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

真菌感染是免疫功能低下者机会性感染（OI）的常见原因。最严重的HIV/AIDS相关的OIs是真菌性脑膜炎。隐球菌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）阿替霉素B联合口服氟胞嘧啶（5 FC）治疗隐球菌性脑膜炎;然而，在许多资源有限的环境中，阿替霉素很少用于常规护理。可用性的障碍包括冷链运输、4 ℃储存、IV给药和毒性。即使在资源丰富的环境中，如美国，IV治疗和强化毒性监测的必要性延长了住院时间，增加了医疗保健成本和医院感染的风险。 然而，已经开发了一种创新的口服吸收的包封的阿替西汀B（cAMB）。口服cAMB是包裹在基于大豆的脂蛋白（即脂质卷）中的阿替霉素B，其被单核细胞/巨噬细胞吸收并摄取，用于靶向细胞内递送。cAMB在吞噬的酵母驻留的地方达到高细胞内浓度，但细胞外浓度低，导致毒性最小。 我们已经在乌干达完成了隐球菌脑膜炎的I期和II期人体试验，其中每日1.8g口服cAMB的分次剂量耐受性良好，只有轻微的胃肠道副作用。两个标准的IV阿替霉素B负荷剂量，然后所有口服cAMB治疗6周，与5 FC联合治疗，我们实现了97.5%（39/40）的30天生存率和90%（36/40）的18周生存率。 我们建议进行一项III期多中心随机临床试验，作为关键的FDA注册试验，以确定cAMB用于HIV相关隐球菌脑膜炎初始治疗的有效性和安全性。具体目标1。确定在HIV相关隐球菌性脑膜炎中，与静脉注射阿替西霉素B和5 FC相比，阿替西霉素B（cAMB）口服制剂和5 FC是否具有非劣效性生存率。具体目标2。测定口服cAMB的CSF酵母菌清除率，以量化其机制活性。具体目标3。确定口服cAMB是否具有优于IV阿替霉素B的安全性特征。假设：我们假设：1）口服cAMB将具有非劣效性的14天和18周生存期，满足FDA可接受的<10%的非劣效性界值; 2）CSF早期杀真菌活性将在2周内>0.30 log 10隐球菌菌落形成单位（CFU）/mL CSF/天; 3）口服cAMB将具有统计学上更低的>3级急性肾损伤、贫血、低钾血症和低钠血症的发生率。影响：该临床试验的结果有可能将第一种口服阿替霉素B制剂推向全球市场，大大扩展了目前在世界各地资源有限的环境中对许多隐球菌病患者不可用的金标准治疗，并使门诊阿替霉素治疗成为可能。

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.