Safety, efficacy, and pharmacokinetic evaluations of artemisinin-based combination therapies and chloroquine with concomitant primaquine use to treat malaria vivax in Brazil: an open label randomized clinical trial.

Background Control of Plasmodium vivax is a major public health challenge for Brazil where 84% of the 143.552 cases were due to vivax in 2014. New approaches to treat vivax malaria are critical to accelerate progress towards vivax elimination. Methods The efficacy and safety of three malaria vivax treatments using either Artemisinin-based Combination Therapies (ACT) or chloroquine with a concomitant seven day primaquine regimen (total dose 3 - 4.2 mg/kg) were evaluated in this open label, randomized clinical trial in Brazil. The primary objective was to achieve cure rates above 90% in each study arm until day 63. Pharmacokinetics parameters of all drugs were determined in dry whole blood filter paper samples using a HPLC-MS/MS single method. Exploratory analyses using generalized linear models were done to understand factors that might have influenced outcomes. Results All three regimens, fixed dose artemether and lumefantrine (AL), fixed dose artesunate and mefloquine (ASMQ) or (Cq) with short-course primaquine were efficacious and safe when treating uncomplicated vivax malaria . 247 of 264 enrolled patients were evaluated at 42 days. Cure rates were 98% (95%CI 95-100) in the ASMQ arm, 93% (95%CI 87- 99) at the Cq group, and 94% (95%CI 89-99) in patients that received AL. Pharmacokinetics parameters are described. Two serious adverse events (AE) related to the treatment were reported. Patients recovered completely. Most of the AE were mild. Conclusions This is one of the first trials to provide safety information of short-course 7 days primaquine regimen with these ACTs in concomitant use. This is an innovation needed for control and elimination of P. vivax that comprises the use of drugs in combination, a treatment to all malaria species and a patient-friendly regimen. This study provides insights on the safety of ACT with primaquine concomitant use, supporting it was safe and efficacious in the dose range and population studied.