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: 10364704
• 负责人: David R Boulware
• 金额: $ 62.6万
• 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/10364704
• 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

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的人的机会性感染的常见原因。之中 最严重的感染是真菌脑膜炎。隐球菌脑膜炎是成人的最常见原因 非洲的脑膜炎和加密环球在全球范围内导致15％的与艾滋病相关的死亡率。 两性霉素B组合抗真菌是推荐的隐球菌脑膜炎治疗。然而， 在南非以外的撒哈拉以南非洲，两性霉素在常规护理中很少获得。障碍 两性霉素的可用性和使用包括4⁰C，IV施用和毒性的冷链运输和存储。 在美国，IV两性霉素管理的必要条件延长了住院，增加了成本。 然而，已经开发了一种创新的口服吸收性两性霉素B（CAMB）。在 简而 通过单核细胞和巨噬细胞进行靶向细胞内递送。这样的CAMB可实现高细胞内 吞噬酵母但细胞外浓度较低的浓度，导致最少 系统性和肾毒性。在壁内NIH小鼠研究中，氟胞嘧啶以25 mg/kg/天的口服CAMB具有 与注射两性霉素和氟胞嘧啶相似的生存期，这被认为是治疗的目标标准。 人类第一阶段的单一升剂剂量研究已在美国完成200-800mg剂量 仅在800mg时观察到的单剂量，仅观察到的轻度GI副作用。正在进行的 NIH慢性粘膜念珠菌病（n = 3）的NIH II期试验患有Hyper-IgE综合征 已经证明了每天1-2倍（即800毫克/天）的安全性和效率> 12个月。 我们建议进行I阶段多升剂量查找试验，以确定药代动力学，安全性， CAMB的口服耐受性在非洲人每天以多剂量施用。第二，我们将进行 第二阶段试验将8周的安全性和耐受性作为巩固疗法。第三，我们将调查 CAMB对乌干达人患有隐球菌脑膜炎的CSF加密赛清除率的微生物学作用。 具体目的： 1。确定多种剂量给定的口服CAMB的药代动力学，安全性和耐受性 每天发现最大安全可容忍的每日剂量。 2。确定用于隐球菌脑膜炎的长期安全性和口服CAMB的效率 脑膜炎诊断后2至10周合并抗真菌疗法。 3。确定一个经过封闭的口服CAMB是否达到了CSF加密赛清除率的非内部率 与艾滋病毒感染的乌干达人患有隐球菌脑膜炎的IV两性霉素B相比。 假设：我们假设CAMB以〜25mg/kg/天的分裂剂量耐受性良好，口服吸收 与静脉内脑膜炎中的IV两性霉素相比，CSF灭菌的速率将非内部抗性。