一项在健康志愿者中诱导血期疟原虫感染以测试新抗疟药物疗效的初步随机试验。
A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs.
机构信息
Queensland Institute for Medical Research, University of Queensland, Brisbane, Australia.
出版信息
PLoS One. 2011;6(8):e21914. doi: 10.1371/journal.pone.0021914. Epub 2011 Aug 22.
BACKGROUND
Critical to the development of new drugs for treatment of malaria is the capacity to safely evaluate their activity in human subjects. The approach that has been most commonly used is testing in subjects with natural malaria infection, a methodology that may expose symptomatic subjects to the risk of ineffective treatment. Here we describe the development and pilot testing of a system to undertake experimental infection using blood stage Plasmodium falciparum parasites (BSP). The objectives of the study were to assess the feasibility and safety of induced BSP infection as a method for assessment of efficacy of new drug candidates for the treatment of P. falciparum infection.
METHODS AND FINDINGS
A prospective, unblinded, Phase IIa trial was undertaken in 19 healthy, malaria-naïve, male adult volunteers who were infected with BSP and followed with careful clinical and laboratory observation, including a sensitive, quantitative malaria PCR assay. Volunteers were randomly allocated to treatment with either of two licensed antimalarial drug combinations, artemether-lumefantrine (A/L) or atovaquone-proguanil (A/P). In the first cohort (n = 6) where volunteers received ∼360 BSP, none reached the target parasitemia of 1,000 before the day designated for antimalarial treatment (day 6). In the second and third cohorts, 13 volunteers received 1,800 BSP, with all reaching the target parasitemia before receiving treatment (A/L, n = 6; A/P, n = 7) The study demonstrated safety in the 19 volunteers tested, and a significant difference in the clearance kinetics of parasitemia between the drugs in the 13 evaluable subjects, with mean parasite reduction ratios of 759 for A/L and 17 for A/P (95% CI 120-4786 and 7-40 respectively; p<0.01).
CONCLUSIONS
This system offers a flexible and safe approach to testing the in vivo activity of novel antimalarials.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01055002.
背景
开发治疗疟疾的新药的关键是能够安全地在人体受试者中评估其活性。最常使用的方法是在患有自然疟疾感染的受试者中进行测试，这种方法可能使有症状的受试者面临无效治疗的风险。在这里，我们描述了一种使用疟原虫血期寄生虫（BSP）进行实验性感染的系统的开发和初步测试。该研究的目的是评估诱导 BSP 感染作为评估新候选药物治疗恶性疟原虫感染疗效的方法的可行性和安全性。
方法和发现
在 19 名健康、无疟疾的成年男性志愿者中进行了一项前瞻性、非盲、IIa 期试验，这些志愿者感染了 BSP，并进行了仔细的临床和实验室观察，包括一种敏感的定量疟疾 PCR 检测。志愿者被随机分配接受两种已获许可的抗疟药物组合之一的治疗，即青蒿琥酯-咯萘啶（A/L）或阿托伐醌-伯氨喹（A/P）。在第一组（n=6）中，志愿者接受了约 360 个 BSP，在指定的抗疟治疗日（第 6 天）之前，没有人达到 1000 的目标寄生虫血症。在第二和第三组中，13 名志愿者接受了 1800 个 BSP，所有志愿者在接受治疗前都达到了目标寄生虫血症（A/L，n=6；A/P，n=7）。该研究在 19 名接受测试的志愿者中证明了安全性，并且在 13 名可评估受试者中，药物清除寄生虫血症的动力学有显著差异，A/L 的平均寄生虫减少率为 759，A/P 为 17（95%CI 120-4786 和 7-40 分别；p<0.01）。
结论
该系统为测试新型抗疟药物的体内活性提供了一种灵活、安全的方法。
试验注册
ClinicalTrials.gov NCT01055002。
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