Efficacy, Safety and Tolerability of Pyronaridine-artesunate in Asymptomatic Malaria-infected Individuals: a Randomized Controlled Trial

Abstract

Background: Pyronaridine-artesunate (PA) is a registered artemisinin-based combination therapy, potentially useful for mass drug administration campaigns. However, further data are needed to evaluate its efficacy, safety and tolerability as full or incomplete treatment in asymptomatic Plasmodium falciparum-infected individuals.

Methods: This phase II, multi-center, open label, randomized clinical trial was conducted in The Gambia and Zambia. Participants with microscopically confirmed asymptomatic P. falciparum infection were randomly assigned (1:1:1) to receive a 3-day, 2-day, or 1-day treatment regimen of PA (180:60 mg), dosed according to bodyweight. The primary efficacy outcome was polymerase chain reaction (PCR)-adjusted adequate parasitological response (APR) at day 28 in the per-protocol population.

Results: A total of 303 participants were randomized. Day 28 PCR-adjusted APR was 100% for both the 3-day (98/98) and 2-day regimens (96/96), and 96.8% (89/94) for the 1-day regimen. Efficacy was maintained at 100% until day 63 for the 3-day and 2-day regimens but declined to 94.4% (84/89) with the 1-day regimen. Adverse event frequency was similar between the 3-day (51.5% [52/101]), 2-day (52.5% [52/99]), and 1-day (54.4% [56/103]) regimens; the majority of adverse events were of grade 1 or 2 severity (85% [136/160]). Asymptomatic, transient increases (>3 times the upper limit of normal) in alanine aminotransferase/aspartate aminotransferase were observed for 6/301 (2.0%) participants.

Conclusions: PA had high efficacy and good tolerability in asymptomatic P. falciparum-infected individuals, with similar efficacy for the full 3-day and incomplete 2-day regimens. Although good adherence to the 3-day regimen should be encouraged, these results support the further investigation of PA for mass drug administration campaigns.

Clinical trials registration: NCT03814616.

Keywords: asymptomatic; malaria; pediatric; pyronaridine-artesunate; randomized controlled clinical trial.

Figure 1.

Participant disposition. Populations: safety population, all randomized participants who received at least 1 dose of study medication; m-ITT population, all randomized patients who received at least 1 treatment dose and who had confirmed positive parasitemia before treatment; PP population, all randomized patients who completed their treatment, had outcome data for the primary efficacy end point, and complied with the protocol. Abbreviations: mITT, microbiological-intention-to-treat; PA, pyronaridine-artesunate; PP, per-protocol.

Figure 2.

Adequate parasitological response at day 28 in the per-protocol population. Abbreviations: APR, adequate parasitological response; PCR, polymerase chain reaction.

Figure 3.

Kaplan-Meier estimates of (a) recrudescence; and (b) reinfection in the microbiological intention-to-treat population.

Figure 4.

Parasite clearance in the per-protocol population: (a) proportion of participants with asexual parasite clearance until day 3; and (b) mean (SD) log₁₀ area under the curve for gametocytes up to day 14 in participants with or without baseline gametocytes. Abbreviation: AUC, area under the gametocyte density–time curve.

Figure 5.

Most common treatment-emergent adverse events of any cause in the safety population. Adverse events occurring in >1 participant in any one treatment group. Values are percentage frequency. Participants may have had more than one adverse event. Abbreviation: P. falciparum, Plasmodium falciparum.