Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial

真菌感染是免疫受损人群机会性感染的常见原因。其中 最严重的感染是真菌性脑膜炎。隐球菌性脑膜炎是成人最常见的致病原因 在非洲，脑膜炎和隐球菌导致了全球15%的艾滋病相关死亡。 两性霉素B联合抗真菌药物是治疗隐球菌性脑膜炎的推荐疗法；然而， 在除南非以外的撒哈拉以南非洲地区，两性霉素很少在常规护理中使用。障碍： 两性霉素的可获得性和用途包括冷链运输和4⁰C储存、静脉给药和毒性。 在美国，静脉注射两性霉素的必要性延长了住院时间，增加了成本。 然而，一种创新的口服吸收的两性霉素B(Camb)已经被开发出来。在……里面 简而言之，这是两性霉素B，包裹在大豆基脂蛋白(即耳蜗酸盐)中，被吸收和吸收 通过单核细胞和巨噬细胞进行细胞内靶向递送。因此，Camb实现了高胞内 吞噬酵母驻留的浓度，但胞外浓度低，导致最低 全身毒性和肾脏毒性。在NIH小鼠的壁内研究中，Camb以每天25 mg/kg的剂量口服氟胞嘧啶有 存活率与注射两性霉素和氟胞嘧啶相似，后者被认为是治疗的目标标准。 美国已经完成了人体I期单次递增剂量研究，剂量为200-800毫克 耐受性良好，单次给药800毫克时仅观察到轻微的胃肠道副作用。一个正在进行的 NIH对患有高IgE工作综合征患者的慢性皮肤粘膜念珠菌病的II期试验(n=3) 已经证明了400 mg Camb的安全性和有效性，每天服用1-2次(即每天高达800 mg)，持续12个月。 我们建议进行第一阶段多次递增剂量发现试验，以确定药物动力学、安全性、 非洲人每天多次服用Camb的口服耐受性。第二，我们将开展一项 II期试验，研究作为巩固治疗的8周安全性和耐受性。第三，我们将调查 Camb对患有隐球菌性脑膜炎的乌干达人脑脊液隐球菌清除率的微生物学影响。 具体目标： 1.测定多次给药的包衣口服Camb的药代动力学、安全性和耐受性 每天发现最大安全和可耐受的每日剂量。 2.确定口服Camb治疗隐球菌性脑膜炎的长期安全性和有效性 脑膜炎确诊后2-10周巩固抗真菌治疗。 3.确定编织的口腔分枝杆菌是否达到脑脊液隐球菌清除率为 在患有隐球菌性脑膜炎的艾滋病毒感染的乌干达人中与静脉注射两性霉素B进行比较。 假设：我们假设Camb的耐受性很好，每天分剂量口服吸收~25 mg/kg 与静脉注射两性霉素相比，对隐球菌性脑膜炎的脑脊液灭菌率并不逊色。

Fungal infections are a common cause of opportunistic infections in immunocompromised persons. Among the most severe infections is fungal meningitis. Cryptococcal meningitis is the most common cause of adult meningitis in Africa, and Cryptococcus causes 15% of AIDS-related mortality globally. Amphotericin B combination antifungal is the recommended therapy for cryptococcal meningitis; however, in Sub-Saharan Africa outside of South Africa, amphotericin is rarely available in routine care. Barriers to amphotericin availability and use include cold chain shipping and storage at 4⁰C, IV administration, and toxicity. In the United States, the necessity on IV amphotericin administration prolongs hospitalization, increasing costs. However, an innovative orally-absorbed encochleated amphotericin B (cAMB) has been developed. In brief, this is amphotericin B wrapped in a soy-based lipoprotein (i.e. cochleate) that is absorbed and taken up by monocytes and macrophages for targeted intra-cellular delivery. As such cAMB achieves high intracellular concentrations where the phagocytosed yeast reside but low extracellular concentrations, resulting in minimal systemic and nephrotoxicity. In intramural NIH mouse studies, oral cAMB at 25 mg/kg/day with flucytosine has similar survival as injected amphotericin and flucytosine, which is considered the goal standard of therapy. Human phase I single ascending dose studies have been completed in the U.S. where 200-800mg doses have been well tolerated with only mild GI side effects observed at 800mg given as a single dose. An ongoing NIH phase II trial of chronic mucocutaneous candidiasis (n=3) in persons living with hyper-IgE Job syndrome has demonstrated safety and efficacy of 400mg cAMB taken 1-2x daily (i.e. up to 800mg/day) for >12 months. We propose to conduct phase I multiple ascending dose finding trial to determine pharmacokinetics, safety, and oral tolerability of cAMB administered in multiple doses per day in Africans. Second, we will conduct a phase II trial to investigate the 8-week safety and tolerability as consolidation therapy. Third, we will investigate microbiologic effects of cAMB on CSF Cryptococcus clearance rate in Ugandans with cryptococcal meningitis. Specific Aims: 1. Determine the pharmacokinetic, safety, and tolerability of encochleated oral cAMB given in multiple doses per day to discover the maximum safe and tolerable daily dose. 2. Determine the longer-term safety and efficacy of oral cAMB when used for cryptococcal meningitis consolidation antifungal therapy from 2 to 10 weeks after meningitis diagnosis. 3. Determine if an encochleated oral cAMB achieves non-inferior rate of CSF Cryptococcus clearance as compared to IV amphotericin B in HIV-infected Ugandans with cryptococcal meningitis. Hypotheses: We hypothesize that cAMB is well tolerated at ~25mg/kg/day in divided doses, orally absorbed and will have a non-inferior rate of CSF sterilization compared with IV amphotericin in cryptococcal meningitis.