The authors have declared that no competing interests exist.
Conceived and designed the experiments: TMED. Performed the experiments: ML BRM JMB GY CB JW JHK TK LM BK LJR NS LL SK AR-U. Analyzed the data: WAD ML BRM TMED. Wrote the first draft of the manuscript: ML BRM. Wrote the paper: ML BRM JMB GY CB JW JHK TK LM BK LJR NS LL SK WAD AR-U IM PMS IB TMED. Agree with manuscript results and conclusions: ML BRM JMB GY CB JW JHK TK LM BK LJR NS LL SK WAD AR-U IM PMS IB TMED. Enrolled patients: ML BRM JMB GY CB JW. All authors have read, and confirm that they meet, ICMJE criteria for authorship.
In a randomized controlled trial Tim Davis and colleagues investigate Artemisinin-naphthoquine versus artemether-lumefantrine for the treatment of
Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple
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
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
Malaria is a mosquito-borne parasitic disease that kills more than 600,000 people (mainly young children in sub-Saharan Africa) every year.
Because falciparum and vivax malaria respond differently to antimalarial drugs, wherever there is transmission of both types of malaria but limited facilities for species-specific malaria diagnosis—as in Papua New Guinea—compromises have to be made about which ACT should be used for the treatment of malaria. Thus, Papua New Guinea's national guidelines recommend artemether-lumefantrine, which is effective against the more deadly
The researchers assigned nearly 250 children (aged 0.5 to 5 years) with falciparum malaria, vivax malaria, or both types of malaria to receive six doses of artemether-lumefantrine over three days or three daily doses of artemisinin-naphthoquine. They then followed the children to see how many children in each treatment group and with each type of malaria were free of malaria 42 days after treatment (an “adequate clinical and parasitological response”). Among the patients originally infected with
These findings indicate that artemisinin-naphthoquine was non-inferior to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria among young children in Papua New Guinea and had greater efficacy than artemether-lumefantrine against vivax malaria. The accuracy of these findings may be limited by several aspects of the study design. For example, not all the artemether-lumefantrine doses were directly observed, so some children may not have received the full treatment course. Moreover, because all the study participants lived in coastal communities in Papua New Guinea where malaria is highly endemic, treatment responses among children living in areas with lower levels of malaria transmission might be different. Nevertheless, these findings suggest that artemisinin-naphthoquine should be considered alongside other ACTs for the treatment of uncomplicated malaria in regions where there is transmission of multiple
Please access these websites via the online version of this summary at
Information is available from the World Health Organization on
The US Centers for Disease Control and Prevention provides information on
Information is available from the Roll Back Malaria Partnership on the
The Malaria Vaccine Initiative has a fact sheet on
MedlinePlus provides links to additional information on
More information about this
Malaria control programs incorporating artemisinin combination therapy (ACT) have contributed to a decline in malaria morbidity and mortality worldwide, renewing interest in global eradication
Transmission of both
There is a need for assessment of other ACTs that might replicate the high cure rate of artemether-lumefantrine in falciparum malaria while ensuring that vivax malaria is also effectively treated in PNG and similar epidemiologic settings. Of the few available alternatives, artemisinin-naphthoquine has been marketed in a range of countries in Africa, Asia, and Oceania as single-dose treatment based on limited pharmacologic, efficacy, and safety data in adults
The aim of the present study was to compare the efficacy of three daily artemisinin-naphthoquine doses to that of a six-dose, 3-d artemether-lumefantrine regimen in PNG children aged 0.5–5 y with uncomplicated malaria. We hypothesized that artemisinin-naphthoquine would be well tolerated and safe in this younger vulnerable pediatric population, and that its efficacy would be (i) non-inferior to that of artemether-lumefantrine for falciparum malaria and (ii) superior to that of artemether-lumefantrine for vivax malaria.
This open-label, parallel-group trial was conducted at the Mugil and Alexishafen Health Centers, Madang Province, PNG, from 28 March 2011 to 22 April 2013. The primary efficacy endpoints were (i) reappearance of
Since artemether-lumefantrine has a high (>95%) day-42 adequate parasitologic and clinical response (ACPR) for falciparum malaria in the PNG pediatric population
The original study design involved a comparison of conventional artemether-lumefantrine with both artemisinin-naphthoquine and artesunate-pyronaridine. Artesunate-pyronaridine was not initially available because concerns regarding hepatotoxicity were being addressed
The study was approved by the PNG Institute of Medical Research Review Board, the Medical Research Advisory Committee of PNG, and the University of Western Australia Human Research Ethics Committee. Written informed consent was obtained from parents/guardians of all children.
