Efficacy of artesunate-amodiaquine and artemether-lumefantrine fixed-dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria among children aged six to 59 months in Nimba County, Liberia: an open-label randomized non-inferiority trial

Abstract

Background: Prospective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development. The in vivo efficacy of artesunate-amodiaquine (ASAQ) fixed-dose combination (FDC) was compared to that of artemether-lumefantrine (AL) among children aged six to 59 months in Nimba County, Liberia, where Plasmodium falciparum malaria is endemic and efficacy data are scarce.

Methods: An open-label, randomized controlled non-inferiority trial compared the genotyping adjusted day 42 cure rates of ASAQ FDC (ASAQ Winthrop®) to AL (Coartem®) in 300 children aged six to 59 months with uncomplicated falciparum malaria. Inclusion was between December 2008 and May 2009. Randomization (1:1) was to a three-day observed oral regimen (ASAQ: once a day; AL: twice a day, given with fatty food). Day 7 desethylamodiaquine and lumefantrine blood-concentrations were also measured.

Results: The day 42 genotyping-adjusted cure rate estimates were 97.3% [95% CI: 91.6-99.1] for ASAQ and 94.2% [88.1-97.2] for AL (Kaplan-Meier survival estimates). The difference in day 42 cure rates was -3.1% [upper limit 95% CI: 1.2%]. These results were confirmed by observed proportion of patients cured at day 42 on the per-protocol population. Parasite clearance was 100% (ASAQ) and 99.3% (AL) on day 3. The probability to remain free of re-infection was 0.55 [95% CI: 0.46-0.63] (ASAQ) and 0.66 [0.57-0.73] (AL) (p = 0.017).

Conclusions: Both ASAQ and AL were highly efficacious and ASAQ was non-inferior to AL. The proportion of patients with re-infection was high in both arms in this highly endemic setting. In 2010, ASAQ FDC was adopted as the first-line national treatment in Liberia. Continuous efficacy monitoring is recommended.

Trial registration: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN51688713, ISRCTN40020296.

Figure 1

Trial profile with mITT and PP populations. RDT = rapid diagnostic test for malaria (Paracheck® ); Pf = Plasmodium falciparum; WH = Weight for Height; mITT = modified Intention to Treat; KM = Kaplan Meier; SAE = Serious Adverse Event; PP = Per Protocol. ^a Second participation excluded from analyses.* Note: one patient was discontinued with recurrent malaria (Pf re-infection, day 30). This patient is listed here among the n = 2 patients pre-maturely discontinued due to SAE (severe malaria). ** Patient was discontinued from participation on day 0 shortly upon enrolment because eligibility criteria were not met: i.e. asexual parasites density was outside the eligibility range (< 2000 or > 200 000 / μl blood). *** Two patients were enrolled with day 0 asexual parasites density outside the eligibility range (< 2000 or > 200 000 / μl blood): n = 1 patient was discontinued on day 0, once the eligibility error was discovered (discontinuation due to incorrect enrolment); n = 1 patient continued the follow-up to day 42. Both patients were excluded from the per-protocol population (protocol deviation). ^# Pre-mature discontinuations other than discontinuations due to adverse event or recurrence of parasitaemia which lead to exclusion from the PP population. ^## For n = 1 patient the care-taker withdrew consent on day 3; for n = 1 patient the care-taker withdrew consent on day 21. ^### n = 1 patient who also missed 2 evening doses is not listed among these n = 19, since the primary reason for exclusion of this patients from PP population was withdrawal of consent by care-taker (day 3) (patient listed among n = 2 consent withdrawn).

Figure 2

Kaplan-Meier survival curves. Modified intention to treat (mITT) population. Full line (ASAQ arm), dashed line (AL arm). (A) genotyping-adjusted probability to be cured. (B) probability to remain free of re-infection.

Figure 3

Pf Gametocyte carriage by malaria blood smear up to day 28, by treatment arm.Pf = Plasmodium falciparum.(A) Percentage of patients with Pf gametocytes by blood smear among total patients by follow up day, by treatment arm, mITT population. (B) Percentage of patients with Pf gametocytes by blood smear among patients who had no gametocytes on day 0, by follow up day, by treatment arm, mITT population.