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 -0.5% (95%CI -2.6, 1.4), i.e., the lower limit of the 2-sided 95%CI for the treatment difference was greater than -10%. 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 post-baseline 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.

Trial registration: Clinicaltrials.gov NCT00440999.

Conflict of interest statement

Competing Interests: Isabelle Borghini-Fuhrer and Stephan Duparc are employees of Medicines for Malaria Venture. Chang-Sik Shin is an employee of Shin Poong Pharmaceutical. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Trial flow and subject disposition.

Figure 2. Cure rate for P. vivax malaria on Days 14, 21, 28, 35, and 42 in the per-protocol population.

Non-inferiority of pyronaridine-artesunate to chloroquine was concluded for all assessments.

Figure 3. Kaplan-Meier estimates of P. vivax parasite clearance time (h) (intent-to-treat population).

Figure 4. Kaplan-Meier estimates of fever clearance time (h) in patients with P. vivax malaria (intent-to-treat population).

Figure 5. Kaplan-Meier estimates of time (h) to P. falciparum infection in patients treated for an initial P. vivax malaria (intent-to-treat population).

Figure 6. Kaplan-Meier estimates of time (h) to P. vivax or P. falciparum infection in patients treated for an initial P. vivax malaria (intent-to-treat population).