Children aged 0.5–5 y presenting with an axillary temperature >37.5°C or a history of fever during the previous 24 h were screened using on-site blood film microscopy. Those with
An initial standardized clinical assessment was performed, and blood was drawn for measurement of hemoglobin and blood glucose (Hemocue 201+, Hemocue, Ängelholm, Sweden), as well as hepatic and renal function (Vitros DT60 II system, Ortho Clinical Diagnostics, Mulgrave, Victoria, Australia) and a full blood count (Coulter Ac·T diff, Beckman Coulter, Brea, California, US). A 12-lead electrocardiograph was taken for measurement of the QT interval. Each QT interval was corrected for heart rate using Bazett's formula (
Based on computer-generated block randomization (24 children per site), eligible patients were allocated 1∶1 to artemether-lumefantrine (1.7 mg/kg artemether plus 10 mg/kg lumefantrine; Novartis Pharma, Basel, Switzerland) twice daily for 3 d or to artemisinin-naphthoquine (20 mg/kg artemisinin plus 8 mg/kg naphthoquine; Kunming Pharmaceutical Corporation, Yunnan, China) daily for 3 d. Randomization was independent of
Treatments were not blinded, primarily because the endpoints were based on objective clinical and parasitologic criteria. In addition, we sought to simplify drug administration as much as possible to maximize patient adherence and retention, including only once daily dosing and the avoidance of potential gastrointestinal side effects with the unnecessary ingestion of milk in children allocated artemisinin-naphthoquine
Standardized assessment, including axillary temperature and blood film microscopy, was repeated on days 1, 2, 3, 7, 14, 28, and 42. Blood was drawn for full blood count and hepatorenal function, and an electrocardiograph was taken, on days 0, 3, and 7. An additional electrocardiograph was performed 4 h after the day-2 dose (at the predicted peak plasma naphthoquine concentration
Efficacy was assessed using WHO definitions
Day-7 plasma lumefantrine concentrations were determined using a validated ultra-high-performance liquid chromatography–tandem mass spectrometry assay as previously described
Per-protocol prespecified analyses included children with complete follow-up or a confirmed treatment failure, and excluded those treated for malaria without confirmatory microscopy, those for whom the alternative
Kaplan-Meier estimates were computed for each endpoint defined by parasite species. Statistical analysis was performed using IBM SPSS Statistics version 20 (IBM Corporation, Somers, New York, US) and STATA/IC 11.2 (StataCorp, College Station, Texas, US). Two-sample comparisons for normally distributed variables were by Student's
The first patient was recruited on 28 March 2011, and the last follow-up was completed on 22 April 2013. No adverse events occurred in the first 50 patients. A further safety assessment was scheduled when one-third of the total planned sample size of 560 had been recruited. Safety data were available for 91 artemether-lumefantrine-treated and 97 artemisinin-naphthoquine-treated children at that time (including those excluded post hoc; see
PCR-corrected denotes correction for reinfections identified by polymerase chain reaction genotyping of polymorphic parasite loci.
