Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial

© 2014 Laman et al. 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.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.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.Australian New Zealand Clinical Trials Registry ACTRN12610000913077.Please see later in the article for the Editors' Summary

Short-course, high-dose primaquine regimens for the treatment of liver-stage vivax malaria in children

Objectives: To assess the pharmacokinetics, safety, and tolerability of two high-dose, short-course primaquine (PQ) regimens compared with standard care in children with Plasmodium vivax infections. Methods: We performed an open-label pediatric dose-escalation study in Madang, Papua New Guinea (Clinicaltrials.gov NCT02364583). Children aged 5-10 years with confirmed blood-stage vivax malaria and normal glucose-6-phosphate dehydrogenase activity were allocated to one of three PQ treatment regimens in a stepwise design (group A: 0.5 mg/kg once daily for 14 days, group B: 1 mg/kg once daily for 7 days, and group C: 1 mg/kg twice daily for 3.5-days). The study assessments were completed at each treatment time point and fortnightly for 2 months after PQ administration. Results: Between August 2013 and May 2018, 707 children were screened and 73 met the eligibility criteria (15, 40, and 16 allocated to groups A, B, and C, respectively). All children completed the study procedures. The three regimens were safe and generally well tolerated. The pharmacokinetic analysis indicated that an additional weight adjustment of the conventionally recommended milligram per kilogram PQ doses is not necessary to ensure the therapeutic plasma concentrations in pediatric patients. Conclusions: A novel, ultra-short 3.5-day PQ regimen has potential benefits for improving the treatment outcomes in children with vivax malaria that warrants further investigation in a large-scale clinical trial

Ultra-short course, high-dose primaquine to prevent Plasmodium vivax infection following uncomplicated pediatric malaria: A randomized, open-label, non-inferiority trial of early versus delayed treatment

Objectives: We aimed to assess safety, tolerability, and Plasmodium vivax relapse rates of ultra-short course (3.5 days) high-dose (1 mg/kg twice daily) primaquine (PQ) for uncomplicated malaria because of any Plasmodium species in children randomized to early- or delayed treatment. Methods: Children aged 0.5 to 12 years with normal glucose-6-phosphate-dehydrogenase (G6PD) activity were enrolled. After artemether-lumefantrine (AL) treatment, children were randomized to receive PQ immediately after (early) or 21 days later (delayed). Primary and secondary endpoints were the appearance of any P. vivax parasitemia within 42 or 84 days, respectively. A non-inferiority margin of 15% was applied (ACTRN12620000855921). Results: A total of 219 children were recruited, 70% with Plasmodium falciparum and 24% with P. vivax. Abdominal pain (3.7% vs 20.9%, P <0.0001) and vomiting (0.9% vs 9.1%, P = 0.01) were more common in the early group. At day 42, P. vivax parasitemia was observed in 14 (13.2%) and 8 (7.8%) in the early and delayed groups, respectively (difference, −5.4%; 95% confidence interval −13.7 to 2.8). At day 84, P. vivax parasitemia was observed in 36 (34.3%) and 17 (17.5%; difference −16.8%, −28.6 to −6.1). Conclusion: Ultra-short high-dose PQ was safe and tolerated without severe adverse events. Early treatment was non-inferior to delayed treatment in preventing P. vivax infection at day 42

Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial

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

Fever and parasite clearance times by <i>Plasmodium</i> species and allocated treatment.

<p>Data are number/total (percentage) or mean (95% confidence interval).</p><p>Fever and parasite clearance times by <i>Plasmodium</i> species and allocated treatment.</p

Hemoglobin concentrations during follow-up after treatment for <i>P. falciparum</i> and for <i>P. vivax</i>.

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

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

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

Kaplan-Meier plots showing percentages of patients positive for PCR-corrected <i>P. falciparum</i> and for PCR-uncorrected <i>P. vivax</i> after treatment.

<p>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). <i>p</i>-Values are for log-rank tests.</p

Incidence rate of main reported or observed signs and symptoms during the first 7 d of follow-up in randomized children, expressed as reports per 100 observations.

<p>Poisson regression with follow-up time as the exposure was used to derive incident rate ratios with artemether-lumefantrine as reference. Data on signs/symptoms from ten children were lost prior to database entry.</p><p>IRR, incident rate ratio.</p><p>Incidence rate of main reported or observed signs and symptoms during the first 7 d of follow-up in randomized children, expressed as reports per 100 observations.</p

Baseline characteristics of patients classified by <i>Plasmodium</i> species and allocated treatment.

<p>Data are percentage, mean ± standard deviation, median (interquartile range), or median [absolute range].</p><p>Baseline characteristics of patients classified by <i>Plasmodium</i> species and allocated treatment.</p