Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia

Abstract

Background: Safety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal.

Methods: Two open-label, randomized trials were conducted in Nimba County, Liberia: i) the main tolerability trial with 1,000 Plasmodium falciparum malaria patients aged over five years (Study-T), and, ii) an efficacy trial with a secondary objective of collecting tolerability data among 300 children age six to 59 months (Study-E). In both studies patients were randomized to fixed-dose artesunate-amodiaquine (ASAQ Winthrop®) or artemether-lumefantrine (AL, Coartem®), respectively. Clinical- and laboratory-adverse events (AEs) were recorded until day 28.

Results: Study-T: most patients experienced at least one AE. Severe AEs were few, primarily asymptomatic blood system disorders or increased liver enzyme values. No treatment or study discontinuation occurred. Mild or moderate fatigue (39.8% vs 16.3%, p < 0.001), vomiting (7.1% vs 1.6%, p < 0.001), nausea (3.2% vs 1.0%, p = 0.01), and anaemia (14.9% vs 9.8%, p = 0.01) were more frequently recorded in the ASAQ versus AL arm. Study-E: mild or moderate AEs were common, including anaemia, fatigue, vomiting or diarrhoea. The few severe events were asymptomatic blood system disorders and four clinical events (pneumonia, malaria, vomiting and stomatitis).

Conclusion: Both ASAQ and AL were well tolerated in patients of all age groups. No unexpected AEs occurred. Certain mild or moderate AEs were more frequent in the ASAQ arm. Standardised safety surveillance should continue for all forms of ACT.

Trial registration: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN40020296, ISRCTN51688713, (http://www.controlled-trials.com).

Figure 1

Trial profile (study-T, > 5 years).* Prescreened for positive Paracheck®, age >5 years, no signs of severe illness, willingness to attend the screening for study participation. ± Patient did not meet the inclusion criteria “asexual P. falciparum malaria parasites by blood smear” (had no asexual parasites on day 0), therefore withdrawn on day 0. ^{± ±} Accidentally discontinued on day 7 (presence of P. falciparum gametocytes by blood smear initially misinterpreted as failure). ψ Withdrawn on day 1 due to underlying severe hepatitis (positive for Hepatitis B s-antigen and anti-HBV core-antibody, indicating probable acute hepatitis at baseline).

Figure 2

Trial profile of (Study-E, 6–59 months). * prescreened for positive Paracheck®, age 6–59 months, no signs of severe illness, willingness to attend the screening for study participation; ^# patient did not meet the inclusion criteria “asexual parasites density <2,000 or >200,000/μl blood” (parasite load of 415,082 trophozoites/μl blood), withdrawn on day 0.

Figure 3

Onset period of specific AEs of interest(Study-T, >5 years). AE = adverse event. Depicted are the percentage of patients who had at least on AE fatigue, vomiting, nausea or anaemia, respectively, classified by event onset time period; i e, between day 0 after treatment intake and day 3, or between day 4 and day 28, respectively, by treatment arm. Safety population.