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Abstract：
Staging and treatment of human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT) required lumbar puncture to assess cerebrospinal fluid (CSF) and intravenous drugs that cross the blood-brain barrier for late-stage infection. These procedures are inconvenient in rural health systems of disease-endemic countries. A pivotal study established fexinidazole as the first oral monotherapy to be effective against non-severe stage 2 g-HAT. We aimed to assess the safety and efficacy of fexinidazole in early g-HAT.
In this prospective, multicentre, open-label, single-arm cohort study, patients with stage 1 or early stage 2 g-HAT were recruited from eight treatment centres in the Democratic Republic of the Congo. Primary inclusion criteria included being older than 15 years, being able to ingest at least one complete meal per day (or at least one sachet of Plumpy\'Nut®), a Karnofsky score higher than 50, evidence of trypanosomes in the blood or lymph but no evidence of trypanosomes in the CSF, willingness to be admitted to hospital to receive treatment, having a permanent address, and being able to comply with the follow-up visit schedule. Exclusion criteria included severe malnutrition, inability to take medication orally, pregnant or breastfeeding women, any clinically important medical condition that could jeopardise patient safety or participation in the study, severely deteriorated general status, any contraindication to imidazole drugs, HAT treatment in the past 2 years, previous enrolment in the study or previous intake of fexinidazole, abnormalities on electrocardiogram that did not return to normal in pretreatment repeated assessments or were considered clinically important, QT interval corrected using Fridericia\'s formula of at least 450 ms, and patients not tested for malaria or not having received appropriate treatment for malaria or for soil-transmitted helminthiasis. Patients were classified into stage 1 or early stage 2 g-HAT groups following evidence of trypanosomes in the blood, lymph, and absence in CSF, and using white-blood-cell count in CSF. Patients received 1800 mg fexinidazole once per day on days 1-4 then 1200 mg fexinidazole on days 5-10. Patients were observed for approximately 19 months in total. Study participants were followed up on day 5 and day 8 during treatment, at end of treatment on day 11, at end of hospitalisation on days 11-18, at week 9 for a subset of patients, and after 6 months, 12 months, and 18 months. The primary endpoint was treatment success at 12 months. Safety was assessed through routine monitoring. Analyses were done in the intention-to-treat population. The acceptable success rate was defined as treatment efficacy in more than 80% of patients. This study is completed and registered with ClinicalTrials.gov (NCT02169557).
Patients were enrolled between April 30, 2014, and April 25, 2017. 238 patients were recruited: 195 (82%) patients with stage 1 g-HAT and 43 (18%) with early stage 2 g-HAT. 189 (97%) of 195 patients with stage 1 g-HAT and 41 (95%) of 43 patients with early stage 2 g-HAT were finally included and completed the 10 day treatment period. Three patients with stage 1 g-HAT died after the 10 day treatment period and before the 12 month primary follow-up visit, considered as treatment failure and were withdrawn from the study. Treatment was effective at 12 months for 227 (99%) of 230 patients (95% CI 96·2-99·7): 186 (98%) of 189 patients (95·4-99·7) with stage 1 and 41 (100%) of 41 patients (91·4-100·0) with early stage 2, indicating that the primary study endpoint was met. No new safety issues were observed. The most frequent adverse events were headache and vomiting. In total, 214 (93%) of 230 patients had treatment-emergent adverse events, mainly common-terminology criteria for adverse events grades 1 to 3. None led to treatment discontinuation.
Fexinidazole is a valuable first-line treatment option in the early stages of g-HAT.
Through the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation, the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (also known as DGIS; Netherlands), the Norwegian Agency for Development Cooperation (also known as Norad; Norway), the Federal Ministry of Education and Research (also known as BMBF) through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the HAT campaign.
For the French translation of the abstract see Supplementary Materials section.
