背景:儿童尤其面临疟疾风险。该分析巩固了来自三项随机临床试验和一项现实世界研究(CANTAM)的儿童pyronaridine-artesunate(PA)儿科颗粒的临床数据。
方法:对来自三项随机临床试验的个体患者数据进行综合安全性分析,其中包括经显微镜证实的恶性疟原虫患者,体重≥5公斤至<20公斤,谁接受了至少一个剂量的研究药物(儿科安全人群)。PA每天给药一次,持续3天;两项试验包括参比剂蒿甲醚-本美特林(AL)。评估了经PCR调整的第28天的适当临床和寄生虫反应(ACPR)。还考虑了真实世界PA颗粒的安全性和有效性。
结果:在综合安全分析中,63.9%(95%CI60.2,67.4;426/667)的患者发生PA后不良事件,62.0%(95%CI56.9,66.9;222/358)的患者发生AL后不良事件。与AL(3.4%[95%CI1.9,5.8;12/358])相比,PA(7.8%[95%CI6.0,10.1;52/667])更常见呕吐,相对风险2.3(95%CI1.3,4.3;P=0.004),主要发生在第一次PA剂量之后(6.7%,45/667),不影响重新给药或依从性。与AL(8.1%[95%CI5.7,11.4;29/358])相比,PA(3.1%[95%CI2.1,4.8;21/667])发生的QT间期延长频率较低,相对危险度0.39(95%CI0.22,0.67;P=0.0007)。在坎塔姆,17.7%(95%CI16.3,19.2;460/2599)的患者报告了不良事件,最常见的呕吐(5.4%[95%CI4.6,6.4;141/2599]),主要是在第一次给药之后,(4.5%[117/2599]),所有患者都成功重新服药,发热(5.4%[95%CI4.6,6.3;140/2599])。在两项比较临床试验中,PA的符合方案人群的第28天ACPR为97.1%(95%CI94.6,98.6;329/339)和100%(95%CI99.3,100;514/514),而AL的98.8%(95%CI95.7,99.9;165/167)和98.4%(95%CI95.5,99.7;188/191),分别。在坎塔姆,PA临床有效率为98.0%(95%CI97.3,98.5;2273/2320)。
结论:PA儿科颗粒每天一次,持续3天的抗疟疾治疗在儿童中具有良好的耐受性,并在临床试验中显示出良好的临床疗效。在现实世界的研究中证实了有效性。试验注册Clinicaltrials.gov:SP-C-003-05:标识符NCT00331136;SP-C-007-07:标识符NCT0541385;SP-C-021-15:标识符NCT03201770。泛非临床试验注册中心:SP-C-013-11:标识符PACTR201105000286876。
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.