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

Fingerprint

Vivax Malaria
Plasmodium vivax
chloroquine
Chloroquine
malaria
antimalarials
Falciparum Malaria
Antimalarials
pyronaridine
artesunate
Infection
infection
Cambodia
incidence
Indonesia
Incidence
Kaplan-Meier Estimate
Plasmodium falciparum
Thailand
Therapeutics

All Science Journal Classification (ASJC) codes

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

Cite this

Poravuth, Y., Socheat, D., Rueangweerayut, R., Uthaisin, C., Phyo, A. P., Valecha, N., ... 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
Poravuth, Yi ; Socheat, Duong ; Rueangweerayut, Ronnatrai ; Uthaisin, Chirapong ; Phyo, Aung Pyae ; Valecha, Neena ; Krishnamoorthy Rao, B. H. ; Tjitra, Emiliana ; Purnama, Asep ; Borghini-Fuhrer, Isabelle ; Duparc, Stephan ; Shin, Chang Sik ; Fleckenstein, Lawrence. / Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax Malaria : A randomized, double-blind, non-inferiority trial. In: PLoS One. 2011 ; Vol. 6, No. 1.
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title = "Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax Malaria: A randomized, double-blind, non-inferiority trial",
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.",
author = "Yi Poravuth and Duong Socheat and Ronnatrai Rueangweerayut and Chirapong Uthaisin and Phyo, {Aung Pyae} and Neena Valecha and {Krishnamoorthy Rao}, {B. H.} and Emiliana Tjitra and Asep Purnama and Isabelle Borghini-Fuhrer and Stephan Duparc and Shin, {Chang Sik} and Lawrence Fleckenstein",
year = "2011",
month = "2",
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doi = "10.1371/journal.pone.0014501",
language = "English",
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Poravuth, Y, Socheat, D, Rueangweerayut, R, Uthaisin, C, Phyo, AP, Valecha, N, Krishnamoorthy Rao, BH, Tjitra, E, Purnama, A, Borghini-Fuhrer, I, Duparc, S, Shin, CS & Fleckenstein, L 2011, 'Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax Malaria: A randomized, double-blind, non-inferiority trial', PLoS One, vol. 6, no. 1, e14501. https://doi.org/10.1371/journal.pone.0014501

Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax Malaria : A randomized, double-blind, non-inferiority trial. / Poravuth, Yi; Socheat, Duong; Rueangweerayut, Ronnatrai; Uthaisin, Chirapong; Phyo, Aung Pyae; Valecha, Neena; Krishnamoorthy Rao, B. H.; Tjitra, Emiliana; Purnama, Asep; Borghini-Fuhrer, Isabelle; Duparc, Stephan; Shin, Chang Sik; Fleckenstein, Lawrence.

In: PLoS One, Vol. 6, No. 1, e14501, 02.02.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax Malaria

T2 - A randomized, double-blind, non-inferiority trial

AU - Poravuth, Yi

AU - Socheat, Duong

AU - Rueangweerayut, Ronnatrai

AU - Uthaisin, Chirapong

AU - Phyo, Aung Pyae

AU - Valecha, Neena

AU - Krishnamoorthy Rao, B. H.

AU - Tjitra, Emiliana

AU - Purnama, Asep

AU - Borghini-Fuhrer, Isabelle

AU - Duparc, Stephan

AU - Shin, Chang Sik

AU - Fleckenstein, Lawrence

PY - 2011/2/2

Y1 - 2011/2/2

N2 - 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.

AB - 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.

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