PDF(Pubmed)
Abstract：
Human African trypanosomiasis caused by Trypanosoma brucei gambiense (gambiense HAT) in patients with late-stage disease requires hospital admission to receive nifurtimox-eflornithine combination therapy (NECT). Fexinidazole, the latest treatment that has been recommended by WHO, also requires systematic admission to hospital, which is problematic in areas with few health-care resources. We aim to assess the safety and efficacy of acoziborole in adult and adolescent patients with gambiense HAT.
This multicentre, prospective, open-label, single-arm, phase 2/3 study recruited patients aged 15 years or older with confirmed gambiense HAT infection from ten hospitals in the Democratic Republic of the Congo and Guinea. Inclusion criteria included a Karnofsky score greater than 50, ability to swallow tablets, a permanent address or traceability, ability to comply with follow-up visits and study requirements, and agreement to hospital admission during treatment. Oral acoziborole was administered as a single 960 mg dose (3 × 320 mg tablets) to fasted patients. Patients were observed in hospital until day 15 after treatment administration then for 18 months as outpatients with visits at 3, 6, 12, and 18 months. The primary efficacy endpoint was the success rate of acoziborole treatment at 18 months in patients with late-stage gambiense HAT (modified intention-to-treat [mITT] population), based on modified WHO criteria. A complementary post-hoc analysis comparing the 18-month success rates for acoziborole and NECT (using historical data) was performed. This study is registered at ClinicalTrials.gov, NCT03087955.
Between Oct 11, 2016, and March 25, 2019, 260 patients were screened, of whom 52 were ineligible and 208 were enrolled (167 with late-stage and 41 with early-stage or intermediate-stage gambiense HAT; primary efficacy analysis set). All 41 (100%) patients with early-stage or intermediate-stage and 160 (96%) of 167 with late-stage disease completed the last 18-month follow-up visit. The mean age of participants was 34·0 years (SD 12·4), including 117 (56%) men and 91 (44%) women. Treatment success rate at 18 months was 95·2% (95% CI 91·2-97·7) reached in 159 of 167 patients with late-stage gambiense HAT (mITT population) and 98·1% (95·1-99·5) reached in 159 of 162 patients (evaluable population). Overall, 155 (75%) of 208 patients had 600 treatment-emergent adverse events. A total of 38 drug-related treatment-emergent adverse events occurred in 29 (14%) patients; all were mild or moderate and most common were pyrexia and asthenia. Four deaths occurred during the study; none were considered treatment related. The post-hoc analysis showed similar results to the estimated historical success rate for NECT of 94%.
Given the high efficacy and favourable safety profile, acoziborole holds promise in the efforts to reach the WHO goal of interrupting HAT transmission by 2030.
Bill & Melinda Gates Foundation, UK Aid, Federal Ministry of Education and Research, Swiss Agency for Development and Cooperation, Médecins Sans Frontières, Dutch Ministry of Foreign Affairs, Norwegian Agency for Development Cooperation, Norwegian Ministry of Foreign Affairs, the Stavros Niarchos Foundation, Spanish Agency for International Development Cooperation, and the Banco Bilbao Vizcaya Argentaria Foundation.
For the French translation of the abstract see Supplementary Materials section.
This multicentre, prospective, open-label, single-arm, phase 2/3 study recruited patients aged 15 years or older with confirmed gambiense HAT infection from ten hospitals in the Democratic Republic of the Congo and Guinea. Inclusion criteria included a Karnofsky score greater than 50, ability to swallow tablets, a permanent address or traceability, ability to comply with follow-up visits and study requirements, and agreement to hospital admission during treatment. Oral acoziborole was administered as a single 960 mg dose (3 × 320 mg tablets) to fasted patients. Patients were observed in hospital until day 15 after treatment administration then for 18 months as outpatients with visits at 3, 6, 12, and 18 months. The primary efficacy endpoint was the success rate of acoziborole treatment at 18 months in patients with late-stage gambiense HAT (modified intention-to-treat [mITT] population), based on modified WHO criteria. A complementary post-hoc analysis comparing the 18-month success rates for acoziborole and NECT (using historical data) was performed. This study is registered at ClinicalTrials.gov, NCT03087955.
Between Oct 11, 2016, and March 25, 2019, 260 patients were screened, of whom 52 were ineligible and 208 were enrolled (167 with late-stage and 41 with early-stage or intermediate-stage gambiense HAT; primary efficacy analysis set). All 41 (100%) patients with early-stage or intermediate-stage and 160 (96%) of 167 with late-stage disease completed the last 18-month follow-up visit. The mean age of participants was 34·0 years (SD 12·4), including 117 (56%) men and 91 (44%) women. Treatment success rate at 18 months was 95·2% (95% CI 91·2-97·7) reached in 159 of 167 patients with late-stage gambiense HAT (mITT population) and 98·1% (95·1-99·5) reached in 159 of 162 patients (evaluable population). Overall, 155 (75%) of 208 patients had 600 treatment-emergent adverse events. A total of 38 drug-related treatment-emergent adverse events occurred in 29 (14%) patients; all were mild or moderate and most common were pyrexia and asthenia. Four deaths occurred during the study; none were considered treatment related. The post-hoc analysis showed similar results to the estimated historical success rate for NECT of 94%.
Given the high efficacy and favourable safety profile, acoziborole holds promise in the efforts to reach the WHO goal of interrupting HAT transmission by 2030.
