An Open-Label, Randomised Study of Dihydroartemisinin-Piperaquine Versus Artesunate- Mefloquine for Falciparum Malaria in Asia

05 Aug 2010

Neena Valecha, Aung Pyae Phyo, Mayfong Mayxay, Paul N. Newton, Srivicha Krudsood, Sommay Keomany, Maniphone Khanthavong, Tiengkham Pongvongsa, Ronnatrai Ruangveerayuth, Chirapong Uthaisil, David Ubben, Stephan Duparc, Antonella Bacchieri, Marco Corsi, Bappanad H. K. Rao, Prabash C. Bhattacharya, Nagesh Dubhashi, Susanta K. Ghosh, Vas Dev, Ashwani Kumar, Sasithon Pukittayakamee

PLOS ONE

DOI:10.1371/journal.pone.001188

 

Abstract

Background: The artemisinin-based combination treatment (ACT) of dihydroartemisinin (DHA) and piperaquine (PQP) is a promising novel anti-malarial drug effective against multi-drug resistant falciparum malaria. The aim of this study was to show non-inferiority of DHA/PQP vs. artesunate-mefloquine (AS+MQ) in Asia.

Methods and Findings: This was an open-label, randomised, non-inferiority, 63-day follow-up study conducted in Thailand, Laos and India. Patients aged 3 months to 65 years with Plasmodium falciparum mono-infection or mixed infection were randomised with an allocation ratio of 2:1 to a fixed-dose DHA/PQP combination tablet (adults: 40 mg/160 mg; children: 20 mg/320 mg; n = 769) or loose combination of AS+MQ (AS: 50 mg, MQ: 250 mg; n = 381). The cumulative doses of study treatment over the 3 days were of about 6.75 mg/kg of DHA and 54 mg/kg of PQP and about 12 mg/kg of AS and 25 mg/kg of MQ. Doses were rounded up to the nearest half tablet. The primary endpoint was day-63 polymerase chain reaction (PCR) genotype-corrected cure rate. Results were 87.9% for DHA/PQP and 86.6% for AS+MQ in the intention-to-treat (ITT; 97.5% onesided confidence interval, CI: .22.87%), and 98.7% and 97.0%, respectively, in the per protocol population (97.5% CI:.20.39%). No country effect was observed. Kaplan-Meier estimates of proportions of patients with new infections on day 63 (secondary endpoint) were significantly lower for DHA/PQP than AS+MQ: 22.7% versus 30.3% (p= 0.0042; ITT). Overall gametocyte prevalence (days 7 to 63; secondary endpoint), measured as person-gametocyte-weeks, was significantly higher for DHA/PQP than AS+MQ (10.15% versus 4.88%; p = 0.003; ITT). Fifteen serious adverse events were reported, 12 (1.6%) in DHA/ PQP and three (0.8%) in AS+MQ, among which six (0.8%) were considered related to DHA/PQP and three (0.8%) to AS+MQ.

Conclusions: DHA/PQP was a highly efficacious drug for P. falciparum malaria in areas where multidrug parasites are prevalent. The DHA/PQP combination can play an important role in the first-line treatment of uncomplicated falciparum malaria.