Of 267 randomized children, 36 (13.5%) were excluded post hoc because of protocol violations (20 allocated to artemether-lumefantrine and 16 to artemisinin-naphthoquine; see
Of the remaining 230 children, the day-42 retention was ≥92% for all species/treatment groups. Ten children (six allocated to artemether-lumefantrine and four to artemisinin-naphthoquine, all with falciparum malaria) withdrew during follow-up. None of these children had experienced adverse effects; they had all relocated outside the study catchment areas. Two children with
There were no significant differences in baseline demographic and anthropometric characteristics (age, sex, weight, height, and mid-upper-arm circumference), vital signs (axillary temperature, heart rate, and respiratory rate), hematologic parameters (white and red blood cell counts, platelet count, and hemoglobin concentration), or blood glucose concentrations between the 91 children allocated to artemether-lumefantrine and the 97 who received artemisinin-naphthoquine in the detailed safety assessment (
Parameter | Artemether-Lumefantrine | Artemisinin-Naphthoquine | |||
Mean ± SD, Median (IQR), or Percentage | Mean ± SD, Median (IQR), or Percentage | ||||
Age (months) | 91 | 44.2±14.2 | 97 | 42.7±4.6 | 0.50 |
Sex (percent male) | 91 | 44.0% | 97 | 49.5% | 0.47 |
Body weight (kg) | 90 | 12.7±2.1 | 95 | 12.7±2.5 | 0.87 |
Height (cm) | 83 | 93.8±10.3 | 91 | 92.9±10.3 | 0.55 |
Mid-upper-arm circumference (cm) | 90 | 15.0 (14.0–15.0) | 94 | 14.5 (14.0–15.5) | 0.39 |
Axillary temperature (°C) | 90 | 38.0±1.3 | 95 | 38.1±1.4 | 0.74 |
Pulse rate (/min) | 89 | 123±20 | 92 | 126±21 | 0.26 |
Respiratory rate (/min) | 89 | 32 (28–37) | 93 | 32 (26–38) | 0.55 |
White blood cells (× 109/l) | 85 | 6.9 (5.4–9.8) | 91 | 7.4 (5.0–9.3) | 0.78 |
Red blood cells (× 1012/l) | 85 | 3.68 (3.03–4.27) | 91 | 3.77 (3.23–4.34) | 0.55 |
Platelets (× 109/l) | 84 | 85 (64–132) | 91 | 102 (63–137) | 0.78 |
Hemoglobin (g/l) | 89 | 93 (81–104) | 94 | 91 (81–102) | 0.31 |
Blood glucose (mmol/l) | 83 | 6.4 (5.7–7.6) | 87 | 6.7 (5.8–7.4) | 0.59 |
Reticulocytes (percent) | 48 | 1.2% (0.6%–2.9%) | 48 | 0.8% (0.6%–2.0%) | 0.21 |
Axillary temperature (°C) | 88 | 36.4±0.4 | 94 | 36.2±0.5 | 0.002 |
Pulse rate (/min) | 87 | 107±15 | 94 | 107±17 | 0.36 |
Respiratory rate (/min) | 88 | 28 (24–32) | 94 | 28 (24–32) | 0.95 |
White blood cells (× 109/l) | 87 | 7.0 (5.5–8.7) | 90 | 7.1 (5.9–8.5) | 0.71 |
Red blood cells (× 1012/l) | 87 | 3.47 (3.03–3.91) | 90 | 3.57 (3.03–4.09) | 0.65 |
Platelets (× 109/l) | 87 | 142 (107–180) | 90 | 149 (102–188) | 0.63 |
Hemoglobin (g/l) | 88 | 87 (75–96) | 94 | 86 (73–99) | 0.92 |
Blood glucose (mmol/l) | 78 | 5.9 (5.3–6.5) | 81 | 5.8 (5.3–6.6) | 0.73 |
Reticulocytes (percent) | 49 | 1.2% (0.6%–3.4%) | 49 | 0.8% (0.5%–1.3%) | 0.10 |
Axillary temperature (°C) | 89 | 36.5±0.6 | 92 | 36.6±0.6 | 0.51 |
Pulse rate (/min) | 89 | 105±18 | 94 | 106±19 | 0.68 |
Respiratory rate (/min) | 89 | 28 (24–31) | 94 | 28 (24–32) | 0.41 |
White blood cells (× 109/l) | 87 | 8.1 (6.1–9.5) | 88 | 8.4 (7.1–10.7) | 0.01 |
Red blood cells (× 1012/l) | 87 | 3.64 (3.34–4.25) | 88 | 3.61 (3.15–4.19) | 0.43 |
Platelets (× 109/l) | 87 | 245 (191–337) | 88 | 257 (187–315) | 0.59 |
Hemoglobin (g/l) | 87 | 93 (80–102) | 94 | 91 (80–101) | 0.64 |
Blood glucose (mmol/l) | 80 | 5.9 (5.3–6.5) | 82 | 6.1 (5.4–6.5) | 0.70 |
Reticulocytes (percent) | 49 | 3.6% (1.4%–6.2%) | 49 | 2.3% (1.3%–3.6%) | 0.05 |
IQR, interquartile range; SD, standard deviation.
