背景:恰加斯病(CD)对全球健康产生重大影响,但安全,有效的治疗仍然难以捉摸。硝基咪唑非辛硝唑是一种潜在的治疗方法。
方法:这种双盲,随机化,安慰剂对照,剂量发现,在玻利维亚进行了概念验证研究。将血清学证实为慢性不确定CD和PCR阳性的成年人随机分配到6种非西硝唑方案中的1种(1200或1800mg/天,持续2、4或8周)或安慰剂。目标招募为20名患者/臂。主要终点是在意向治疗(ITT)人群中,从治疗结束(EOT)到6个月随访,通过连续阴性qPCR进行持续的寄生虫清除。随访时间延长至12个月。
结果:4/47例患者出现短暂性无症状3级和4级中性粒细胞减少症后,登记中断。在施用>2周的所有患者中停止正在进行的患者的治疗。从3天到8周,共有40例患者接受了非西硝唑治疗。在非西硝唑患者中发现了延迟性中性粒细胞减少症(n=8)和肝酶升高(n=8),而在安慰剂组中则没有。在ITT分析中,从EOT到12个月随访的持续寄生虫清除率在66.7%(1200mg-2周)和100.0%(1800mg-2周)之间变化。快速,在所有接受治疗的患者中观察到寄生虫血症的持续清除,但安慰剂组的任何患者都没有,12个月时(P=.0056)。进一步的探索性暴露反应分析表明,低剂量的非西硝唑可能是安全有效的。
结论:需要进一步评估以确定非西硝唑的最小有效剂量和风险-收益关系。结果表明有效治疗方案<10天的可能性。
背景:NCT02498782。
Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole
fexinidazole is a potential treatment.
This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-to-treat (ITT) population. Follow-up was extended to 12 months.
Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with
fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in
fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P = .0056). Further exploratory exposure-response analysis suggested low dosages of
fexinidazole may be safe and effective.
Further evaluation is needed to establish
fexinidazole\'s minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days.
NCT02498782.