Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente (CEADES), Cochabamba, Bolivia; Universidad Mayor de San Simón, Cochabamba, Bolivia.
Barcelona Institute for Global Health, Barcelona, Spain; Universitat de Barcelona, Barcelona, Spain.
Lancet Infect Dis. 2021 Aug;21(8):1129-1140. doi: 10.1016/S1473-3099(20)30844-6. Epub 2021 Apr 6.
Current treatment for Chagas disease with the only available drugs, benznidazole or nifurtimox, has substantial limitations, including long treatment duration and safety and tolerability concerns. We aimed to evaluate the efficacy and safety of new benznidazole monotherapy regimens and combinations with fosravuconazole, in the treatment of Chagas disease.
We did a double-blind, double-dummy, phase 2, multicentre, randomised trial in three outpatient units in Bolivia. Adults aged 18-50 years with chronic indeterminate Chagas disease, confirmed by serological testing and positive qualitative PCR results, were randomly assigned (1:1:1:1:1:1:1) to one of seven treatment groups using a balanced block randomisation scheme with an interactive response system. Participants were assigned to benznidazole 300 mg daily for 8 weeks, 4 weeks, or 2 weeks, benznidazole 150 mg daily for 4 weeks, benznidazole 150 mg daily for 4 weeks plus fosravuconazole, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, or placebo, with a 12-month follow-up period. The primary endpoints were sustained parasitological clearance at 6 months, defined as persistent negative qualitative PCR results from end of treatment, and incidence and severity of treatment-emergent adverse events, serious adverse events, and adverse events leading to treatment discontinuation. Primary efficacy analysis was based on the intention-to-treat and per-protocol populations and secondary efficacy analyses on the per-protocol population. Safety analyses were based on the as-treated population. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03378661.
Between Nov 30, 2016, and July 27, 2017, we screened 518 patients, and 210 were enrolled and randomised. 30 patients (14%) were assigned to each treatment group. All 210 randomised patients were included in the intention-to-treat population, and 190 (90%) were included in the per-protocol population. In the intention-to-treat analysis, only one (3%) of 30 patients in the placebo group had sustained parasitological clearance at 6 months of follow-up. Sustained parasitological clearance at 6 months was observed in 25 (89%) of 28 patients receiving benznidazole 300 mg daily for 8 weeks (rate difference vs placebo 86% [95% CI 73-99]), 25 (89%) of 28 receiving benznidazole 300 mg daily for 4 weeks (86% [73-99]), 24 (83%) of 29 receiving benznidazole 300 mg daily for 2 weeks (79% [64-95]), 25 (83%) of 30 receiving benznidazole 150 mg daily for 4 weeks (80% [65-95]), 23 (85%) of 28 receiving benznidazole 150 mg daily for 4 weeks plus fosravuconazole (82% [67-97]), and 24 (83%) of 29 receiving benznidazole 300 mg weekly for 8 weeks plus fosravuconazole (79% [64-95]; p<0·0001 for all group comparisons with placebo). Six patients (3%) had ten serious adverse events (leukopenia [n=3], neutropenia [n=2], pyrexia, maculopapular rash, acute cholecystitis, biliary polyp, and breast cancer), eight had 12 severe adverse events (defined as interfering substantially with the patient's usual functions; elevated alanine aminotransferase [n=4], elevated gamma-glutamyltransferase [n=2], elevated aspartate aminotransferase [n=1], neutropenia [n=3], leukopenia [n=1], and breast cancer [n=1]), and 15 (7%) had adverse events that led to treatment discontinuation (most of these were in the groups who received benznidazole 300 mg daily for 8 weeks, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, and benznidazole 150 mg daily for 4 weeks plus fosravuconazole). No adverse events leading to treatment discontinuation were observed in patients treated with benznidazole 300 mg daily for 2 weeks or placebo. There were no treatment-related deaths.
Benznidazole induced effective antiparasitic response, regardless of treatment duration, dose, or combination with fosravuconazole, and was well tolerated in adult patients with chronic Chagas disease. Shorter or reduced regimens of benznidazole could substantially improve treatment tolerability and accessibility, but further studies are needed to confirm these results.
Drugs for Neglected Diseases initiative (DNDi).
For the Spanish translation of the abstract see Supplementary Materials section.
