Encochleated Oral Amphotericin for HIV-related Cryptococcal Meningitis Trial: Phase 3 Trial

真菌感染是免疫缺陷患者机会性感染(OIS)的常见原因。与艾滋病毒/艾滋病相关的最严重的OIS是真菌性脑膜炎。隐球菌性脑膜炎是非洲成人脑膜炎的最常见原因，占全球艾滋病毒/艾滋病相关死亡的约15%。推荐静脉注射(IV)两性霉素B和口服氟胞嘧啶(5FC)治疗隐球菌性脑膜炎；然而，在许多资源有限的情况下，两性霉素很少在常规护理中使用。供应障碍包括冷链运输、4⁰C储存、静脉给药和毒性。即使在美国这样资源丰富的地区，静脉注射治疗和密集毒性监测的必要性也延长了住院时间，增加了医疗成本和医院感染的风险。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。口服Camb是包裹在大豆基脂蛋白(即耳蜗酸盐)中的两性霉素B，它被单核/巨噬细胞吸收和摄取，在细胞内进行靶向递送。Camb在吞噬酵母所在的细胞内达到较高的浓度，但在细胞外浓度较低，导致毒性最小。我们已经在乌干达完成了隐球菌性脑膜炎的第一阶段和第二阶段人体试验，在乌干达，每天分两次服用1.8g Camb的耐受性很好，只有轻微的GI副作用。用两个标准剂量的两性霉素B，然后口服Camb治疗6周，联合5FC，30天存活率97.5%(39/40)，18周存活率90%(36/40)。我们建议进行一项III期多点随机临床试验，作为FDA的一项关键注册试验，以确定Camb用于HIV相关性隐球菌性脑膜炎初始治疗的有效性和安全性。具体目的1.确定含5FC的两性霉素B(Camb)口服制剂与含5FC的静脉注射两性霉素B相比，在治疗HIV相关的隐球菌性脑膜炎方面是否获得了非劣质的生存。具体目的2.测定口腔分枝杆菌的脑脊液酵母菌清除率，以量化其机械活性。具体目的3.确定口腔Camb是否具有比静脉注射两性霉素B更好的安全性假设：我们假设1)口腔Camb将具有非劣质的14天和18周的存活率，满足&lt；10%的非劣质边缘，FDA可以接受；2)CSF的早期杀菌活性将是&gt；0.30log10隐球菌落形成单位(CFU)/毫升CSF/天超过2周；3)口腔Camb将有统计学上较低的发生率；3)急性肾损伤、贫血、低钾和低钠血症。影响：这项临床试验的结果有可能将第一个口服两性霉素B制剂推向全球市场，极大地扩大目前世界各地资源有限的许多隐球菌病患者无法获得的黄金标准疗法，并使门诊两性霉素疗法成为可能。

Fungal infections are a common cause of opportunistic infections (OIs) in immunocompromised persons. Among the most severe HIV/AIDS-related OIs are fungal meningitis. Cryptococcal meningitis is the most common cause of adult meningitis in Africa and accounts for ~15% of HIV/AIDS-related deaths globally. Intravenous (IV) amphotericin B with oral flucytosine (5FC) is recommended for cryptococcal meningitis; however, in many resource-limited settings amphotericin is rarely available in routine care. Barriers to availability include cold chain shipping, storage at 4⁰C, IV administration, and toxicity. Even in resource-rich settings like the United States, the necessity of IV therapy and intensive toxicity monitoring prolong hospitalization, increasing both healthcare costs and risks of nosocomial infections. However, an innovative orally-absorbed encochleated amphotericin B (cAMB) has been developed. Oral cAMB is amphotericin B wrapped in a soy-based lipoprotein (i.e. cochleate) that is absorbed and taken up by monocytes/macrophages for targeted intra-cellular delivery. cAMB achieves high intracellular concentrations where the phagocytosed yeast reside but low extracellular concentrations, resulting in minimal toxicity. We have completed Phase I and Phase II human trials in cryptococcal meningitis in Uganda where divided daily doses of 1.8g of oral cAMB were well tolerated with only mild GI side effects. With two standard IV amphotericin B loading doses followed by all oral cAMB therapy through 6 weeks in combination with 5FC, we achieved 97.5% (39/40) 30-day survival and 90% (36/40) 18-week survival. We propose to conduct a phase III multi-site randomized clinical trial as a pivotal FDA registrational trial to determine efficacy and safety of cAMB for initial therapy for HIV-related cryptococcal meningitis. Specific Aim 1. Determine if an encochleated oral formulation of amphotericin B (cAMB) with 5FC achieves non-inferior survival compared with IV amphotericin B with 5FC for HIV-related cryptococcal meningitis. Specific Aim 2. Determine the CSF yeast clearance rate of oral cAMB to quantify its mechanistic activity. Specific Aim 3. Determine if oral cAMB has a superior safety profile as compared to IV amphotericin B. Hypotheses: We hypothesize that 1) oral cAMB will have non-inferior 14-day and 18-week survival, meeting <10% non-inferiority margin, acceptable to FDA; 2) the CSF early fungicidal activity will be >0.30 log10 Cryptococcus colony forming units (CFU)/mL CSF/day over 2 weeks; 3) oral cAMB will have statistically lower incidence of Grade >3 acute kidney injury, anemia, hypokalemia, and hyponatremia. Impact: The results of this clinical trial have the potential to bring the first oral amphotericin B formulation to the global market, substantially expanding a gold-standard treatment currently unavailable for many with cryptococcosis in resource-limited settings around the world and enable outpatient amphotericin therapy.