Artemisinin-naphthoquine versus artemether-lumefantrine for uncomplicated malaria in Papua New Guinean children: an open-label randomized trial

Abstract

Background: Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5-5 y.

Methods and findings: An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI -3.0% to 8.4%] versus -5.0% non-inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%-87.2%], p<0.001). Limitations included the exclusion of 11% of randomized patients with sub-threshold parasitemias on confirmatory microscopy and direct observation of only morning artemether-lumefantrine dosing.

Conclusions: Artemisinin-naphthoquine is non-inferior to artemether-lumefantrine in PNG children with falciparum malaria but has greater efficacy against vivax malaria, findings with implications in similar geo-epidemiologic settings within and beyond Oceania.

Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000913077. Please see later in the article for the Editors' Summary.

Figure 1. Trial profile showing numbers of patients remaining in the study from screening to day-42 assessment.

PCR-corrected denotes correction for reinfections identified by polymerase chain reaction genotyping of polymorphic parasite loci.

Figure 2. Electrocardiographic QT_c intervals after treatment for uncomplicated malaria.

Data are median and interquartile range (vertical bars) for artemether-lumefantrine (▴, solid lines) and artemisinin-naphthoquine (•, dashed lines). **p<0.01 for between-treatment comparisons.

Figure 3. Kaplan-Meier plots showing percentages of patients positive for PCR-corrected P. falciparum and for PCR-uncorrected P. vivax after treatment.

Data are for artemether-lumefantrine (solid lines) and artemisinin-naphthoquine (dashed lines). Numbers of children at risk at each time point are shown for artemether-lumefantrine (AL) and artemisinin-naphthoquine (AN). p-Values are for log-rank tests.

Figure 4. Proportions of patients with gametocytes during follow-up after treatment for P. falciparum and for P. vivax.

Data are for artemether-lumefantrine (▴, solid lines) and artemisinin-naphthoquine (•, dashed lines). *p<0.05, **p<0.01 for between-treatment comparisons.

Figure 5. Hemoglobin concentrations during follow-up after treatment for P. falciparum and for P. vivax.

Data are mean and standard deviation (vertical bars) for artemether-lumefantrine (▴, solid lines) and artemisinin-naphthoquine (•, dashed lines). **p<0.01 for between-treatment comparisons.