Prospective observational study to evaluate the clinical safety of the fixed-dose artemisinin-based combination Eurartesim® (dihydroartemisinin/piperaquine), in public health facilities in Burkina Faso, Mozambique, Ghana, and Tanzania

Abstract

BackgroundThe World Health Organization recommends artemisinin-based combination (ACT) for the treatment of uncomplicated malaria. Post-licensure safety data on newly registered ACT is critical for evaluating their risk/benefit profile in malaria endemic countries. The clinical safety of the newly registered combination, Eurartesim®, following its introduction into the public health system in four African countries was assessed.MethodsThis was a prospective, observational, open-label, non-comparative, longitudinal, multi-centre study using cohort event monitoring. Patients with confirmed malaria had their first dose observed and instructed on how to take the second and the third doses at home. Patients were contacted on day 5 ± 2 to assess adherence and adverse events (AEs). Spontaneous reporting of AEs was continued till day 28. A nested cohort who completed full treatment course had repeated electrocardiogram (ECG) measurements to assess effect on QTc interval.ResultsA total of 10,925 uncomplicated malaria patients were treated with Eurartesim®. Most patients,95% (10,359/10,925), did not report any adverse event following at least one dose of Eurartesim®. A total of 797 adverse events were reported. The most frequently reported, by system organ classification, were infections and infestations (3. 24%) and gastrointestinal disorders (1. 37%). In the nested cohort, no patient had QTcF > 500 ms prior to day 3 pre-dose 3. Three patients had QTcF > 500 ms (509 ms, 501 ms, 538 ms) three to four hours after intake of the last dose. All the QTcF values in the three patients had returned to <500 ms at the next scheduled ECG on day 7 (470 ms, 442 ms, 411 ms). On day 3 pre- and post-dose 3, 70 and 89 patients, respectively, had a QTcF increase of ≥ 60 ms compared to their baseline, but returned to nearly baseline values on day 7.ConclusionEurartesim® single course treatment for uncomplicated falciparum malaria is well-tolerated. QT interval prolongation above 500 ms may occur at a rate of three per 1,002 patients after the third dose with no association of any clinical symptoms. QT interval prolongation above 60 ms was detected in less than 10% of the patients without any clinical abnormalities.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0664-9) contains supplementary material, which is available to authorized users.

New developments in anti-malarial target candidate and product profiles

“…For amodiaquine–artesunate, a study with over 15,000 malaria cases in Ivory Coast was required as part of the WHO-approved Risk Management Plan. Dihydroartemisinin (DHA)–piperaquine was linked to an increased QTc (corrected Q-T wave) interval but no further cardiac sequelae ; gathering data from over 16,000 patients [31], and 10,000 patients, including a nested study of 1000 patients with thorough electrocardiogram (ECG) monitoring [32] has been required for this treatment to be accepted for WHO prequalification. Pyronaridine–artesunate (Pyramax ® ) produced an acute, transient and asymptomatic elevation of liver enzyme levels in phase III patients, also seen in healthy Caucasian volunteers after re-dosing.…”

Safety of a fixed-dose combination of artesunate and amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in real-life conditions of use in Côte d’Ivoire

“…No previous observational CEM study has evaluated the incidence of AEs in patients treated specifically with an identified ASAQ fixed-dose combination tablet, and several previous studies have evaluated different anti-malarial drugs in the same study. The present study is also much larger than previous studies, which included <5000 patients (with the exception of one recent multinational study that also recruited >10,000 patients [21]). In addition, different methods of data collection have been used in these various CEM studies.…”

“…Other CEM studies of ACT in Nigeria [25] and of artemether–lumefantrine (Coartem ® ) in Tanzania [26] also required patients to return to the HC or to contact a CHW. The study that is perhaps the closest to the present one in design is the INDEPTH study of a fixed-dose combination of dihydroartemisinin and piperaquine phosphate (Eurartesim ® ), conducted in four African countries between 2013 and 2014 [21], which included 11,097 patients with RDT-confirmed P. falciparum infections who were followed up by home visits from a CHW or by telephone. More recently, a study in Ghana of patients prescribed ACT [27] has compared telephone contact and home visits by a CHW and found that the former method elicited more AEs and was less expensive to implement.…”

RTS,S malaria vaccine development: progress and considerations for postapproval introduction

“…This includes the WHO collaborating centers of excellence in pharmacovigilance in some countries such as Ghana 58 and efforts by the INDEPTH Network, a nongovernmental organization made up of research institutions with health and demographic surveillance systems. 59 The key challenge in Phase IV studies is the lack of baseline disease profiles of rare diseases due to inadequate diagnostic tools in many health facilities in sub-Saharan Africa. As a result, Phase IV malaria vaccine studies to be carried out in subSaharan Africa would require further assessments of some rare diseases reported to be associated with vaccines such as intussusception 60 and Kawasaki Syndrome.…”