Measurement | Artemether-Lumefantrine | Artemisinin-Naphthoquine | |
Serum creatinine (µmol/l) | 38 (29–47) ( |
23 (28–43) ( |
0.09 |
Elevated creatinine |
0 (0%) | 0 (0%) | >0.99 |
Serum ALT (U/l) | 20 (13–35) ( |
20 (13–28) ( |
0.86 |
Elevated ALT |
2 (2.8%) | 0 (0%) | 0.50 |
Serum total bilirubin (µmol/l) | 20 (12–25) ( |
21 (12–26) ( |
0.77 |
Elevated bilirubin |
22 (29.7%) | 26 (34.7%) | 0.60 |
Serum creatinine (µmol/l) | 36 (27–41) ( |
37 (31–44) ( |
0.23 |
Elevated creatinine |
0 (0%) | 0 (0%) | >0.99 |
Serum ALT (U/l) | 18 (16–20) ( |
20 (17–26) ( |
0.16 |
Elevated ALT |
1 (1.4%) | 1 (1.5%) | >0.99 |
Serum total bilirubin (µmol/l) | 14 (6–17) ( |
13 (6–17) ( |
0.94 |
Elevated bilirubin |
2 (2.9%) | 1 (1.5%) | >0.99 |
Serum creatinine (µmol/l) | 29 (22–34) ( |
28 (24–40) ( |
0.43 |
Elevated creatinine |
0 (0%) | 0 (0%) | >0.99 |
Serum ALT (U/l) | 18 (12–25) ( |
21 (16–29) ( |
0.03 |
Elevated ALT |
0 (0%) | 0 (0%) | >0.99 |
Serum total bilirubin (µmol/l) | 11 (8–16) ( |
14 (9–15) ( |
0.63 |
Elevated bilirubin |
2 (2.8%) | 5 (7.2%) | 0.27 |
Data are median (interquartile range) or
*Elevated serum creatinine (≥112 µmol/l), serum ALT (≥130 U/l), and total serum bilirubin (≥23.8 µmol/l) are defined as>3 times the upper limit of normal values in PNG children aged <5 y
Both treatments were well tolerated, and there were no between-group differences in the incidence rates of reported/observed signs and symptoms during the first 7 d of follow-up, apart from a significantly greater incidence of abdominal pain in the artemisinin-naphthoquine-treated patients (incidence rate 11.6% versus 7.8% in the artemether-lumefantrine group; incidence rate ratio 1.48 [95% CI 1.03–2.13],
Sign/Symptom | Incident Rate (95% CI) | IRR (95% CI) | ||
Artemether-Lumefantrine ( |
Artemisinin-Naphthoquine ( |
|||
Fever | 27.9 (24.4–31.5) | 30.7 (27.1–34.5) | 1.10 (0.90–1.35) | 0.37 |
Chills | 5.8 (4.1–7.9) | 6.3 (4.5–8.5) | 1.08 (0.69–1.70) | 0.72 |
Headaches | 7.5 (5.6–9.8) | 10.1 (7.9–12.8) | 1.35 (0.93–1.97) | 0.12 |
Child irritable/frequent crying | 2.7 (1.6–4.2) | 3.4 (2.1–5.11) | 1.27 (0.67–2.41) | 0.46 |
Trouble sleeping | 0.9 (0.4–2.0) | 1.3 (0.6–2.5) | 1.37 (0.48–3.95) | 0.56 |
Problems eating/breast feeding | 12.4 (10.0–15.2) | 11.7 (9.3–14.5) | 0.94 (0.68–1.29) | 0.70 |
Vomiting | 4.2 (2.8–6.1) | 5.8 (4.1–7.9) | 1.37 (0.83–2.26) | 0.21 |
Diarrhea | 4.9 (3.3–6.8) | 3.5 (3.2–5.3) | 0.73 (0.42–1.26) | 0.26 |
Abdominal pain | 7.8 (5.8–10.1) | 11.6 (9.2–14.3) | 1.48 (1.03–2.13) | 0.03 |
Cough | 24.0 (20.8–27.5) | 29.1 (25.6–32.8) | 1.21 (0.98–1.50) | 0.08 |
Difficulty breathing | 0.9 (0.3–2.0) | 0.3 (0.0–1.2) | 0.34 (0.07–1.70) | 0.19 |
Rhinorrhea | 23.9 (20.6–27.4) | 22.1 (18.9–25.6) | 0.93 (0.74–1.17) | 0.53 |
Skin rash (reported) | 3.3 (2.0–5.0) | 3.1 (1.9–4.7) | 0.93 (0.50–1.73) | 0.82 |
Skin rash (observed) | 0.3 (0.0–1.1) | 1.1 (0.5–2.3) | 3.60 (0.75–17.33) | 0.11 |
Skin lesion | 2.7 (1.6–4.2) | 2.4 (1.4–4.0) | 0.91 (0.45–1.82) | 0.79 |
Pallor | 6.7 (4.9–8.9) | 9.3 (7.2–11.9) | 1.39 (0.94–2.06) | 0.10 |
Crackles at lung bases | 3.0 (1.8–4.6) | 1.6 (0.8–2.9) | 0.54 (0.25–1.16) | 0.12 |
Presence of enlarged spleen | 22.9 (19.7–26.4) | 26.5 (23.1–30.2) | 1.16 (0.92–1.44) | 0.20 |
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.