Bill & Melinda Gates Foundation, UK Aid, Federal Ministry of Education and Research, Swiss Agency for Development and Cooperation, Médecins Sans Frontières, Dutch Ministry of Foreign Affairs, Norwegian Agency for Development Cooperation, Norwegian Ministry of Foreign Affairs, the Stavros Niarchos Foundation, Spanish Agency for International Development Cooperation, and the Banco Bilbao Vizcaya Argentaria Foundation.
For the French translation of the abstract see Supplementary Materials section.
摘要：
背景：晚期疾病患者中由布氏冈比亚锥虫（gambienseHAT）引起的人类非洲锥虫病需要入院接受硝呋替莫-依氟鸟氨酸联合治疗（NECT）。Fexinidazole,世卫组织推荐的最新治疗方法，还需要系统的入院，这在医疗保健资源很少的地区是有问题的。我们的目的是评估成人和青少年冈比亚HAT患者使用acoziborole的安全性和有效性。
方法：这个多中心，prospective,开放标签，单臂,2/3期研究从刚果民主共和国和几内亚的10家医院招募了15岁或以上确诊冈比亚HAT感染的患者.纳入标准包括Karnofsky得分小于50，吞咽片剂的能力，永久地址或可追溯性，遵守后续访问和学习要求的能力，并同意在治疗期间入院。口服acoziborole以单次960mg剂量（3×320mg片剂）给予禁食的患者。在医院中观察患者直到治疗给药后15天,然后作为门诊患者在3、6、12和18个月时就诊18个月。主要疗效终点是晚期冈比亚HAT（改良意向治疗[mITT]人群）患者在18个月时的acoziborole治疗成功率，根据修改后的世卫组织标准。进行了补充事后分析，比较了acoziborole和NECT的18个月成功率（使用历史数据）。这项研究在ClinicalTrials.gov注册，NCT03087955。
结果：在2016年10月11日至2019年3月25日之间，对260名患者进行了筛查，其中52人不合格,208人纳入(167人晚期,41人早期或中期冈比亚HAT;主要疗效分析集).所有41名（100％）早期或中期患者和167名晚期疾病患者中的160名（96％）完成了最后18个月的随访。参与者的平均年龄为34·0岁(SD12·4)，其中男性117人（56%），女性91人（44%）。在167例晚期冈比亚HAT患者（mITT人群）中，有159例达到18个月的治疗成功率为95·2％（95％CI91·2-97·7），在162例患者（可评估人群）中，有159例达到98·1％（95·1-99·5）。总的来说,208例患者中有155例（75%）出现600例治疗引起的不良事件。29例（14％）患者发生了38例与药物相关的治疗引起的不良事件；所有患者均为轻度或中度，最常见的是发热和虚弱。研究期间发生4例死亡；没有人被认为与治疗相关。事后分析显示，与NECT的估计历史成功率94％相似。
结论：鉴于高疗效和良好的安全性，acoziborole有望实现世卫组织到2030年阻断HAT传播的目标。
背景：比尔和梅琳达·盖茨基金会，英国援助，联邦教育和研究部，瑞士发展与合作署，无国界医生，荷兰外交部,挪威发展合作署，挪威外交部,StavrosNiarchos基金会,西班牙国际发展合作署，和毕尔巴鄂比斯卡亚银行阿根廷基金会。
UNASSIGNED：有关摘要的法语翻译，请参见补充材料部分。
方法：这个多中心，prospective,开放标签，单臂,2/3期研究从刚果民主共和国和几内亚的10家医院招募了15岁或以上确诊冈比亚HAT感染的患者.纳入标准包括Karnofsky得分小于50，吞咽片剂的能力，永久地址或可追溯性，遵守后续访问和学习要求的能力，并同意在治疗期间入院。口服acoziborole以单次960mg剂量（3×320mg片剂）给予禁食的患者。在医院中观察患者直到治疗给药后15天,然后作为门诊患者在3、6、12和18个月时就诊18个月。主要疗效终点是晚期冈比亚HAT（改良意向治疗[mITT]人群）患者在18个月时的acoziborole治疗成功率，根据修改后的世卫组织标准。进行了补充事后分析，比较了acoziborole和NECT的18个月成功率（使用历史数据）。这项研究在ClinicalTrials.gov注册，NCT03087955。
结果：在2016年10月11日至2019年3月25日之间，对260名患者进行了筛查，其中52人不合格,208人纳入(167人晚期,41人早期或中期冈比亚HAT;主要疗效分析集).所有41名（100％）早期或中期患者和167名晚期疾病患者中的160名（96％）完成了最后18个月的随访。参与者的平均年龄为34·0岁(SD12·4)，其中男性117人（56%），女性91人（44%）。在167例晚期冈比亚HAT患者（mITT人群）中，有159例达到18个月的治疗成功率为95·2％（95％CI91·2-97·7），在162例患者（可评估人群）中，有159例达到98·1％（95·1-99·5）。总的来说,208例患者中有155例（75%）出现600例治疗引起的不良事件。29例（14％）患者发生了38例与药物相关的治疗引起的不良事件；所有患者均为轻度或中度，最常见的是发热和虚弱。研究期间发生4例死亡；没有人被认为与治疗相关。事后分析显示，与NECT的估计历史成功率94％相似。
结论：鉴于高疗效和良好的安全性，acoziborole有望实现世卫组织到2030年阻断HAT传播的目标。
背景：比尔和梅琳达·盖茨基金会，英国援助，联邦教育和研究部，瑞士发展与合作署，无国界医生，荷兰外交部,挪威发展合作署，挪威外交部,StavrosNiarchos基金会,西班牙国际发展合作署，和毕尔巴鄂比斯卡亚银行阿根廷基金会。
UNASSIGNED：有关摘要的法语翻译，请参见补充材料部分。
