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。之间 最严重的感染是真菌性脑膜炎。隐球菌性脑膜炎是成人最常见的病因 隐球菌在非洲引起脑膜炎，而隐球菌在全球艾滋病相关死亡率中占15%。 两性霉素B联合抗真菌药物是隐球菌性脑膜炎的推荐治疗方法;然而， 在南非以外的撒哈拉以南非洲地区，在常规护理中很少能获得阿替西霉素。壁垒 阿替西霉素的可用性和使用包括冷链运输和在4 ℃下储存，IV给药和毒性。 在美国，静脉给药的必要性导致住院，增加了费用。 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）。在 简单地说，这是一种包裹在大豆脂蛋白（即脂质卷）中的黄曲霉素B， 通过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 浓度的吞噬酵母驻留，但低细胞外浓度，导致最小的 全身和肾毒性。在NIH小鼠壁内研究中，25 mg/kg/天cAMB与氟胞嘧啶联合经口给药， 与注射阿替沙星和氟胞嘧啶相似的存活率，这被认为是治疗的目标标准。 已在美国完成了人体I期单次剂量递增研究，其中200- 800 mg剂量 耐受性良好，在800 mg单次给药时仅观察到轻度GI副作用。正在进行的 高IgE Job综合征患者慢性皮肤粘膜念珠菌病的NIH II期试验（n=3） 已经证明了400 mg cAMB每日1- 2次（即高达800 mg/天）服用>12个月的安全性和有效性。 我们建议进行I期多次剂量递增探索试验，以确定药代动力学、安全性， 和非洲人每天多次给予cAMB的口服耐受性。第二，我们会进行一项 II期试验旨在研究巩固治疗的8周安全性和耐受性。第三，我们将调查 cAMB对乌干达隐球菌性脑膜炎患者脑脊液隐球菌清除率的微生物学影响 具体目标： 1.确定多次给药的encoacidated口服cAMB的药代动力学、安全性和耐受性 以发现最大安全和耐受的每日剂量。 2.确定口服cAMB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 ~ 10周巩固抗真菌治疗。 3.确定是否encomerated口服cAMB达到CSF隐球菌清除率的非劣效性， 与IV阿替霉素B相比，在HIV感染的乌干达隐球菌脑膜炎患者中。 假设：我们假设cAMB在约25 mg/kg/天的分次剂量下耐受良好，经口吸收 并且在隐球菌性脑膜炎中，与静脉注射阿替沙星相比，其CSF灭菌率不劣于阿替沙星。