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。与艾滋病毒/艾滋病相关的最严重的oi是真菌性脑膜炎。隐球菌性脑膜炎是非洲成人脑膜炎最常见的原因，占全球艾滋病毒/艾滋病相关死亡的约15%。对于隐球菌性脑膜炎，建议静脉注射两性霉素B联合口服氟胞嘧啶（5FC）；然而，在许多资源有限的环境中，两性霉素很少用于常规护理。可用性的障碍包括冷链运输、4⁰C储存、静脉注射和毒性。即使在像美国这样资源丰富的环境中，静脉注射治疗和强化毒性监测的必要性也延长了住院时间，增加了医疗成本和院内感染的风险。然而，一种创新的口服吸收两性霉素B （cAMB）已经被开发出来。口服cAMB是两性霉素B包裹在大豆基脂蛋白（即耳蜗酸盐）中，被单核细胞/巨噬细胞吸收和摄取，用于靶向细胞内递送。cAMB在被吞噬的酵母菌所在的细胞内达到高浓度，但在细胞外达到低浓度，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，每天分次服用1.8g口服cAMB耐受性良好，只有轻微的胃肠道副作用。通过两次标准的静脉两性霉素B负荷剂量，随后全部口服cAMB治疗，联合5FC治疗6周，我们获得了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期多地点随机临床试验，作为FDA注册试验的关键，以确定cAMB初始治疗hiv相关隐球菌性脑膜炎的有效性和安全性。具体目标确定口服两性霉素B （cAMB）加5FC制剂与静脉两性霉素B加5FC治疗hiv相关隐球菌性脑膜炎相比，是否能获得非劣势生存期。具体目标2。测定口服cAMB的CSF酵母清除率，量化其机制活性。具体目标3。确定口服cAMB与静脉两性霉素b相比是否具有更高的安全性假设：我们假设：1)口服cAMB将具有非劣势的14天和18周生存期，满足<10%的非劣效边际，FDA可接受；2) 2周后，脑脊液早期杀真菌活性为100 - 0.30 log10隐球菌菌落形成单位(CFU)/mL CSF/天；3)口服cAMB对bbbb3级急性肾损伤、贫血、低钾血症和低钠血症的发生率有统计学意义上的降低。影响：该临床试验的结果有可能将首个口服两性霉素B制剂推向全球市场，大大扩大目前在世界各地资源有限的环境中无法获得的金标准治疗，并使门诊两性霉素治疗成为可能。