IRR, incident rate ratio.
Despite the technical challenges associated with performing electrocardiography in unwell children in a rural clinic, interpretable traces were obtained from between 68% and 88% of the children in each group at each time point. The QTc increased from baseline to 4 h after the last dose of artemisinin-naphthoquine by a median of 28 msec0.5 (interquartile range 18–36) (
Data are median and interquartile range (vertical bars) for artemether-lumefantrine (▴, solid lines) and artemisinin-naphthoquine (•, dashed lines). **
QTc (msec0.5) | Artemether-Lumefantrine | Artemisinin-Naphthoquine | |
Median (IQR) | 422 (408–443) | 422 (411–444) | 0.96 |
≤440 | 73.5% | 70.0% | 0.25 |
441–450 | 11.8% | 17.5% | |
451–460 | 10.3% | 3.8% | |
>460 | 4.4% | 8.8% | |
Median (IQR) | 439 (427–445) | 447 (433–472) | 0.003 |
≤440 | 55.6% | 34.7% | 0.005 |
441–450 | 33.3% | 20.0% | |
451–460 | 7.4% | 12.0% | |
>460 | 3.7% | 33.3% | |
Median (IQR) | 444 (430–454) | 443 (428–454) | 0.82 |
≤440 | 41.9% | 44.0% | 0.87 |
441–450 | 30.6% | 27.4% | |
451–460 | 14.5% | 11.9% | |
>460 | 12.9% | 16.7% | |
Median (IQR) | 432 (415–444) | 425 (414–444) | 0.64 |
≤440 | 66.7% | 67.1% | 0.83 |
441–450 | 17.4% | 21.2% | |
451–460 | 11.6% | 8.2% | |
>460 | 4.3% | 3.5% |
IQR, interquartile range.
The only severe adverse event was considered non-drug related. A 48-mo-old child allocated to artemisinin-naphthoquine was hospitalized with, and treated successfully for, lobar pneumonia diagnosed on day 23 of follow-up. This patient was negative by both microscopy and PCR for malaria at the time of re-presentation.
The two falciparum malaria treatment groups were well matched for age, sex, anthropometric measures, vital signs, and other characteristics (see
Characteristic | Falciparum Malaria | Vivax Malaria | ||||
Artemether-Lumefantrine ( |
Artemisinin-Naphthoquine ( |
Artemether-Lumefantrine ( |
Artemisinin-Naphthoquine ( |
|||
50.0% | 57.1% | 0.32 | 40.0% | 40.7% | >0.99 | |
43.4±15.6 | 44.8±15.7 | 0.54 | 37.1±15.2 | 36.0±13.9 | 0.81 | |
12.6±2.4 | 12.8±2.6 | 0.58 | 12.2±2.2 | 11.9±2.2 | 0.63 | |
14.4±1.1 | 14.5±1.3 | 0.62 | 14.1±0.9 | 14.4±0.9 | 0.26 | |
14.4±1.7 | 14.7±2.0 | 0.38 | 14.5±1.3 | 14.8±1.8 | 0.56 | |
123±21 | 125±22 | 0.50 | 121±24 | 120±18 | 0.93 | |
32±8 | 32±9 | 0.86 | 34±11 | 33±13 | 0.79 | |
38.2±1.3 | 38.2±1.4 | 0.82 | 38.2±1.5 | 37.9±1.7 | 0.52 | |
49.4% | 53.4% | 0.65 | 52.9% | 33.3% | 0.34 | |
23,277 (9,447–45,613) | 24,976 (13,674–51,867) | 0.33 | 6,146 (1,545–18,893) | 7,252 (1,372–15,724) | 0.86 | |
92.0±17.0 | 90.9±16.9 | 0.66 | 92.6±17.9 | 98.0±16.3 | 0.29 | |
6.9±2.1 | 6.7±1.9 | 0.46 | 6.2±2.4 | 7.1±1.8 | 0.21 | |
Artemether | 12.0 [8.6–20.0] | 11.2 [8.6–16.0] | ||||
Lumefantrine | 72.0 [51.4–120.0] | 67.4 [51.4–96.0] | ||||
Artemisinin | 62.5 [37.5–75.0] | 68.2 [48.7–75.0] | ||||
Naphthoquine | 25.0 [15–30.0] | 27.3 [19.5–30.0] |
Data are percentage, mean ± standard deviation, median (interquartile range), or median [absolute range].
