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

包埋口服两性霉素治疗 HIV 相关隐球菌性脑膜炎试验：3 期试验

• 批准号: 10619788
• 负责人: David R Boulware
• 金额: $ 214.51万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10619788
• 关键词: AIDS-Related Opportunistic Infections; Acquired Immunodeficiency Syndrome; Acute Renal Failure with Renal Papillary Necrosis; Adult; Africa; Africa South of the Sahara; Amphotericin; Amphotericin B; Anemia; Antifungal Agents; Aspergillus; Blastomycosis; Botswana; Candida auris; Care given by nurses; Caring; Central Nervous System; Central Nervous System Infections; Cessation of life; Clinical Trials; Cold Chains; Colony-forming units; Consolidation Therapy; Control Groups; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Data; Dose; Drug Delivery Systems; Electricity; Failure; Fluconazole; Flucytosine; Formulation; Fungal Meningitis; Future; Goals; HIV; HIV antiretroviral; HIV therapy; HIV/AIDS; Health; Health Care Costs; Histoplasmosis; Hospitalization; Hospitals; Human; Hypokalemia; Hyponatremia; Immunocompromised Host; Incidence; International; Intravenous; Laboratories; Lipoproteins; Macrophage; Marketing; Meningitis; Metabolic Clearance Rate; Modeling; Monitor; Morbidity - disease rate; Mycoses; National Institute of Allergy and Infectious Disease; Neoadjuvant Therapy; Neurologic; Neurological outcome; Nosocomial Infections; Opportunistic Infections; Oral; Outpatients; Persons; Phase; Plasma; Randomized; Recommendation; Regimen; Relapse; Resistant candida; Resource-limited setting; Resources; Risk; Safety; Sample Size; Shipping; Site; South Africa; Survivors; Testing; Time; Toxic effect; Uganda; United States; United States National Institutes of Health; Yeasts; absorption; antiretroviral therapy; attributable mortality; clinical application; clinical care; cohort; data modeling; deoxycholate; disability; efficacy evaluation; experimental arm; extracellular; fungicide; fungus; improved; innovation; intravenous administration; low and middle-income countries; meetings; monocyte; mortality; mouse model; novel; novel therapeutics; nursing skill; phase II trial; phase III trial; pre-clinical; randomized trial; randomized, clinical trials; routine care; side effect; soy; standard care; standard of care; technology platform

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.

真菌感染是免疫功能低下者机会性感染 (OIs) 的常见原因，其中最严重的艾滋病毒/艾滋病相关的 OIs 是真菌性脑膜炎，它是非洲成人脑膜炎的最常见原因，约占艾滋病毒的 15%。 /全球范围内与艾滋病相关的死亡被推荐用于治疗隐球菌性脑膜炎；在许多资源有限的地区，两性霉素在常规护理中很少获得，其获取障碍包括冷链运输、4°C 储存、静脉注射和毒性，即使在美国等资源丰富的地区，也需要静脉注射治疗和强化治疗。毒性监测延长了住院时间，增加了医疗费用和医院感染的风险。然而，一种创新的口服吸收型两性霉素 B (cAMB) 已被开发出来。两性霉素 B 包裹在大豆基脂蛋白（即耳蜗）中，被单核细胞/巨噬细胞吸收并摄取，用于靶向细胞内递送，在被吞噬的酵母所在的细胞内达到高浓度，但细胞外浓度较低，从而产生最小的毒性。我们已在乌干达完成了针对隐球菌性脑膜炎的 I 期和 II 期人体试验，每日分剂量 1.8g 口服 cAMB 耐受性良好仅具有轻微的胃肠道副作用。使用两种标准 IV 两性霉素 B 负荷剂量，然后联合 5FC 进行 6 周的所有口服 cAMB 治疗，我们实现了 97.5% (39/40) 的 30 天生存率和 90% (36/40)。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 相关初始治疗的有效性和安全性。具体目标 1. 确定两性霉素 B (cAMB) 与 5FC 的包埋口服制剂与 IV 两性霉素 B 与 5FC 相比，对于 HIV 相关的隐球菌性脑膜炎是否具有非较差的存活率。 具体目标 2. 确定 CSF 酵母菌清除率。口服 cAMB 来量化其机械活性。 具体目标 3. 确定口服 cAMB 是否存在。与静脉注射两性霉素 B 相比，具有优越的安全性。假设：我们认为 1) 口服 cAMB 将具有非劣效的 14 天和 18 周生存率，满足 FDA 可接受的 <10% 非劣效裕度 2)； CSF 早期杀菌活性将在 2 周内 >0.30 log10 隐球菌菌落形成单位 (CFU)/mL CSF/天 3)；口服 cAMB 将显着降低 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个口服两性霉素 B 制剂推向全球市场，从而大幅扩大黄金市场。 -目前在世界各地资源有限的环境中，许多隐球菌病患者无法获得标准治疗，并且可以进行门诊两性霉素治疗。