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

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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.
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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",
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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.

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U2 - 10.1093/cid/cix779

DO - 10.1093/cid/cix779

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JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

SN - 1058-4838

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