Universidad Mayor de San Simón and Fundación CEADES, Cochabamba, Bolivia.
Barcelona Institute for Global Health (ISGlobal), Hospital Clinic-University of Barcelona; CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III (CIBERINFEC, ISCIII), Barcelona, Spain.
Clin Infect Dis. 2023 Feb 8;76(3):e1186-e1194. doi: 10.1093/cid/ciac579.
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.
恰加斯病（CD）对全球健康有重大影响，但仍缺乏安全有效的治疗方法。硝基咪唑类药物非达霉素是一种有潜力的治疗药物。
这是一项在玻利维亚进行的双盲、随机、安慰剂对照、剂量探索、概念验证研究。成人血清学证实为慢性不确定期 CD 和阳性 PCR 者被随机分配至 6 个非达霉素治疗方案（1200 或 1800mg/天，疗程 2、4 或 8 周）或安慰剂组。每组目标入组 20 例患者。主要终点是意向治疗人群（ITT）中，从治疗结束（EOT）至 6 个月随访的连续阴性 qPCR 检测到的寄生虫学持续清除。随访延长至 12 个月。
在 4/47 例患者出现短暂无症状的 3 级和 4 级中性粒细胞减少症后，入组被中断。所有接受>2 周治疗的患者均停止治疗。共 40 例患者接受了非达霉素治疗，疗程为 3 天至 8 周。非达霉素组有 8 例出现迟发性中性粒细胞减少症（n=8）和 8 例肝功能酶升高，而安慰剂组无此类事件。在 ITT 分析中，从 EOT 到 12 个月随访的寄生虫学持续清除率在 1200mg-2 周方案为 66.7%（n=12），在 1800mg-2 周方案为 100.0%（n=12）。所有可获得数据的治疗患者在 12 个月时均观察到寄生虫血症的快速、持续清除，但安慰剂组无一例患者出现这种情况（P=0.0056）。进一步的探索性暴露-反应分析表明，低剂量非达霉素可能是安全有效的。
需要进一步评估以确定非达霉素的最小有效剂量和风险-效益关系。结果表明，<10 天的治疗方案有潜力成为有效的治疗方案。
NCT02498782。
