Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax Malaria: A randomized, double-blind, non-inferiority trial

Yi Poravuth, Duong Socheat, Ronnatrai Rueangweerayut, Chirapong Uthaisin, Aung Pyae Phyo, Neena Valecha, B. H. Krishnamoorthy Rao, Emiliana Tjitra, Asep Purnama, Isabelle Borghini-Fuhrer, Stephan Duparc, Chang Sik Shin, Lawrence Fleckenstein

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Abstract

Background: New antimalarials are needed for P. vivax and P. falciparum malaria. This study compared the efficacy and safety of pyronaridine-artesunate with that of chloroquine for the treatment of uncomplicated P. vivax malaria. Methods and Findings: This phase III randomized, double-blind, non-inferiority trial included five centers across Cambodia, Thailand, India, and Indonesia. In a double-dummy design, patients (aged >3-≤60 years) with microscopically confirmed P. vivax mono-infection were randomized (1:1) to receive pyronaridine-artesunate (target dose 7.2:2.4 mg/kg to 13.8:4.6 mg/ kg) or chloroquine (standard dose) once daily for three days. Each treatment group included 228 randomized patients. Outcomes for the primary endpoint, Day-14 cure rate in the per-protocol population, were 99.5%, (217/218; 95%CI 97.5, 100) with pyronaridine-artesunate and 100% (209/209; 95%CI 98.3, 100) with chloroquine. Pyronaridine was non-inferior to chloroquine: treatment difference 20.5% (95%CI 22.6, 1.4), i.e., the lower limit of the 2-sided 95%CI for the treatment difference was greater than 210%. Pyronaridine-artesunate cure rates were non-inferior to chloroquine for Days 21, 28, 35 and 42. Parasite clearance time was shorter with pyronaridine-artesunate (median 23.0 h) versus chloroquine (32.0 h; p<0.0001), as was fever clearance time (median 15.9 h and 23.8 h, respectively; p = 0.0017). Kaplan-Meier estimates of postbaseline P. falciparum infection incidence until Day 42 were 2.5% with pyronaridine-artesunate, 6.1% with chloroquine (p = 0.048, log-rank test). Post-baseline P. vivax or P. falciparum infection incidence until Day 42 was 6.8% and 12.4%, respectively (p = 0.022, log rank test). There were no deaths. Adverse events occurred in 92/228 (40.4%) patients with pyronaridine-artesunate and 72/228 (31.6%) with chloroquine. Mild and transient increases in hepatic enzymes were observed for pyronaridine-artesunate. Conclusion: Pyronaridine-artesunate efficacy in acute uncomplicated P. vivax malaria was at least that of chloroquine. As pyronaridine-artesunate is also efficacious against P. falciparum malaria, this combination has potential utility as a global antimalarial drug.

Original languageEnglish
Article numbere14501
JournalPLoS One
Volume6
Issue number1
DOIs
Publication statusPublished - 02-02-2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Poravuth, Y., Socheat, D., Rueangweerayut, R., Uthaisin, C., Phyo, A. P., Valecha, N., Krishnamoorthy Rao, B. H., Tjitra, E., Purnama, A., Borghini-Fuhrer, I., Duparc, S., Shin, C. S., & Fleckenstein, L. (2011). Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax Malaria: A randomized, double-blind, non-inferiority trial. PLoS One, 6(1), [e14501]. https://doi.org/10.1371/journal.pone.0014501