Response Measure | ||||||
Artemether-Lumefantrine ( |
Artemisinin-Naphthoquine ( |
Artemether-Lumefantrine ( |
Artemisinin-Naphthoquine ( |
|||
Day 1 | 88/100 (88.0%) | 88/98 (89.8%) | 0.82 | 17/20 (85.0%) | 26/27 (96.3%) | 0.30 |
Day 2 | 95/98 (96.9%) | 93/98 (94.9%) | 0.72 | 17/19 (89.5%) | 26/27 (96.3%) | 0.56 |
Day 3 | 99/99 (100%) | 96/98 (98.0%) | 0.25 | 19/19 (100%) | 26/26 (100%) | — |
Day 7 | 93/99 (93.9%) | 94/98 (95.9%) | 0.75 | 20/20 (100%) | 24/26 (92.3%) | 0.50 |
1.2 (1.1–1.3) | 1.1 (1.0–1.2) | 0.28 | 1.4 (1.0–1.8) | 1.1 (0.9–1.4) | 0.50 | |
Day 1 | 33/99 (33.3%) | 30/98 (30.6%) | 0.76 | 16/19 (84.2%) | 23/27 (85.2%) | >0.99 |
Day 2 | 88/99 (88.9%) | 86/98 (87.8%) | 0.83 | 20/20 (100%) | 27/27 (100%) | — |
Day 3 | 97/98 (99.0%) | 96/98 (98.0%) | >0.99 | 20/20 (100%) | 27/27 (100%) | — |
Day 7 | 98/98 (100%) | 98/98 (100%) | — | 20/20 (100%) | 27/27 (100%) | — |
1.8 (1.7–1.9) | 1.8 (1.7–1.9) | 0.66 | 1.2 (1.0–1.3) | 1.1 (1.0–1.3) | 0.99 |
Data are number/total (percentage) or mean (95% confidence interval).
The PCR-corrected
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).
Endpoint | Number and Category | Total | Artemether-Lumefantrine | Artemisinin-Naphthoquine | Difference (95% CI) | |
190 | 94 | 96 | ||||
ACPR |
189 | 93 | 96 | |||
Percent (95% CI) | 99.5 (96.7–100) | 98.9 (93.4–100) | 100 (95.2–100) | 1.1 (−3.8 to 6.6) | 0.50 (one-sided) | |
ETF/LCF/LPF (percent) | 0/0/0.5 | 0/0/1.1 | 0/0/0 | |||
186 | 92 | 94 | ||||
ACPR |
184 | 90 | 94 | |||
Percent (95% CI) | 98.9 (95.8–99.8) | 97.8 (91.6–99.6) | 100 (95.1–100) | 2.2 (−3.0 to 8.4) | 0.24 (one-sided) | |
ETF/LCF/LPF (percent) | 0/0.5/0.5 | 0/1.1/1.1 | 0/0/0 | |||
46 | 20 | 26 | ||||
ACPR |
39 | 13 | 26 | |||
Percent (95% CI) | 84.8 (70.5–93.2) | 65.0 (41.0–83.7) | 100 (84.0–100) | 35.0 (10.7 to 59.1) | 0.001 (two-sided) | |
ETF/LCF/LPF (percent) | 0/0/15.2 | 0/0/35.0 | 0/0/0 | |||
46 | 20 | 26 | ||||
ACPR |
32 | 6 | 26 | |||
Percent (95% CI) | 69.6 (54.1–81.8) | 30.0 (12.8–54.3) | 100 (84.5–100) | 70.0 (40.9 to 87.2) | <0.001 (two-sided) | |
ETF/LCF/LPF (percent) | 0/2.2/28.3 | 0/5.0/65.0 | 0/0/0 | |||
188 | 94 | 94 | ||||
ACPR |
156 | 62 | 94 | |||
Percent (95% CI) | 83.0 (76.7–87.9) | 66.0 (55.4–75.2) | 100 (95.1–100) | 34.0 (23.6 to 44.6) | <0.001 (one-sided) | |
ETF/LCF/LPF (percent) | 0/0/17.0 | 0/0/34.0 | 0/0/0 |
The prespecified secondary endpoint of day-42 uncorrected ACPR was significantly greater in the artemisinin-naphthoquine group (100% [95% CI 95.1%–100%] versus 94.6% [95% CI 87.2%–98.0%] in the artemether-lumefantrine-treated children,
Endpoint | Number and Category | Total | Artemether-Lumefantrine | Artemisinin-Naphthoquine | Difference (95% CI) | |
190 | 94 | 96 | ||||
ACPR |
188 | 92 | 96 | |||
Percent (95% CI) | 98.9 (95.9–99.8) | 97.9 (91.8–99.6) | 100 (95.2–100) | 2.1 (–3.0 to 8.2) | 0.24 | |
ETF/LCF/LPF (percent) | 0/0.5/0.5 | 0/1.1/1.1 | 0/0/0 | |||
186 | 92 | 94 | ||||
ACPR |
181 | 87 | 94 | |||
Percent (95% CI) | 97.3 (93.5– 99.0) | 94.6 (87.2–98.0) | 100 (95.1–100) | 5.4 (−0.5 to 12.8) | 0.028 | |
ETF/LCF/LPF (percent) | 0/0.5/2.2 | 0/1.1/4.3 | 0/0/0 | |||
46 | 20 | 26 | ||||
ACPR |
42 | 16 | 26 | |||
Percent (95% CI) | 91.3 (78.3–97.2) | 80.0 (55.7–93.4) | 100 (84.0–100) | 20.0 (−0.9 to 44.3) | 0.030 | |
