title: A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severe Plasmodium knowlesi malaria in Sabah, Malaysia (ACT KNOW trial).
abstract: BACKGROUND
  Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species.
  
  
  METHODS
  ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (α 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis.
  
  
  BACKGROUND
  This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform knowlesi malaria treatment policy in this region through peer-reviewed publications and academic presentations.
  
  
  BACKGROUND
  NCT01708876.
authors.affiliation: Global Health and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, KotaKinabalu, Sabah, Malaysia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Grigg
authors.affiliation: Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, KotaKinabalu, Sabah, Malaysia Infectious Diseases Unit, Clinical Research Centre, Queen Elizabeth Hospital, KotaKinabalu, Sabah, Malaysia Sabah Department of Health, KotaKinabalu, Sabah, Malaysia.
authors.forename: T
authors.initials: T
authors.lastname: William
authors.affiliation: Sabah Department of Health, KotaKinabalu, Sabah, Malaysia Kudat District Hospital, Kudat, Sabah, Malaysia.
authors.forename: P
authors.initials: P
authors.lastname: Dhanaraj
authors.affiliation: Sabah Department of Health, KotaKinabalu, Sabah, Malaysia.
authors.forename: J
authors.initials: J
authors.lastname: Menon
authors.affiliation: Global Health and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, KotaKinabalu, Sabah, Malaysia.
authors.forename: B E
authors.initials: BE
authors.lastname: Barber
authors.affiliation: Global Health and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia Mahidol-Oxford Research Unit, Bangkok, Thailand.
authors.forename: L
authors.initials: L
authors.lastname: von Seidlein
authors.affiliation: Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, KotaKinabalu, Sabah, Malaysia Infectious Diseases Unit, Clinical Research Centre, Queen Elizabeth Hospital, KotaKinabalu, Sabah, Malaysia.
authors.forename: G
authors.initials: G
authors.lastname: Rajahram
authors.affiliation: Global Health and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford, UK.
authors.forename: R N
authors.initials: RN
authors.lastname: Price
authors.affiliation: Global Health and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, KotaKinabalu, Sabah, Malaysia Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia.
authors.forename: N M
authors.initials: NM
authors.lastname: Anstey
authors.affiliation: Global Health and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, KotaKinabalu, Sabah, Malaysia Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
authors.forename: T W
authors.initials: TW
authors.lastname: Yeo
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D000077332:Artesunate; D002738:Chloroquine / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008296:Malaysia; D008297:Male; D015767:Mefloquine / Q000627:therapeutic use*; D016790:Plasmodium knowlesi; D012107:Research Design; D012720:Severity of Illness Index
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D002738:Chloroquine; D015767:Mefloquine
keywords: INFECTIOUS DISEASES; PARASITOLOGY