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)

Matthew Grigg, Timothy Williams, Prabakaran Dhanaraj, Jayaram Menon, Bridget Barber, Lorenz Von Seidlein, Giri Rajahram, Ric Price, Nicholas Anstey, Tsin Yeo

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    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 (? 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.
    Original languageEnglish
    Pages (from-to)1-10
    Number of pages10
    JournalBMJ Open
    Volume4
    Issue number8
    DOIs
    Publication statusPublished - 2014

    Fingerprint

    Plasmodium knowlesi
    Plasmodium malariae
    Mefloquine
    Malaysia
    Chloroquine
    Malaria
    Clinical Trials
    Therapeutics
    Parasites
    artesunate
    artemisinine
    Ethics Committees
    Intention to Treat Analysis
    Plasmodium
    Far East
    Falciparum Malaria
    Antimalarials
    Insurance Benefits
    Survival Analysis
    Clinical Protocols

    Cite this

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    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 = "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 (? 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 = "artesunate plus mefloquine, chloroquine, glucose 6 phosphate dehydrogenase, hemoglobin, antimalarial agent, artemisinin derivative, artesunate, mefloquine, analysis, article, clinical protocol, controlled study, drug bioavailability, drug efficacy, drug safety, drug treatment failure, female, follow up, gametocyte, health care cost, human, human tissue, length of stay, Malaysia, male, parasite clearance, Plasmodium knowlesi malaria, randomized controlled trial, recurrent infection, comparative study, malaria, methodology, parasitology, Plasmodium knowlesi, severity of illness index, Antimalarials, Artemisinins, Chloroquine, Female, Humans, Malaria, Male, Mefloquine, Research Design, Severity of Illness Index",
    author = "Matthew Grigg and Timothy Williams and Prabakaran Dhanaraj and Jayaram Menon and Bridget Barber and {Von Seidlein}, Lorenz and Giri Rajahram and Ric Price and Nicholas Anstey and Tsin Yeo",
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    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). / Grigg, Matthew; Williams, Timothy; Dhanaraj, Prabakaran; Menon, Jayaram; Barber, Bridget; Von Seidlein, Lorenz; Rajahram, Giri; Price, Ric; Anstey, Nicholas; Yeo, Tsin.

    In: BMJ Open, Vol. 4, No. 8, 2014, p. 1-10.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - 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)

    AU - Grigg, Matthew

    AU - Williams, Timothy

    AU - Dhanaraj, Prabakaran

    AU - Menon, Jayaram

    AU - Barber, Bridget

    AU - Von Seidlein, Lorenz

    AU - Rajahram, Giri

    AU - Price, Ric

    AU - Anstey, Nicholas

    AU - Yeo, Tsin

    PY - 2014

    Y1 - 2014

    N2 - 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 (? 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.

    AB - 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 (? 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.

    KW - artesunate plus mefloquine

    KW - chloroquine

    KW - glucose 6 phosphate dehydrogenase

    KW - hemoglobin

    KW - antimalarial agent

    KW - artemisinin derivative

    KW - artesunate

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    KW - analysis

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    KW - controlled study

    KW - drug bioavailability

    KW - drug efficacy

    KW - drug safety

    KW - drug treatment failure

    KW - female

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    KW - gametocyte

    KW - health care cost

    KW - human

    KW - human tissue

    KW - length of stay

    KW - Malaysia

    KW - male

    KW - parasite clearance

    KW - Plasmodium knowlesi malaria

    KW - randomized controlled trial

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    KW - malaria

    KW - methodology

    KW - parasitology

    KW - Plasmodium knowlesi

    KW - severity of illness index

    KW - Antimalarials

    KW - Artemisinins

    KW - Chloroquine

    KW - Female

    KW - Humans

    KW - Malaria

    KW - Male

    KW - Mefloquine

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