In this prospective, multicentre, open-label, single-arm cohort study, patients with stage 1 or early stage 2 g-HAT were recruited from eight treatment centres in the Democratic Republic of the Congo. Primary inclusion criteria included being older than 15 years, being able to ingest at least one complete meal per day (or at least one sachet of Plumpy\'Nut®), a Karnofsky score higher than 50, evidence of trypanosomes in the blood or lymph but no evidence of trypanosomes in the CSF, willingness to be admitted to hospital to receive treatment, having a permanent address, and being able to comply with the follow-up visit schedule. Exclusion criteria included severe malnutrition, inability to take medication orally, pregnant or breastfeeding women, any clinically important medical condition that could jeopardise patient safety or participation in the study, severely deteriorated general status, any contraindication to imidazole drugs, HAT treatment in the past 2 years, previous enrolment in the study or previous intake of fexinidazole, abnormalities on electrocardiogram that did not return to normal in pretreatment repeated assessments or were considered clinically important, QT interval corrected using Fridericia\'s formula of at least 450 ms, and patients not tested for malaria or not having received appropriate treatment for malaria or for soil-transmitted helminthiasis. Patients were classified into stage 1 or early stage 2 g-HAT groups following evidence of trypanosomes in the blood, lymph, and absence in CSF, and using white-blood-cell count in CSF. Patients received 1800 mg fexinidazole once per day on days 1-4 then 1200 mg fexinidazole on days 5-10. Patients were observed for approximately 19 months in total. Study participants were followed up on day 5 and day 8 during treatment, at end of treatment on day 11, at end of hospitalisation on days 11-18, at week 9 for a subset of patients, and after 6 months, 12 months, and 18 months. The primary endpoint was treatment success at 12 months. Safety was assessed through routine monitoring. Analyses were done in the intention-to-treat population. The acceptable success rate was defined as treatment efficacy in more than 80% of patients. This study is completed and registered with ClinicalTrials.gov (NCT02169557).
Patients were enrolled between April 30, 2014, and April 25, 2017. 238 patients were recruited: 195 (82%) patients with stage 1 g-HAT and 43 (18%) with early stage 2 g-HAT. 189 (97%) of 195 patients with stage 1 g-HAT and 41 (95%) of 43 patients with early stage 2 g-HAT were finally included and completed the 10 day treatment period. Three patients with stage 1 g-HAT died after the 10 day treatment period and before the 12 month primary follow-up visit, considered as treatment failure and were withdrawn from the study. Treatment was effective at 12 months for 227 (99%) of 230 patients (95% CI 96·2-99·7): 186 (98%) of 189 patients (95·4-99·7) with stage 1 and 41 (100%) of 41 patients (91·4-100·0) with early stage 2, indicating that the primary study endpoint was met. No new safety issues were observed. The most frequent adverse events were headache and vomiting. In total, 214 (93%) of 230 patients had treatment-emergent adverse events, mainly common-terminology criteria for adverse events grades 1 to 3. None led to treatment discontinuation.
