Safety and efficacy of pyronaridine-artesunate paediatric granules in the treatment of uncomplicated malaria in children: insights from randomized clinical trials and a real-world study

Abstract

Background: Children are particularly at risk of malaria. This analysis consolidates the clinical data for pyronaridine-artesunate (PA) paediatric granules in children from three randomized clinical trials and a real-world study (CANTAM).

Methods: An integrated safety analysis of individual patient data from three randomized clinical trials included patients with microscopically-confirmed Plasmodium falciparum, body weight ≥ 5 kg to < 20 kg, who received at least one dose of study drug (paediatric safety population). PA was administered once daily for 3 days; two trials included the comparator artemether-lumefantrine (AL). PCR-adjusted day 28 adequate clinical and parasitological response (ACPR) was evaluated. Real-world PA granules safety and effectiveness was also considered.

Results: In the integrated safety analysis, 63.9% (95% CI 60.2, 67.4; 426/667) of patients had adverse events following PA and 62.0% (95% CI 56.9, 66.9; 222/358) with AL. Vomiting was more common with PA (7.8% [95% CI 6.0, 10.1; 52/667]) than AL (3.4% [95% CI 1.9, 5.8; 12/358]), relative risk 2.3 (95% CI 1.3, 4.3; P = 0.004), occurring mainly following the first PA dose (6.7%, 45/667), without affecting re-dosing or adherence. Prolonged QT interval occurred less frequently with PA (3.1% [95% CI 2.1, 4.8; 21/667]) than AL (8.1% [95% CI 5.7, 11.4; 29/358]), relative risk 0.39 (95% CI 0.22, 0.67; P = 0.0007). In CANTAM, adverse events were reported for 17.7% (95% CI 16.3, 19.2; 460/2599) of patients, most commonly vomiting (5.4% [95% CI 4.6, 6.4; 141/2599]), mainly following the first dose, (4.5% [117/2599]), with all patients successfully re-dosed, and pyrexia (5.4% [95% CI 4.6, 6.3; 140/2599]). In the two comparative clinical trials, Day 28 ACPR in the per-protocol population for PA was 97.1% (95% CI 94.6, 98.6; 329/339) and 100% (95% CI 99.3, 100; 514/514) versus 98.8% (95% CI 95.7, 99.9; 165/167) and 98.4% (95% CI 95.5, 99.7; 188/191) for AL, respectively. In CANTAM, PA clinical effectiveness was 98.0% (95% CI 97.3, 98.5; 2273/2320).

Conclusions: Anti-malarial treatment with PA paediatric granules administered once daily for 3 days was well tolerated in children and displayed good clinical efficacy in clinical trials, with effectiveness confirmed in a real-world study. Trial registration Clinicaltrials.gov: SP-C-003-05: identifier NCT00331136; SP-C-007-07: identifier NCT0541385; SP-C-021-15: identifier NCT03201770. Pan African Clinical Trials Registry: SP-C-013-11: identifier PACTR201105000286876.

Keywords: Plasmodium falciparum; Anti-malarial; Granule formulation; Malaria; Paediatric; Pyronaridine–artesunate.

Fig. 1

Disposition of the paediatric safety population

Fig. 2

Overview of adverse events by body weight category. A Integrated safety analysis. B CANTAM (SP-C-021-15).  Data are the percentage of patients. AE adverse event, AL artemether–lumefantrine, PA pyronaridine–artesunate

Fig. 3

Integrated safety analysis peak bilirubin versus A peak ALT and B peak AST. Values are from day 3 until day 28 inclusive. ALT alanine aminotransferase, AL artemether–lumefantrine, AST aspartate aminotransferase, PA pyronaridine–artesunate, ULN upper limit of normal

Fig. 4

Study SP-C-007-07: day 28 PCR-adjusted ACPR by age (PP population) [11]. ACPR adequate clinical and parasitological response, AL artemether–lumefantrine, PA pyronaridine–artesunate, PCR polymerase chain reaction, PP per-protocol

Fig. 5

WANECAM (SP-C-013-11): PCR-adjusted ACPR by body weight (PP population). A Day 28 PCR-adjusted ACPR. B Day 42 PCR-adjusted ACPR. ACPR adequate clinical and parasitological response, AL artemether–lumefantrine, ASAQ artesunate–amodiaquine, PA pyronaridine–artesunate, PCR polymerase chain reaction, PP per-protocol

Fig. 6

CANTAM (SP-C-021-15): PA granules day 28 PCR-adjusted cure rate (PP population). A Day 28 PCR-adjusted cure rate by body weight. B Day 28 PCR-adjusted cure rate by age. PA pyronaridine–artesunate, PCR polymerase chain reaction, PP per-protocol