Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial

包埋口服两性霉素治疗隐球菌性脑膜炎试验

• 批准号: 10163929
• 负责人: David R Boulware
• 金额: $ 63.22万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163929
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Africa; Africa South of the Sahara; African; Amphotericin; Amphotericin B; Antifungal Agents; Antifungal Therapy; Aspergillus; Blastomycosis; Botswana; Candida auris; Care given by nurses; Caring; Central Nervous System Infections; Cessation of life; Chronic Mucocutaneous Candidiasis; Cold Chains; Combined Modality Therapy; Consolidation Therapy; Control Groups; Country; Cryptococcal Meningitis; Cryptococcus; Data; Diagnosis; Dose; Drug Kinetics; Electricity; Failure; Fluconazole; Flucytosine; Formulation; Fungal Meningitis; Future; Goals; Gold; HIV; HIV antiretroviral; Histoplasmosis; Hospitalization; Hospitals; Human; IgE; Immunocompromised Host; Incidence; Industrial fungicide; Infection; International; Intravenous; Job' s Syndrome; Laboratories; Lipoproteins; Liposomes; Medicine; Meningitis; Metabolic Clearance Rate; Microbiology; Modeling; Monitor; Morbidity - disease rate; Mycoses; NIH Mouse; National Institute of Allergy and Infectious Disease; Neoadjuvant Therapy; Neurologic; Neurological outcome; Opportunistic Infections; Oral; Outpatients; Persons; Phase; Phase I/II Trial; Phase III Clinical Trials; Prophylactic treatment; Randomized; Resistant candida; Resources; Safety; Sample Size; Shipping; South Africa; Sterilization; Surrogate Endpoint; Survivors; Testing; Time; Toxic effect; Transplant Recipients; Uganda; United States; United States National Institutes of Health; Work; Yeasts; antiretroviral therapy; attributable mortality; base; clinical application; clinical care; cost; data modeling; deoxycholate; disability; extracellular; fungus; improved; innovation; macrophage; monocyte; mortality; mouse model; nephrotoxicity; novel; phase 2 study; phase I trial; phase II trial; routine care; side effect; soy; standard of care; virology

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.

真菌感染是免疫功能低下者机会性感染的常见原因。之中 最严重的感染是真菌性脑膜炎。隐球菌性脑膜炎是成人脑膜炎的最常见原因 非洲的脑膜炎和隐球菌导致了全球 15% 的艾滋病相关死亡率。 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， 在南非以外的撒哈拉以南非洲地区，两性霉素很少用于常规护理。障碍 两性霉素的可用性和使用包括冷链运输和 4°C 储存、静脉注射给药和毒性。 在美国，静脉注射两性霉素的必要性延长了住院时间，增加了费用。 然而，一种创新的口服吸收型两性霉素 B (cAMB) 已被开发出来。在 简而言之，这是包裹在大豆基脂蛋白（即蜗壳）中的两性霉素 B，可被吸收和摄取 由单核细胞和巨噬细胞进行靶向细胞内递送。因此，cAMB 实现了高细胞内 吞噬酵母所在的浓度，但细胞外浓度较低，导致最小 全身和肾毒性。在 NIH 小鼠壁内研究中，口服 25 mg/kg/天的 cAMB 与氟胞嘧啶具有 与注射两性霉素和氟胞嘧啶的生存率相似，这被认为是治疗的目标标准。 人类 I 期单剂量递增研究已在美国完成，剂量为 200-800 毫克 单剂量 800mg 时，耐受性良好，仅观察到轻微的胃肠道副作用。正在进行的 NIH 对高 IgE 乔布综合征患者进行慢性皮肤粘膜念珠菌病 (n=3) 的 II 期试验 已证明每天服用 1-2 次（即最多 800 毫克/天）400 毫克 cAMB 的安全性和有效性，持续时间 > 12 个月。 我们建议进行 I 期多次递增剂量探索试验，以确定药代动力学、安全性、 以及非洲人每天多次服用 cAMB 的口服耐受性。其次，我们将进行 II 期试验旨在调查 8 周巩固治疗的安全性和耐受性。三、我们将进行调查 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. 确定多剂量口服 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 用于治疗隐球菌性脑膜炎的长期安全性和有效性 脑膜炎诊断后 2 至 10 周进行巩固抗真菌治疗。 3. 确定加蜗壳的口服 cAMB 是否能达到 CSF 隐球菌清除率的非劣效： 与 IV 两性霉素 B 治疗患有隐球菌性脑膜炎的 HIV 感染乌干达人相比。 假设：我们假设 cAMB 在约 25 毫克/公斤/天的剂量下具有良好的耐受性，口服吸收 与静脉注射两性霉素治疗隐球菌性脑膜炎相比，其脑脊液灭菌率不逊色。