Fexinidazole is a valuable first-line treatment option in the early stages of g-HAT.
Through the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation, the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (also known as DGIS; Netherlands), the Norwegian Agency for Development Cooperation (also known as Norad; Norway), the Federal Ministry of Education and Research (also known as BMBF) through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the HAT campaign.
For the French translation of the abstract see Supplementary Materials section.
摘要：
由布氏冈比亚锥虫（g-HAT）引起的人类非洲锥虫病的分期和治疗需要腰椎穿刺以评估脑脊液（CSF）和静脉内穿过血脑屏障的药物以进行晚期感染。这些程序在疾病流行国家的农村卫生系统中不方便。一项关键研究确立了非西硝唑作为第一个有效对抗非重度2g-HAT的口服单一疗法。我们旨在评估非西硝唑在早期g-HAT中的安全性和有效性。
在这个前景中，多中心,开放标签，单臂队列研究，我们从刚果民主共和国的8个治疗中心招募了1期或2期早期g-HAT患者.主要纳入标准包括年龄超过15岁，能够每天摄取至少一餐（或至少一袋Plumpy\'Nut®），Karnofsky评分高于50，血液或淋巴中有锥虫的证据，但CSF中没有锥虫的证据，愿意入院接受治疗，有一个永久地址，并能够遵守后续访问时间表。排除标准包括严重营养不良，无法口服药物，孕妇或哺乳期妇女，任何可能危及患者安全或参与研究的临床重要医疗状况，总体状况严重恶化，任何咪唑药物的禁忌症，在过去的两年中，HAT治疗，以前参加研究或以前摄入非西硝唑，在治疗前重复评估中未恢复正常或被认为具有临床重要性的心电图异常,使用至少450ms的Fridericia公式校正的QT间隔，以及未接受疟疾测试或未接受疟疾或土壤传播蠕虫病适当治疗的患者。根据血液中锥虫的证据，将患者分为1期或2期早期g-HAT组，淋巴，和脑脊液缺失，并使用脑脊液中的白细胞计数。患者在第1-4天每天一次接受1800mg非西硝唑，然后在第5-10天接受1200mg非西硝唑。总共观察患者约19个月。研究参与者在治疗期间的第5天和第8天进行随访，在第11天治疗结束时，在第11-18天住院结束时，在第9周，六个月后，12个月,还有18个月.主要终点是12个月时的治疗成功。通过常规监测评估安全性。在意向治疗人群中进行了分析。可接受的成功率定义为超过80％的患者的治疗效果。本研究已完成并在ClinicalTrials.gov（NCT02169557）注册。
患者的入组时间为2014年4月30日至2017年4月25日。招募了238名患者：195名（82％）患有1g-HAT的患者和43名（18％）患有早期2g-HAT的患者。最终纳入了195例1g-HAT期患者中的189例（97％）和43例早期2g-HAT患者中的41例（95％），并完成了10天的治疗期。3例1g-HAT期患者在10天治疗期后和12个月初次随访前死亡，被认为是治疗失败，并从研究中退出。在12个月时，230名患者中的227名（99％）（95％CI96·2-99·7）治疗有效：189名患者（95·4-99·7）中的186名（98％）为1期，41名患者（91·4-100·0）为2期早期患者中的41名（100％），表明达到了主要研究终点。没有观察到新的安全问题。最常见的不良事件是头痛和呕吐。总的来说,230例患者中有214例（93%）出现因治疗引起的不良事件，主要是1至3级不良事件的常用术语标准。没有导致治疗中断。
Fexinidazole是g-HAT早期有价值的一线治疗选择。
通过“被忽视疾病药物”倡议：比尔和梅林达·盖茨基金会，日内瓦共和国和州(瑞士)，荷兰外交部（也称为DGIS；荷兰），挪威发展合作署(又称挪威)，联邦教育和研究部（也称为BMBF）通过KfW（德国），BrianMercer慈善信托基金（英国），以及HAT运动中的其他私人基金会和个人。
有关摘要的法语翻译，请参见补充材料部分。
在这个前景中，多中心,开放标签，单臂队列研究，我们从刚果民主共和国的8个治疗中心招募了1期或2期早期g-HAT患者.主要纳入标准包括年龄超过15岁，能够每天摄取至少一餐（或至少一袋Plumpy\'Nut®），Karnofsky评分高于50，血液或淋巴中有锥虫的证据，但CSF中没有锥虫的证据，愿意入院接受治疗，有一个永久地址，并能够遵守后续访问时间表。排除标准包括严重营养不良，无法口服药物，孕妇或哺乳期妇女，任何可能危及患者安全或参与研究的临床重要医疗状况，总体状况严重恶化，任何咪唑药物的禁忌症，在过去的两年中，HAT治疗，以前参加研究或以前摄入非西硝唑，在治疗前重复评估中未恢复正常或被认为具有临床重要性的心电图异常,使用至少450ms的Fridericia公式校正的QT间隔，以及未接受疟疾测试或未接受疟疾或土壤传播蠕虫病适当治疗的患者。根据血液中锥虫的证据，将患者分为1期或2期早期g-HAT组，淋巴，和脑脊液缺失，并使用脑脊液中的白细胞计数。患者在第1-4天每天一次接受1800mg非西硝唑，然后在第5-10天接受1200mg非西硝唑。总共观察患者约19个月。研究参与者在治疗期间的第5天和第8天进行随访，在第11天治疗结束时，在第11-18天住院结束时，在第9周，六个月后，12个月,还有18个月.主要终点是12个月时的治疗成功。通过常规监测评估安全性。在意向治疗人群中进行了分析。可接受的成功率定义为超过80％的患者的治疗效果。本研究已完成并在ClinicalTrials.gov（NCT02169557）注册。
患者的入组时间为2014年4月30日至2017年4月25日。招募了238名患者：195名（82％）患有1g-HAT的患者和43名（18％）患有早期2g-HAT的患者。最终纳入了195例1g-HAT期患者中的189例（97％）和43例早期2g-HAT患者中的41例（95％），并完成了10天的治疗期。3例1g-HAT期患者在10天治疗期后和12个月初次随访前死亡，被认为是治疗失败，并从研究中退出。在12个月时，230名患者中的227名（99％）（95％CI96·2-99·7）治疗有效：189名患者（95·4-99·7）中的186名（98％）为1期，41名患者（91·4-100·0）为2期早期患者中的41名（100％），表明达到了主要研究终点。没有观察到新的安全问题。最常见的不良事件是头痛和呕吐。总的来说,230例患者中有214例（93%）出现因治疗引起的不良事件，主要是1至3级不良事件的常用术语标准。没有导致治疗中断。
Fexinidazole是g-HAT早期有价值的一线治疗选择。
通过“被忽视疾病药物”倡议：比尔和梅林达·盖茨基金会，日内瓦共和国和州(瑞士)，荷兰外交部（也称为DGIS；荷兰），挪威发展合作署(又称挪威)，联邦教育和研究部（也称为BMBF）通过KfW（德国），BrianMercer慈善信托基金（英国），以及HAT运动中的其他私人基金会和个人。
有关摘要的法语翻译，请参见补充材料部分。
