Molefi Mooketsi, Chofle Awilly A, Molloy Síle F, Kalluvya Samuel, Changalucha John M, Cainelli Francesca, Leeme Tshepo, Lekwape Nametso, Goldberg Drew W, Haverkamp Miriam, Bisson Gregory P, Perfect John R, Letang Emili, Fenner Lukas, Meintjes Graeme, Burton Rosie, Makadzange Tariro, Ndhlovu Chiratidzo E, Hope William, Harrison Thomas S, Jarvis Joseph N
Department of Family Medicine and Public Health, Faculty of Medicine, University of Botswana, P.O.Box 1357 ABG, Gaborone, Botswana.
Botswana-Upenn Partnership, Gaborone, Botswana.
Trials. 2015 Jun 17;16:276. doi: 10.1186/s13063-015-0799-6.
Cryptococcal meningitis (CM) is a leading cause of mortality among HIV-infected individuals in Africa. Poor outcomes from conventional antifungal therapies, unavailability of flucytosine, and difficulties administering 14 days of amphotericin B are key drivers of this mortality. Novel treatment regimes are needed. This study examines whether short-course high-dose liposomal amphotericin B (AmBisome), given with high dose fluconazole, is non-inferior (in terms of microbiological and clinical endpoints) to standard-dose 14-day courses of AmBisome plus high dose fluconazole for treatment of HIV-associated CM.
METHODOLOGY/DESIGN: This is an adaptive open-label phase II/III randomised non-inferiority trial comparing alternative short course AmBisome regimens. Step 1 (phase II) will compare four treatment arms in 160 adult patients (≥ 18 years old) with a first episode of HIV-associated CM, using early fungicidal activity (EFA) as the primary outcome: 1) AmBisome 10 mg/kg day one (single dose); 2) AmBisome 10 mg/kg day one and AmBisome 5 mg/kg day three (two doses); 3) AmBisome 10 mg/kg day one, and AmBisome 5 mg/kg days three and seven (three doses); and 4) AmBisome 3 mg/kg/d for 14 days (control); all given with fluconazole 1200 mg daily for 14 days. STEP 2 (phase III) will enrol 300 participants and compare two treatment arms using all-cause mortality within 70 days as the primary outcome: 1) the shortest course AmBisome regimen found to be non-inferior in terms of EFA to the 14-day control arm in STEP 1, and 2) AmBisome 3 mg/kg/d for 14 days (control), both given with fluconazole 1200 mg daily for 14 days. STEP 2 analysis will include all patients from STEP 1 and STEP 2 taking the STEP 2 regimens. All patients will be followed for ten weeks, and mortality and safety data recorded. All patients will receive consolidation therapy with fluconazole 400-800 mg daily and ART in accordance with local guidelines. The primary analysis (for both STEP 1 and STEP 2) will be intention-to-treat.
ISRCTN10248064. Date of Registration: 22 January 2014.
隐球菌性脑膜炎（CM）是非洲艾滋病毒感染者死亡的主要原因。传统抗真菌治疗效果不佳、氟胞嘧啶无法获取以及难以给予14天的两性霉素B是导致这种死亡率的关键因素。需要新的治疗方案。本研究旨在探讨短疗程高剂量脂质体两性霉素B（安必素）联合高剂量氟康唑治疗与标准剂量14天疗程的安必素加氟康唑治疗艾滋病毒相关CM相比，在微生物学和临床终点方面是否非劣效。
方法/设计：这是一项适应性开放标签的II/III期随机非劣效性试验，比较替代短疗程安必素方案。第一步（II期）将在160名首次发作艾滋病毒相关CM的成年患者（≥18岁）中比较四个治疗组，以早期杀菌活性（EFA）作为主要结局：1）第1天给予安必素10mg/kg（单剂量）；2）第1天给予安必素10mg/kg，第3天给予安必素5mg/kg（两剂量）；3）第1天给予安必素10mg/kg，第3天和第7天给予安必素5mg/kg（三剂量）；4）安必素3mg/kg/d，共14天（对照组）；所有治疗均联合氟康唑1200mg，每日一次，共14天。第二步（III期）将招募300名参与者，以70天内全因死亡率作为主要结局比较两个治疗组：1）在第一步中发现EFA方面非劣于14天对照组的最短疗程安必素方案，2）安必素3mg/kg/d，共14天（对照组），两者均联合氟康唑1200mg，每日一次，共14天。第二步分析将包括第一步和第二步中接受第二步方案的所有患者。所有患者将随访十周，并记录死亡率和安全性数据。所有患者将根据当地指南接受氟康唑400 - 800mg每日的巩固治疗和抗逆转录病毒治疗。主要分析（第一步和第二步）将采用意向性分析。
ISRCTN10248064。注册日期：2014年1月22日。
