A Multi-Site, Open-Label, Randomized Trial to Assess the Efficacy, Safety, and Tolerability of Dihydroartemisinin-Piperaquine Plus Mefloquine Compared to Dihydroartemisinin-Piperaquine or Artesunate-Mefloquine in Patients With Uncomplicated Falciparum Malaria in Cambodia

Dihydroartemisinin-piperaquine (DHA-PPQ) Cambodia s frontline artemisinin (ART) combination therapy (ACT) for Plasmodium falciparum malaria is failing to cure nearly half of patients in its western provinces. These treatment failures are caused by parasite strains that are resistant to both ART and PPQ, yet sensitive to mefloquine (MQ) in vitro and in vivo. These findings, and previous studies showing that PPQ treats MQ-resistant infections in patients, led us to hypothesize that parasites have not developed cross-resistance to both PPQ and MQ. Given that DHA-PPQ and AS+MQ have both failed rapidly to resistance when used alone, we propose to treat patients with triple ACT (TACT) containing DHA-PPQ + MQ. We believe that this TACT will more effectively cure patients than either ACT alone, and will continue to achieve acceptably high cure rates and help to eliminate malaria in Cambodia until new drugs are developed and deployed. This protocol thus aims to measure the efficacy, safety, and tolerability of DHA-PPQ + MQ versus DHA-PPQ or AS-MQ alone in a multi-site, open-label, randomized clinical trial. In each of three Cambodian provinces (Pursat, Preah Vihear, and Ratanakiri) where DHA-PPQ is failing, we will recruit subjects aged 2 to 65 years with uncomplicated falciparum malaria (randomized 1:1), In Pursat and Preah Vihear we will treat them with either DHA-PPQ + MQ or AS-MQ alone and in Ratanakiri we will treat them with either DHA-PPQ + MQ or DHA-PPQ alone for three days, and follow them for 42 days to assess for recrudescent parasitemia an indicator of treatment failure. The main safety concern of this study is that DHA-PPQ + MQ may cause electrocardiographic (ECG) changes that could predispose a patient to develop clinically significant arrhythmias. This is because PPQ is known to cause prolongation of the ECG corrected QT (QTc) interval, and MQ may further increase PPQ levels (and thus the risk of further QTc prolongation) through pharmacokinetic interactions involving CYP3A4, a liver enzyme that metabolizes both drugs. To monitor for such an event, we will obtain ECG recordings before and after each drug dose. The safety and tolerability of TACT versus ACT will also be assessed through periodic tests of hematopoietic, hepatic, and renal function, and frequent symptom questionnaires. We will also administer a single low dose of primaquine, which kills P. falciparum gametocytes, on Day 2 to interrupt the transmission of parasites to mosquitoes and promote the elimination of malaria in Cambodia. During hospitalization and followup, we will obtain a series of research blood samples to estimate the prevalence of genetic markers for ART, PPQ, and MQ resistance; to develop a genotyping platform for rapidly surveying known drug resistance-associated mutations; investigate the genomic and transcriptomic basis of drug-resistance mechanisms; confirm the elimination of parasites and gametocytes from the bloodstream using sensitive molecular methods; measure the ex-vivo susceptibility of parasites to antimalarial drugs, and cryopreserve parasites for future studies to elucidate the molecular mechanisms of drug resistance.