Abstract

BackgroundEuropean travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)–piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap.MethodsParticipants were recruited through Health Care Provider’s safety registry in 15 centres across 6 European countries in the period 2013–2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett’s (QTcB) or Fridericia’s (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females.ResultsAmong 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%).ConclusionsAPQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries.Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942

Highlights

  • European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions

  • adverse events (AE) and QT prolongation were in the range of those obtained in larger cohorts from endemic countries

  • The most common side-effects observed with artenimol (previously dihydroartemisinin)–piperaquine (APQ) use in uncomplicated malaria patients (1–10 patients in 100) are anaemia, headache, corrected QT segment (QTc) prolongation and tachycardia [4]

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Summary

Introduction

European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The QTc prolongation risk was monitored during the clinical development of APQ, in the pivotal clinical trials DM040010 and DM040011, where APQ was compared to loose combination of artesunate + mefloquine and fixed dose combination of artemether and lumefantrine regimen, respectively [13, 14]. In these studies, ECGs were performed on days 0 and 2 (last treatment day) and 7 after starting treatment. Other studies showed less QTc prolongations after APQ treatment in fasting conditions [21.0 ms (15.7–26.4) vs 46.0 ms (39.6–52.3) with high-fat/high caloric breakfast] [4, 16]

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