A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severePlasmodium knowlesimalaria in Sabah, Malaysia (ACT KNOW trial)

Abstract

IntroductionMalaria 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 analysisACT 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 disseminationThis 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 numberNCT01708876.

Efficacy and safety of artemisinin combination therapy (ACT) for non-falciparum malaria: a systematic review

“…In a retrospective study, parasite clearance time of AL and injectable artesunate, compared to CQ and quinine, was faster, with fewer deaths with artesunate than quinine[ 66 ]. More trials are needed and currently two trials are initiated: “ACT KNOW” (Clinicaltrials.gov: NCT01708876[ 116 ]), a RCT to test whether fixed combination of artesunate-mefloquine is superior to CQ and “CAN KNOW” (NCT02001012), a RCT to test whether AL is superior to CQ.…”

Plasmodium knowlesi malaria: Overview Focussing on Travel-Associated Infections

“…A randomised study comparing artesunate-mefloquine combined therapy versus chloroquine in uncomplicated P. knowlesi malaria is expected to complete recruitment at the end of 2014 but it is unlikely that mefloquine will play a relevant role in treating P. knowlesi due to better-tolerated alternative drugs [39]. P. knowlesi is considered as sensitive to chloroquine [40•].…”

An Autochthonous Case of Severe Plasmodium knowlesi Malaria in Thailand

“…It is noteworthy that all these knowlesi malaria patients, either having monoor mixed species infections, had uncomplicated symptoms and were responsive to chloroquine and a combination of artesunate and mefloquine. [4][5][6] Herein, we describe severe manifestations of knowlesi malaria in a newly recognized Thai patient.…”