ETF/LCF/LPF (percent) | 0/2.2/6.5 | 0/5.0/15.0 | 0/0/0 | |||
46 | 20 | 26 | ||||
ACPR |
38 | 12 | 26 | |||
Percent (95% CI) | 82.6 (68.1–91.7) | 60.0 (36.4–80.0) | 100 (84.0–100) | 40.0 (14.4 to 63.6) | <0.001 | |
ETF/LCF/LPF (percent) | 0/2.2/15.2 | 0/5.0/35.0 | 0/0/0 |
Endpoint | Number and Category | Total | Artemether-Lumefantrine | Artemisinin-Naphthoquine | Difference (95% CI) | |
198 | 100 | 98 | ||||
ACPR |
189 | 93 | 96 | |||
Percent (95% CI) | 95.5 (91.3–97.8) | 93.0 (85.6–96.9) | 98.0 (92.1–99.7) | 5.0 (−2.1 to 12.5) | 0.09 (one-sided) | |
198 | 100 | 98 | ||||
ACPR |
184 | 90 | 94 | |||
Percent (95% CI) | 92.9 (88.2–95.9) | 90.0 (82.0–94.8) | 95.9 (89.3–98.7) | 5.9 (−2.3 to 14.4) | 0.09 (one-sided) | |
47 | 20 | 27 | ||||
ACPR |
39 | 13 | 26 | |||
Percent (95% CI) | 83.0 (68.7–91.9) | 65.0 (41.0–83.7) | 96.3 (79.1–99.8) | 31.3 (5.9 to 55.6) | 0.007 (two-sided) | |
47 | 20 | 27 | ||||
ACPR |
32 | 6 | 26 | |||
Percent (95% CI) | 68.1 (52.8–80.5) | 30.0 (12.8–54.3) | 96.3 (79.1–99.8) | 66.3 (36.5 to 83.8) | <0.001 (two-sided) | |
198 | 100 | 98 | ||||
ACPR |
156 | 62 | 94 | |||
Percent (95% CI) | 78.8 (72.3–84.1) | 62.0 (51.7–71.4) | 95.9 (89.3–98.7) | 33.9 (22.5 to 44.6) | <0.001 (one-sided) |
Endpoint | Number and Category | Total | Artemether-Lumefantrine | Artemisinin-Naphthoquine | Difference (95% CI) | |
198 | 100 | 98 | ||||
ACPR |
197 | 99 | 98 | |||
Percent (95% CI) | 99.5 (96.8–100) | 99.0 (93.8–100) | 100 (95.3–100) | 1.0 (−3.8 to 6.2) | 0.51 (one-sided) | |
198 | 100 | 98 | ||||
ACPR |
196 | 98 | 98 | |||
Percent (95% CI) | 99.0 (96.0–99.8) | 98.0 (92.3–99.7) | 100 (95.3–100) | 2.0 (−3.0 to 7.7) | 0.25 (one-sided) | |
47 | 20 | 27 | ||||
ACPR |
40 | 13 | 27 | |||
Percent (95% CI) | 84.8 (70.5–93.2) | 65.0 (41.0–83.7) | 100 (84.5–100) | 35.0 (10.7 to 59.1) | 0.001 (two-sided) | |
47 | 20 | 27 | ||||
ACPR |
33 | 6 | 27 | |||
Percent (95% CI) | 69.6 (54.1–81.8) | 30.0 (12.8–54.3) | 100 (84.5–100) | 70.0 (41.2 to 87.2) | <0.001 (two-sided) | |
198 | 100 | 98 | ||||
ACPR |
166 | 68 | 98 | |||
Percent (95% CI) | 83.8 (77.8–88.5) | 68.0 (57.8–76.8) | 100 (95.3–100) | 32.0 (22.0 to 42.2) | <0.001 (one-sided) |
The two vivax malaria treatment groups were also well matched for baseline characteristics (see
The day-42 PCR-uncorrected ACPR for
The single patient with
The percentage of children carrying
Data are for artemether-lumefantrine (▴, solid lines) and artemisinin-naphthoquine (•, dashed lines). *
In patients with vivax malaria, there was prompt gametocyte clearance in both groups by day 4, but, consistent with more frequent treatment failure in the artemether-lumefantrine group, a significant proportion of patients (40.0%) had become positive for gametocytes by day 42, while none of the artemisinin-naphthoquine-treated children were gametocytemic at that time (see
Hemoglobin concentrations in children treated for falciparum malaria were similar in the two treatment groups until day 42 after treatment, when the artemisinin-naphthoquine-treated children had a significantly higher mean concentration (109±13 g/l versus 102±12 g/l in the artemether-lumefantrine group,
Data are mean and standard deviation (vertical bars) for artemether-lumefantrine (▴, solid lines) and artemisinin-naphthoquine (•, dashed lines). **
