Dose-finding study of the efficacy of fixed-combination artemether/lumefantrine for the treatment of multidrug-resistant Plasmodium falciparum malaria in Thailand

Objective: To investigate the efficacy and tolerability of three different regimens of the fixed combination artemether/lumefantrine (artemether/benfl umetol) in patients with multidrug-resistant Plasmodium falciparum malaria. Design: Randomised, double-blind, dose-finding study. Setting: Two centres in Thailand (the Bangkok Hospital for Tropical Disease s and Mae-Sot Malaria Clinic). Patients and Interventions: 260 patients (aged between 14 and 60 years and weighing greater than or equal to 35kg) with acute uncomplicated P. falcipa rum malaria were randomised to receive one of three regimens of the fixed c ombination artemether/lumefantrine (CGP 56697; one tablet contains artemeth er 20mg and lumefantrine 120mg). Regimen I: four tablets at 0, 8, 24 and 48 hours (n = 87); Regimen II: two tablets at 0, 8, 24 and 48 hours (n = 87); Regimen III: four tablets at 0, 8 and 24 hours (n = 86). Main Outcome Measures and Results: With only one exception, all patients in the three groups had a rapid initial response with comparable parasite cle arance time (PCT) and fever clearance time (FCT). 19, 35 and 37 patients re ceiving regimen I, II and III, respectively, had recrudescence between days 7 and 28 (median 17 days). The cure rate of 79.5% with regimen I was signi ficantly higher than that with the other two regimens (54.7 and 55.3% for r egimen II and III, respectively; both p < 0.001). Six patients (two and fou r in regimens I and III) who had Fl vivax malaria on admission were cleared , although reappearance of P. vivax was seen in all groups. Conclusions: The low cure rates obtained in this study suggest that these t hree regimens of artemether/lumefantrine map not be optimal for multidrug-r esistant P. falciparum strains in Thailand. The highest dose combination us ed in this trial was well tolerated and more effective than the other regim ens. There is therefore still room for the use of a higher dose regimen of this combination in the treatment of multidrug-resistant falciparum in Thai land.