J
authors: AJ
authors: Humberstone
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use*; D006262:Health; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects*; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology*; D008297:Male; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010865:Pilot Projects; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials