Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW)

an open-label, randomised controlled trial

Matthew Grigg, Timothy Williams, Jayaram Menon, Prabakaran Dhanaraj, Bridget Barber, Christopher Wilkes, Lorenz Von Seidlein, Giri Rajahram, Cielo Pasay, James McCarthy, Ric Price, Nicholas Anstey, Tsin Yeo

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate–mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children.

    Methods: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate–mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876.

    Findings: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate–mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76–91]) of 115 patients in the artesunate–mefloquine group versus 61 (55% [45–64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0–40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate–mefloquine than in those given chloroquine (18·0 h [range 6·0–48·0] vs 24·0 h [6·0–60·0]; p<0·0001), with faster clearance of ring stages in the artesunate–mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9–9·4] vs 13·8 h [12·1–15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate–mefloquine group (71 [62%; 95% CI 52·2–70·6]) than in those in the chloroquine group (83 [75%; 65·6–82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate–mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate–mefloquine group (mean 11·5 h [95% CI 8·3–14·6]) than in the chloroquine group (14·8 h [11·7–17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate–mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812–0·906]; p<0·0001). One (<1%) patient in the artesunate–mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug.

    Interpretation: Artesunate–mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas.

    Funding: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.

    Original languageEnglish
    Pages (from-to)180-188
    Number of pages9
    JournalLancet Infectious Diseases
    Volume16
    Issue number2
    DOIs
    Publication statusPublished - 2016

    Fingerprint

    Plasmodium knowlesi
    Plasmodium malariae
    Mefloquine
    Malaysia
    Chloroquine
    Randomized Controlled Trials
    Malaria
    Therapeutics
    Parasites
    artesunate
    Bed Occupancy
    Endpoint Determination
    Pharmaceutical Preparations
    Southeastern Asia
    Plasmodium
    District Hospitals
    Nursing Staff
    Zoonoses
    Random Allocation

    Cite this

    Grigg, Matthew ; Williams, Timothy ; Menon, Jayaram ; Dhanaraj, Prabakaran ; Barber, Bridget ; Wilkes, Christopher ; Von Seidlein, Lorenz ; Rajahram, Giri ; Pasay, Cielo ; McCarthy, James ; Price, Ric ; Anstey, Nicholas ; Yeo, Tsin. / Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW) : an open-label, randomised controlled trial. In: Lancet Infectious Diseases. 2016 ; Vol. 16, No. 2. pp. 180-188.
    @article{154d1f5380c346c1b26ae42997647162,
    title = "Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): an open-label, randomised controlled trial",
    abstract = "Background: The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate–mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children. Methods: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate–mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. Findings: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate–mefloquine (n=127) or chloroquine (n=125); 226 (90{\%}) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84{\%} [95{\%} CI 76–91]) of 115 patients in the artesunate–mefloquine group versus 61 (55{\%} [45–64]) of 111 patients in the chloroquine group (difference in proportion 29{\%} [95{\%} CI 18·0–40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate–mefloquine than in those given chloroquine (18·0 h [range 6·0–48·0] vs 24·0 h [6·0–60·0]; p<0·0001), with faster clearance of ring stages in the artesunate–mefloquine group (mean time to 50{\%} clearance of baseline parasites 8·6 h [95{\%} CI 7·9–9·4] vs 13·8 h [12·1–15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate–mefloquine group (71 [62{\%}; 95{\%} CI 52·2–70·6]) than in those in the chloroquine group (83 [75{\%}; 65·6–82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86{\%}) of 51 patients in the artesunate–mefloquine group and 41 (84{\%}) of 49 patients in the chloroquine group at baseline, and in three (6{\%}) of 49 patients and two (4{\%}) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate–mefloquine group (mean 11·5 h [95{\%} CI 8·3–14·6]) than in the chloroquine group (14·8 h [11·7–17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate–mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95{\%} CI 0·812–0·906]; p<0·0001). One (<1{\%}) patient in the artesunate–mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug. Interpretation: Artesunate–mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas. Funding: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.",
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    author = "Matthew Grigg and Timothy Williams and Jayaram Menon and Prabakaran Dhanaraj and Bridget Barber and Christopher Wilkes and {Von Seidlein}, Lorenz and Giri Rajahram and Cielo Pasay and James McCarthy and Ric Price and Nicholas Anstey and Tsin Yeo",
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    pages = "180--188",
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    }

    Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW) : an open-label, randomised controlled trial. / Grigg, Matthew; Williams, Timothy; Menon, Jayaram; Dhanaraj, Prabakaran; Barber, Bridget; Wilkes, Christopher; Von Seidlein, Lorenz; Rajahram, Giri; Pasay, Cielo; McCarthy, James; Price, Ric; Anstey, Nicholas; Yeo, Tsin.

    In: Lancet Infectious Diseases, Vol. 16, No. 2, 2016, p. 180-188.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW)

    T2 - an open-label, randomised controlled trial

    AU - Grigg, Matthew

    AU - Williams, Timothy

    AU - Menon, Jayaram

    AU - Dhanaraj, Prabakaran

    AU - Barber, Bridget

    AU - Wilkes, Christopher

    AU - Von Seidlein, Lorenz

    AU - Rajahram, Giri

    AU - Pasay, Cielo

    AU - McCarthy, James

    AU - Price, Ric

    AU - Anstey, Nicholas

    AU - Yeo, Tsin

    PY - 2016

    Y1 - 2016

    N2 - Background: The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate–mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children. Methods: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate–mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. Findings: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate–mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76–91]) of 115 patients in the artesunate–mefloquine group versus 61 (55% [45–64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0–40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate–mefloquine than in those given chloroquine (18·0 h [range 6·0–48·0] vs 24·0 h [6·0–60·0]; p<0·0001), with faster clearance of ring stages in the artesunate–mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9–9·4] vs 13·8 h [12·1–15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate–mefloquine group (71 [62%; 95% CI 52·2–70·6]) than in those in the chloroquine group (83 [75%; 65·6–82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate–mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate–mefloquine group (mean 11·5 h [95% CI 8·3–14·6]) than in the chloroquine group (14·8 h [11·7–17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate–mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812–0·906]; p<0·0001). One (<1%) patient in the artesunate–mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug. Interpretation: Artesunate–mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas. Funding: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.

    AB - Background: The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate–mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children. Methods: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate–mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. Findings: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate–mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76–91]) of 115 patients in the artesunate–mefloquine group versus 61 (55% [45–64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0–40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate–mefloquine than in those given chloroquine (18·0 h [range 6·0–48·0] vs 24·0 h [6·0–60·0]; p<0·0001), with faster clearance of ring stages in the artesunate–mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9–9·4] vs 13·8 h [12·1–15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate–mefloquine group (71 [62%; 95% CI 52·2–70·6]) than in those in the chloroquine group (83 [75%; 65·6–82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate–mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate–mefloquine group (mean 11·5 h [95% CI 8·3–14·6]) than in the chloroquine group (14·8 h [11·7–17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate–mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812–0·906]; p<0·0001). One (<1%) patient in the artesunate–mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug. Interpretation: Artesunate–mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas. Funding: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.

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    KW - fever

    KW - gametocyte

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    KW - human

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    KW - Malaysia

    KW - male

    KW - multicenter study

    KW - parasite clearance

    KW - Plasmodium knowlesi malaria

    KW - priority journal

    KW - randomized controlled trial

    KW - reverse transcription polymerase chain reaction

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