Background Chagas disease (CD) has significant global health impact, but safe and effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. Methods This double-blind, randomised, 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 one of six 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 population (ITT). Follow-up was extended to 12 months. Results 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 from 3 days to 8 weeks of treatment with fexinidazole. Delayed onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients, versus none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (“1200mg-2week”) and 100.0% (“1800mg-2week”). 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 = 0.0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. Conclusions Further evaluation is needed to establish fexinidazole’s minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens of <10 days.

中文翻译：

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口服非昔硝唑治疗慢性不确定恰加斯病成人的 2 期、随机、多中心、安慰剂对照、概念验证试验

背景 南美锥虫病 (CD) 对全球健康具有重大影响，但安全有效的治疗方法仍然难以捉摸。硝基咪唑非昔硝唑是一种潜在的治疗方法。方法 这项双盲、随机、安慰剂对照、剂量探索、概念验证研究在玻利维亚进行。患有血清学确诊的慢性不确定 CD 和阳性 PCR 的成人被随机分配到六种非昔硝唑方案（1200 或 1800 mg/天，持续 2、4 或 8 周）或安慰剂中的一种。招募目标为 20 名患者/手臂。主要终点是从治疗结束 (EOT) 到意向治疗人群 (ITT) 随访 6 个月期间通过连续阴性 qPCR 持续清除寄生虫。随访延长至 12 个月。结果 在 4/47 名患者出现短暂的无症状 3 级和 4 级中性粒细胞减少症后，登记被中断。在给药＞2周的所有患者中停止对正在进行的患者的治疗。共有 40 名患者接受了 3 天至 8 周的非昔硝唑治疗。非昔硝唑患者出现迟发性中性粒细胞减少症 (n = 8) 和肝酶升高 (n = 8)，而安慰剂组则没有。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-2week”）和 100.0%（“1800mg-2week”）之间变化。在 12 个月时，在所有有可用数据的治疗患者中观察到寄生虫血症快速、持续清除，但在安慰剂组的任何患者中均未观察到（p = 0.0056）。进一步的探索性暴露-反应分析表明，低剂量的非昔硝唑可能是安全有效的。结论 需要进一步评价以建立非昔硝唑的最低有效剂量和风险-收益关系。结果表明＜10天的有效治疗方案的潜力。