Randomised controlled trial of two sequential artemisinin-based combination therapy regimens to treat uncomplicated falciparum malaria in African children: a protocol to investigate safety, efficacy and adherence

Abstract

BackgroundManagement of uncomplicated Plasmodium falciparum malaria relies on artemisinin-based combination therapies (ACTs). These highly effective regimens have contributed to reductions in malaria morbidity and mortality. However, artemisinin resistance in Asia and changing parasite susceptibility to ACT in Africa have now been well documented. Strategies that retain current ACT as efficacious treatments are urgently needed.MethodsWe present an open-label, randomised three-arm clinical trial protocol in three African settings representative of varying malaria epidemiology to investigate whether prolonged ACT-based regimens using currently available formulations can eliminate potentially resistant parasites. The protocol investigates whether a sequential course of two licensed ACT in 1080 children aged 6–120 months exhibits superior efficacy against acute P. falciparum malaria and non-inferior safety compared with standard single-course ACT given to 540 children. The primary endpoint is PCR-corrected clinical and parasitological response at day 42 or day 63 of follow-up. Persistence of PCR-detectable parasitaemia at day 3 is analysed as a key covariate. Secondary endpoints include gametocytaemia, occurrence of treatment-related adverse events in the double-ACT versus single-ACT arms, carriage of molecular markers of drug resistance, drug kinetics and patient adherence to treatment.DiscussionThis protocol addresses efficacy and safety of sequential ACT regimens in P. falciparum malaria in Africa. The approach is designed to extend the useful life of this class of antimalarials with maximal impact and minimal delay, by deploying licensed medicines that could be swiftly implemented as sequential double ACT by National Malaria Control Programmes, before emerging drug resistance in Africa becomes a major threat to public health.

Elucidating Mechanisms of Drug-Resistant Plasmodium falciparum

“…Studies with isogenic lines expressing one or two copies of pfmdr1 showed no difference in MFQ IC 50 values (Dhingra et al, 2017), and some isolates have been found to carry multicopy pfmdr1 and plasmepsin II (Bopp et al, 2018), suggesting that resistance to both drugs in a single parasite is possible. Similarly, changing the dosing regimen to ''sequential double ACT'' may be sufficient to overpower transient dormancy-like ART resistance and is also being tested in a clinical trial (Schallig et al, 2017). In contrast, ''split dosing,'' i.e., splitting a once-daily dose into a twice-daily dose to increase daily ART exposure, did not increase the efficacy of ART, likely because splenic parasite clearance was exceeded (White et al, 2017).…”

Modulation of triple artemisinin-based combination therapy pharmacodynamics byPlasmodium falciparumgenotype

“…This platform could also be utilized for the evaluation of sequential ACT therapy, another proposed modification to existing ACT therapy to improve clinical efficacy and reduce the emergence of drug resistant parasites. In such protocols two different approved ACTs would be administered sequentially over 6 days (two three-day 22 treatments), ideally with partner drugs with validated mechanisms of action that exert opposing pressure on genetic determinants that modulate drug susceptibility (53). During the second half of treatment, there would be remaining exposure of the initial ACT partner drug, thereby establishing a three-day timeframe of triple-drug exposure.…”

Genetic markers of artemisinin resistance in Plasmodium spp. parasites

“…In the next section, arguments based on the parasite cell cycle will be used to support this unorthodox suggestion, and lend further support to the strategy of extended artemisinin regimens to radically cure P. falciparum infections [25].…”

“…Certainly, there is no doubt that K13-independent artemisinin susceptibility phenotypes have arisen [10,36], and may continue to arise in the future, under universal selection pressure from ACT deployment worldwide. This threat makes it imperative that strategies to preserve the efficacy of our current regimens are vigorously pursued in the short term, as we await the next generation of antimalarial drugs [25].…”

“…Thus, regimens such as two sequential ACTs with different partner drugs have been postulated as a rational response to signs of falling 3-day ACT efficacy, and a protocol has been developed to evaluate such regimes before ACT failure becomes a serious problem [25].…”