目前，贝那唑嗪或硝呋替莫是唯一可用的治疗药物，用于治疗恰加斯病，但这些药物存在许多局限性，包括治疗周期长、安全性和耐受性问题。本研究旨在评估新型贝那唑嗪单药治疗方案和联合福沙韦康治疗恰加斯病的疗效和安全性。
我们在玻利维亚的三个门诊单位进行了一项双盲、双模拟、多中心、随机 2 期临床试验。年龄在 18-50 岁之间的慢性不确定期恰加斯病患者，通过血清学检测和定性 PCR 阳性结果确诊，按 1:1:1:1:1:1:1 的比例随机分配到 7 个治疗组之一，使用平衡区组随机化方案和交互式反应系统。参与者接受贝那唑嗪 300 mg 每日 1 次治疗 8 周、4 周或 2 周，贝那唑嗪 150 mg 每日 1 次治疗 4 周，贝那唑嗪 150 mg 每日 1 次治疗 4 周加福沙韦康，贝那唑嗪 300 mg 每周 1 次治疗 8 周加福沙韦康，或安慰剂，随访 12 个月。主要终点是 6 个月时的持续寄生虫清除，定义为治疗结束时持续阴性定性 PCR 结果，以及治疗期间出现的不良事件、严重不良事件和导致治疗中断的不良事件的发生率和严重程度。主要疗效分析基于意向治疗和方案人群，次要疗效分析基于方案人群。安全性分析基于实际治疗人群。招募现已结束。本试验在 ClinicalTrials.gov 注册，NCT03378661。
2016 年 11 月 30 日至 2017 年 7 月 27 日，我们共筛查了 518 例患者，其中 210 例入选并随机分组。每组各有 30 例患者。所有 210 名随机患者均纳入意向治疗人群，190 名（90%）纳入方案人群。意向治疗分析中，安慰剂组仅 1 例（3%）患者在随访 6 个月时寄生虫持续清除。贝那唑嗪 300 mg 每日 1 次治疗 8 周的患者中，28 例中有 25 例（89%）在 6 个月时寄生虫持续清除（与安慰剂组相比，清除率差异为 86%[73-99%]），贝那唑嗪 300 mg 每日 1 次治疗 4 周的患者中，28 例中有 25 例（89%）寄生虫持续清除（86%[73-99%]），贝那唑嗪 300 mg 每日 1 次治疗 2 周的患者中，29 例中有 24 例（83%）寄生虫持续清除（79%[64-95%]），贝那唑嗪 150 mg 每日 1 次治疗 4 周的患者中，28 例中有 25 例（83%）寄生虫持续清除（80%[65-95%]），贝那唑嗪 150 mg 每日 1 次治疗 4 周加福沙韦康的患者中，28 例中有 23 例（85%）寄生虫持续清除（82%[67-97%]），贝那唑嗪 300 mg 每周 1 次治疗 8 周加福沙韦康的患者中，29 例中有 24 例（83%）寄生虫持续清除（79%[64-95%]）；与安慰剂组相比，所有组比较差异均有统计学意义（均 P<0·0001）。6 例患者（3%）出现 10 例严重不良事件（白细胞减少症[3 例]、中性粒细胞减少症[2 例]、发热、斑丘疹、急性胆囊炎、胆囊息肉、乳腺癌），8 例出现 12 例严重不良事件（定义为严重影响患者的日常功能；丙氨酸氨基转移酶升高[4 例]、γ-谷氨酰转移酶升高[2 例]、天冬氨酸氨基转移酶升高[1 例]、中性粒细胞减少症[3 例]、白细胞减少症[1 例]和乳腺癌[1 例]），15 例（7%）发生导致治疗中断的不良事件（这些不良事件大多发生在接受贝那唑嗪 300 mg 每日 1 次治疗 8 周、贝那唑嗪每周 1 次治疗 8 周加福沙韦康和贝那唑嗪 150 mg 每日 1 次治疗 4 周加福沙韦康的患者中）。接受贝那唑嗪 300 mg 每日 2 周或安慰剂治疗的患者中，没有观察到导致治疗中断的不良事件。没有治疗相关的死亡病例。
贝那唑嗪诱导有效的抗寄生虫反应，无论治疗持续时间、剂量或与福沙韦康联合使用，在慢性恰加斯病患者中均具有良好的耐受性。缩短或减少贝那唑嗪治疗方案可能会显著提高治疗的耐受性和可及性，但还需要进一步的研究来证实这些结果。
药品专利池组织（DNDi）。
