AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial.
AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial.
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DOI：
10.1186/s13063-018-3026-4
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发表时间：
2018-11-23
期刊：
影响因子：
2.5
通讯作者：
Jarvis JN
中科院分区：
文献类型：
--
作者：
Lawrence DS;Youssouf N;Molloy SF;Alanio A;Alufandika M;Boulware DR;Boyer-Chammard T;Chen T;Dromer F;Hlupeni A;Hope W;Hosseinipour MC;Kanyama C;Lortholary O;Loyse A;Meya DB;Mosepele M;Muzoora C;Mwandumba HC;Ndhlovu CE;Niessen L;Schutz C;Stott KE;Wang D;Lalloo DG;Meintjes G;Jaffar S;Harrison TS;Jarvis JN
尽管获得抗逆转录病毒疗法(ART)的机会越来越多，但隐球菌性脑膜炎(CM)仍是非洲艾滋病毒方案中死亡的主要原因。死亡率的部分原因是以两性霉素为基础的治疗的可获得性有限、两性霉素B脱氧胆酸盐的药物毒性以及住院时间延长。据报道，在氟康唑骨架上单次大剂量脂质体两性霉素(L-Amb，Ambiome)在减少真菌负担方面不逊于14天的标准剂量L-Amb。这项试验考察了单剂量、大剂量L-Amb与大剂量氟康唑和氟胞嘧啶一起服用是否不逊于两性霉素B脱氧胆酸盐加氟胞嘧啶(目前世界卫生组织推荐的治疗方案)的7天疗程。一项开放标签第三阶段随机对照非劣势试验在撒哈拉以南非洲的五个国家进行：博茨瓦纳、马拉维、南非、乌干达和津巴布韦。该试验将比较CM诱导治疗与(1)单剂量(10 mg/kg)L-Amb联合14天氟康唑(1200 mg/kg/d)和氟胞嘧啶(100 mg/kg/d)与(2)7天两性霉素B脱氧胆酸(1 mg/kg/d)同时给予7天氟胞嘧啶(100 mg/kg/d)和7天氟康唑(1200 mg/d)。主要终点是10周时的全因死亡率，非劣效度分别为10%和90%。次要终点是早期杀菌活性、III/IV级不良事件的比例、药代动力学参数和药代动力学/药效学关联、卫生服务成本、前两周和四周内的全因死亡率、前十周内的全因死亡率(优势分析)以及十周内CM复发、免疫重建炎症综合征和致残率。总共有850名年龄在18岁、首次出现≥ 相关CM的患者将被登记(每组随机425人)。所有患者将接受为期16周的随访。所有患者均接受氟康唑800 mg/d的巩固治疗，完成10周的治疗，随后按当地指导进行氟康唑维持和ART治疗。一种安全、可持续和易于管理的L-AMB方案，不低于每天7天的两性霉素B脱氧胆酸盐治疗，可能会减少接受两性霉素B脱氧胆酸盐治疗的患者出现的不良事件数量，并缩短住院时间，为目前世卫组织推荐的一线治疗提供了一个非常有利和可实施的替代方案。ISRCTN，ISRCTN72509687。注册日期为2017年7月13日。本文的在线版本(10.1186/s13063-0183026-4)包含向授权用户提供的补充材料。
Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. ISRCTN, ISRCTN72509687. Registered on 13 July 2017. The online version of this article (10.1186/s13063-018-3026-4) contains supplementary material, which is available to authorized users.
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DOI：
10.1016/s1473-3099(10)70170-5
发表时间：
2010-11
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Haddow LJ;Colebunders R;Meintjes G;Lawn SD;Elliott JH;Manabe YC;Bohjanen PR;Sungkanuparph S;Easterbrook PJ;French MA;Boulware DR;International Network for the Study of HIV-associated IRIS (INSHI)
通讯作者：
International Network for the Study of HIV-associated IRIS (INSHI)
影响因子：
168.9
作者：
Brouwer, AE;Rajanuwong, A;Harrison, TS
通讯作者：
Harrison, TS
影响因子：
5.2
作者：
Vogelsinger, Helene;Weiler, Stefan;Bellmann, Romuald
通讯作者：
Bellmann, Romuald
影响因子：
4.3
作者：
Mehta, P;Vinks, A;Davies, S
通讯作者：
Davies, S
影响因子：
3.7
作者：
Jarvis JN;Meintjes G;Williams A;Brown Y;Crede T;Harrison TS
通讯作者：
Harrison TS