Three daily doses of artemisinin-naphthoquine proved a highly efficacious treatment for both falciparum and vivax malaria in PNG children living in an area of intense transmission of multiple
There were no reappearances of asexual forms of either
We hypothesize that the better efficacy of artemisinin-naphthoquine reflects naphthoquine's relatively long terminal elimination half-life and wide therapeutic index. The mean elimination half-life of naphthoquine in PNG children is 21–25 d
There are theoretical reasons why artemisinin-naphthoquine may be a suboptimal ACT. As shown by ourselves
Despite potential pharmacokinetic/pharmacodynamic shortcomings, initial asexual parasite clearance was as rapid with artemisinin-naphthoquine as with artemether-lumefantrine. There is in vitro evidence of cross-resistance between chloroquine and naphthoquine in
Naphthoquine is a tetra-aminoquinoline drug, and our previous preliminary safety study of artemisinin-naphthoquine in older PNG children did not find evidence of aminoquinoline-specific side effects such as hearing loss, orthostatic hypotension, and hypoglycemia
Many aminoquinoline drugs cause QTc prolongation. Chloroquine increases the QTc by a mean of up to 30 msec0.5 in healthy volunteers
This latter observation, amongst other considerations, suggests that the artemisinin-naphthoquine regimen used in the present study was not pro-arrhythmic. Relatively frequent QTc prolongation has been observed in young children presenting with untreated malaria
Our study had limitations. Baseline microscopy by study staff under field conditions led to 11% of the 267 randomized patients being included when they had sub-threshold parasitemia based on expert microscopy, while electrocardiography proved difficult in a significant minority of children. We did not directly observe all artemether-lumefantrine doses, but parents/guardians were instructed as to the importance of all doses given at home, adherence was assessed at the next follow-up visit, and day-7 plasma lumefantrine concentrations were consistent with full adherence in each case. The children screened and recruited were drawn from coastal PNG communities that are typical of those in Oceania where hyper- or holo-endemic transmission of multiple
The efficacy, tolerability, and safety of three daily doses of artemisinin-naphthoquine suggest that this regimen should be considered together with other currently available effective ACTs for treatment of uncomplicated malaria in PNG and similar epidemiologic settings with transmission of multiple
(DOC)
(DOC)
We gratefully acknowledge the support of patients and their families, staff at the Mugil and Alexishafen Health Centers, and staff in the Vector Borne Diseases Unit of the PNG Institute of Medical Research.
artemisinin combination therapy
adequate clinical and parasitologic response
alanine aminotransferase
early treatment failure
fever clearance time
late clinical failure
late parasitologic failure
Papua New Guinea
polymerase chain reaction
parasite clearance time
electrocardiographic QT interval corrected for heart rate
upper limit of the reference range
World Health Organization