Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials

Abstract

Background: Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria.

Methods: Individual patient data on safety outcomes were integrated from six randomized clinical trials conducted in Africa and Asia in patients with microscopically confirmed P. falciparum (five studies) or P. vivax (one study) malaria. Efficacy against P. falciparum was evaluated across three Phase III clinical trials.

Results: The safety population included 2,815 patients randomized to PA, 1,254 to comparators: mefloquine + artesunate (MQ + AS), artemether-lumefantrine (AL), or chloroquine. All treatments were generally well tolerated. Adverse events occurred in 57.2% (1,611/2,815) of patients with PA versus 51.5% (646/1,254) for comparators, most commonly (PA; comparators): headache (10.6%; 9.9%), cough (5.9%; 5.6%) and anaemia (4.5%; 2.9%). Serious averse events were uncommon for all treatments (0-0.7%). Transient increases in alanine aminotransferase and aspartate aminotransferase were observed with PA but did not lead to any clinical sequelae. For P. falciparum malaria, day-28 PCR-corrected adequate clinical and parasitological response with PA was 93.6% ([1,921/2,052] 95% CI 92.6, 94.7) in the intent-to-treat population and 98.5% ([1,852/1,880] 95% CI 98.0, 99.1) in the per-protocol population. Median parasite clearance time was 24.1 h with PA, 31.9 h with MQ + AS, and 24.0 h with AL. Median fever clearance time was 15.5 h with PA, 15.8 h with MQ + AS, and 14.0 h with AL. By day 42, P. falciparum gametocytes had declined to near zero for all treatments.

Conclusions: Pyronaridine-artesunate was well tolerated with no safety concerns with the exception of mostly mild transient rises in transaminases. Efficacy was high and met the requirements for use as first-line therapy. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes.

Trial registration: Clinicaltrials.gov: NCT00331136; NCT00403260; NCT00422084; NCT00440999; NCT00541385; NCT01594931.

Figure 1

Changes from baseline in haematology parameters in patients receiving pyronaridine-artesunate or combined comparators (safety population). NB: Day-28 values are available for the Plasmodium vivax study only [23].

Figure 2

Changes from baseline in liver enzymes and total bilirubin in patients receiving pyronaridine-artesunate or combined comparators (safety population). NB: Day-28 values are available for the Plasmodium vivax study only [23].

Figure 3

Day-28 adequate clinical and parasitological response (ACPR): A) PCR-corrected; B) uncorrected. Two-sided 95% confidence intervals (Wald) were adjusted for study.

Figure 4

Plasmodium falciparum A) recrudescence rate B) re-infection rate. Kaplan-Meier survival plot for the integrated efficacy analysis (intent-to-treat population).

Figure 5

Parasite clearance time for A) all centres; B) Cambodia versus Thailand. Kaplan-Meier survival plot for the integrated efficacy analysis (intent-to-treat population).

Figure 6

Fever clearance time. Kaplan-Meier survival plot for the integrated efficacy analysis (intent-to-treat population)

Figure 7

Proportion of patients with Plasmodium falciparum gametocytes. Integrated efficacy analysis (intent-to-treat population). Two-sided 95% confidence intervals (Wald) were adjusted for study.

Figure 8

Plasmodium falciparum gametocyte density over time. A) Study SP-C-004-06 comparing pyronaridine-artesunate to mefloquine + artesunate gametocyte density over time in patients with baseline gametocytes and B) no gametocytes at baseline and post-baseline gametocytes. C) Study SP-C-005-06 comparing pyronaridine-artesunate to artemether-lumefantrine gametocyte density over time in patients with baseline gametocytes and D) no gametocytes at baseline and post-baseline gametocytes. All data are for the intent-to-treat population.