Artemether-Lumefantrine Versus Chloroquine for the Treatment of Uncomplicated Plasmodium knowlesi Malaria

An Open-Label Randomized Controlled Trial CAN KNOW

Matthew Grigg, Timothy William, Bridget Barber, Giri Shan Rajahram, Jayaram Menon, Emma Schimann, Christopher S. Wilkes, Kaajal Patel, Arjun Chandna, Ric Price, Tsin Yeo, Nicholas Anstey

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    Abstract

    Background: Plasmodium knowlesi is reported increasingly across Southeast Asia and is the most common cause of malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for knowlesi malaria.

    Methods: A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated knowlesi malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis.

    Results: From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%–86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%–72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0–1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82–.91]; P < .001). There were no serious adverse events.

    Conclusions: AL is highly efficacious for treating uncomplicated knowlesi malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia.
    Original languageEnglish
    Pages (from-to)229-236
    Number of pages8
    JournalClinical Infectious Diseases
    Volume66
    Issue number2
    DOIs
    Publication statusPublished - 15 Jan 2018

    Fingerprint

    Plasmodium knowlesi
    Plasmodium malariae
    Chloroquine
    Randomized Controlled Trials
    Malaysia
    Malaria
    Confidence Intervals
    Therapeutics
    Parasites
    Bed Occupancy
    Southeastern Asia
    Intention to Treat Analysis
    Plasmodium
    Parasitemia
    District Hospitals
    lumefantrine
    artemether
    Plasmodium falciparum
    Treatment Failure
    Routine Diagnostic Tests

    Cite this

    Grigg, Matthew ; William, Timothy ; Barber, Bridget ; Rajahram, Giri Shan ; Menon, Jayaram ; Schimann, Emma ; Wilkes, Christopher S. ; Patel, Kaajal ; Chandna, Arjun ; Price, Ric ; Yeo, Tsin ; Anstey, Nicholas. / Artemether-Lumefantrine Versus Chloroquine for the Treatment of Uncomplicated Plasmodium knowlesi Malaria : An Open-Label Randomized Controlled Trial CAN KNOW. In: Clinical Infectious Diseases. 2018 ; Vol. 66, No. 2. pp. 229-236.
    @article{e2c54b92b51543dc8c4424309cff9d19,
    title = "Artemether-Lumefantrine Versus Chloroquine for the Treatment of Uncomplicated Plasmodium knowlesi Malaria: An Open-Label Randomized Controlled Trial CAN KNOW",
    abstract = "Background: Plasmodium knowlesi is reported increasingly across Southeast Asia and is the most common cause of malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for knowlesi malaria.Methods: A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated knowlesi malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis.Results: From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76{\%} of patients administered AL (95{\%} confidence interval [CI], 63{\%}–86{\%}; 44 of 58) were aparasitemic, compared with 60{\%} administered CQ (47{\%}–72{\%}; 39 of 65; risk ratio, 1.3 [95{\%} CI, 1.0–1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95{\%} CI, .82–.91]; P < .001). There were no serious adverse events.Conclusions: AL is highly efficacious for treating uncomplicated knowlesi malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia.",
    author = "Matthew Grigg and Timothy William and Bridget Barber and Rajahram, {Giri Shan} and Jayaram Menon and Emma Schimann and Wilkes, {Christopher S.} and Kaajal Patel and Arjun Chandna and Ric Price and Tsin Yeo and Nicholas Anstey",
    year = "2018",
    month = "1",
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    doi = "10.1093/cid/cix779",
    language = "English",
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    pages = "229--236",
    journal = "Clinical Infectious Diseases",
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    publisher = "Oxford University Press",
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    }

    Artemether-Lumefantrine Versus Chloroquine for the Treatment of Uncomplicated Plasmodium knowlesi Malaria : An Open-Label Randomized Controlled Trial CAN KNOW. / Grigg, Matthew; William, Timothy; Barber, Bridget; Rajahram, Giri Shan; Menon, Jayaram; Schimann, Emma ; Wilkes, Christopher S.; Patel, Kaajal ; Chandna, Arjun ; Price, Ric; Yeo, Tsin; Anstey, Nicholas.

    In: Clinical Infectious Diseases, Vol. 66, No. 2, 15.01.2018, p. 229-236.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Artemether-Lumefantrine Versus Chloroquine for the Treatment of Uncomplicated Plasmodium knowlesi Malaria

    T2 - An Open-Label Randomized Controlled Trial CAN KNOW

    AU - Grigg, Matthew

    AU - William, Timothy

    AU - Barber, Bridget

    AU - Rajahram, Giri Shan

    AU - Menon, Jayaram

    AU - Schimann, Emma

    AU - Wilkes, Christopher S.

    AU - Patel, Kaajal

    AU - Chandna, Arjun

    AU - Price, Ric

    AU - Yeo, Tsin

    AU - Anstey, Nicholas

    PY - 2018/1/15

    Y1 - 2018/1/15

    N2 - Background: Plasmodium knowlesi is reported increasingly across Southeast Asia and is the most common cause of malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for knowlesi malaria.Methods: A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated knowlesi malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis.Results: From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%–86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%–72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0–1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82–.91]; P < .001). There were no serious adverse events.Conclusions: AL is highly efficacious for treating uncomplicated knowlesi malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia.

    AB - Background: Plasmodium knowlesi is reported increasingly across Southeast Asia and is the most common cause of malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for knowlesi malaria.Methods: A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated knowlesi malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis.Results: From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%–86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%–72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0–1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82–.91]; P < .001). There were no serious adverse events.Conclusions: AL is highly efficacious for treating uncomplicated knowlesi malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia.

    UR - http://www.scopus.com/inward/record.url?scp=85040620492&partnerID=8YFLogxK

    U2 - 10.1093/cid/cix779

    DO - 10.1093/cid/cix779

    M3 - Article

    VL - 66

    SP - 229

    EP - 236

    JO - Clinical Infectious Diseases

    JF - Clinical Infectious Diseases

    SN - 1058-4838

    IS - 2

    ER -