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)

M J Grigg, T William, P Dhanaraj, J Menon, B E Barber, L von Seidlein, G Rajahram, R N Price, N M Anstey, T W Yeo, M J Grigg, T William, P Dhanaraj, J Menon, B E Barber, L von Seidlein, G Rajahram, R N Price, N M Anstey, T W Yeo

Abstract

Introduction: 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 and analysis: 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.

Ethics and dissemination: 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.

Trial registration number: NCT01708876.

Keywords: INFECTIOUS DISEASES; PARASITOLOGY.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1
Figure 1
Map of study sites.
Figure 2
Figure 2
Artesunate-mefloquine (AS-MQ) dosing guide.
Figure 3
Figure 3
Dosing schedule.
Figure 4
Figure 4
Timeline of activities.

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