Prevention of Invasive Candidiasis: PK, Safety, and Neurodevelopmental Outcomes

预防侵袭性念珠菌病：PK、安全性和神经发育结果

• 批准号: 7436384
• 负责人: DANIEL K. BENJAMIN
• 金额: $ 71.98万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-20 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7436384
• 关键词: Adult; Age; Amphotericin B; Amphotericin B Liposomal; Anidulafungin; Antifungal Agents; Antifungal Therapy; Appointment; Benefits and Risks; Birth; Birth Weight; Blood; Blood specimen; Body Fluids; Brain; Candida; Candidiasis; Caring; Cessation of life; Childhood; Clinical; Clinical Research; Clinical Trials; Collaborations; Committee Members; Communicable Diseases; Completion Status; Data; Diagnosis; Disease; Dose; Drug Kinetics; Early Diagnosis; End Point; Enrollment; Environment; Epidemiology; Etiology; Failure; Feces; Fluconazole; Foundations; Fungal Drug Resistance; Future; Hearing; Immunocompromised Host; Impairment; Incidence; Infant; Infant Development; Infection; Inguinal region; Institutes; Invasive; Joints; Label; Left; Life; Measures; Medical; Methods; Micafungin; Minimum Inhibitory Concentration measurement; Monitor; Morbidity - disease rate; Nasopharynx; National Center for Research Resources; Neonatal; Neonatal Intensive Care Units; Neurodevelopmental Impairment; Neurologic; Newborn Infant; Numbers; Nurseries; Outcome; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pilot Projects; Placebos; Population; Premature Infant; Prevention; Prophylactic treatment; Protocols documentation; Public Health; Randomized; Randomized Controlled Clinical Trials; Recommendation; Recording of previous events; Rectum; Research; Research Contracts; Research Institute; Resistance; Resistance development; Risk; Safety; Serious Adverse Event; Site; Sterility; Survivors; Testing; The science of Mycology; Translational Research; Tube; Umbilicus; United States; United States Food and Drug Administration; Universities; Upper arm; Urine; Vision; Week; Work; base; cohort; concept; data management; day; design; dosage; drug development; endotracheal; experience; follow-up; member; mortality; neonate; older patient; prevent; prophylactic; prospective; skills

DESCRIPTION (provided by applicant): The most common etiology of infection-related death or neurodevelopmental impairment in neonates with birthweight <750 g is invasive candidiasis. Invasive candidiasis is diagnosed by positive culture for Candida sp. from normally sterile body fluid. Over 70% of the premature infants who develop invasive candidiasis will die or suffer severe, permanent neurologic impairment. The highest-risk infants are the very young: the cumulative incidence in neonates with birthweight <750 g is 16%, and most of these infants experience infection by day of life 49. It has been shown that invasive candidiasis is safely prevented by administering fluconazole prophylaxis in immunocompromised adults. Fluconazole has been commonly used off-label in the neonatal intensive care unit, but definitive recommendations for its use in the nursery have been hampered by the limited number of well-designed trials. In neonates weighing <750 g, appropriate dosing is not known, definitive safety and long-term follow up trials have not been completed, and there have not been well-powered trials conducted to establish the efficacy of the product using mortality as part of the primary endpoint. Three recent proof-of-concept studies suggest that fluconazole will be safe and effective, and an ongoing pharmacokinetic study is providing data to give preliminary dosing guidance. The next logical step in drug development is proposed by this research: to conduct a pivotal trial to determine the safety and efficacy of fluconazole in premature infants with 2-year neurodevelopmental follow-up assessment. This will be accomplished by randomizing 360 infants, with a birth weight <750g, at 20 centers, to fluconazole or placebo. The primary efficacy endpoint will be Candida-free survival at study day 49. The research will establish definitive dosing, safety, and efficacy of fluconazole; it will also provide critical information on the effects of fluconazole on neurodevelopmental impairment and antifungal resistance. Our collaborative team is uniquely poised to conduct this research. The team includes internationally recognized experts with experience conducting FDA-compliant, randomized neonatal clinical trials, neurodevelopmental assessments, safety studies, and pharmacokinetic studies. The team has the requisite expertise regarding mycology, epidemiology, pharmacology, and regulatory compliance in the context of invasive candidiasis. In the last 6 years, team members have completed or are actively leading the following studies in neonatal candidiasis: the NICHD-sponsored Early Diagnosis of Candidiasis trial (Benjamin and Stoll); 3 proof-of-concept randomized fluconazole studies (Kaufman and Manzoni); the NICHD-sponsored pharmacokinetic study of fluconazole (Wade); and several studies (Benjamin, Reed, and Walsh) of other antifungal agents in the nursery including pharmacokinetic and pharmacodynamic studies of amphotericin B, liposomal amphotericin B products, anidulafungin, and micafungin This research will show that fluconazole decreases invasive infection from Candida in neonates <750 grams birth weight. The research will provide guidance as to the efficacy, safety, and neurodevelopmental outcomes related to fluconazole use.

描述（由申请人提供）：与感染相关死亡或神经发育障碍的最常见病因<750 g是侵入性念珠菌病。侵入性念珠菌病被念珠菌的阳性培养诊断。来自通常无菌体液。超过70％的早产婴儿会死亡或遭受严重的永久神经系统损害。最年轻的婴儿是：出生体重<750 g的新生儿的累积发病率为16％，大多数婴儿在生命的日子前会经历感染49。已显示出侵入性的念珠菌病可以安全地预防免疫增强成人的氟康唑预防。氟康唑通常在新生儿重症监护病房中使用，但在托儿所中使用的最终建议因有限的精心设计的试验而受到阻碍。在重量<750 g的新生儿中，未知适当的给药，确定性的安全性和长期随访试验尚未完成，并且没有进行良好动力的试验来使用死亡率作为主要终点的一部分来确定产品的功效。最近的三项概念验证研究表明，氟康唑将是安全有效的，并且正在进行的药代动力学研究正在提供数据以提供初步给药指南。这项研究提出了药物开发的下一个逻辑步骤：进行关键试验，以确定氟康唑在具有2年神经发育随访评估的早产婴儿中的安全性和功效。这将通过将360名婴儿随机分配给氟康唑或安慰剂，将360名婴儿随机分配<750克。主要疗效终点将是第49天的无念珠菌生存。该研究将确定氟康唑的确定剂量，安全性和功效。它还将提供有关氟康唑对神经发育障碍和抗真菌耐药性的影响的关键信息。我们的合作团队独特地准备进行这项研究。该团队包括国际认可的专家，具有进行符合FDA的，随机的新生儿临床试验，神经发育评估，安全研究和药代动力学研究的经验。在侵入性念珠菌病的背景下，该团队具有关于真菌学，流行病学，药理学和法规合规性的必要专业知识。在过去的六年中，团队成员已经完成或积极领导以下关于新生儿念珠菌病的研究：NICHD赞助的念珠菌病试验的早期诊断（本杰明和斯托尔）； 3概念证明随机氟康唑研究（Kaufman和Manzoni）；氟康唑（韦德）的NICHD赞助的药代动力学研究；以及苗圃中其他抗真菌剂的几项研究（本杰明，里德和沃尔什），包括两性霉素B，脂质体两性霉素B产物，anidulafungin和Micafungin的药代动力学和药效学研究，这项研究将表明，氟康唑从neones neones in neones in neones in neones in neones in neones in neones in neones n neonys n neonynes in neonys n neony n neonne neonne neonne neonne neonne neonne neons neons neonsprots下<750 n neonyne neonne neonyne neons neons neonspoct中均已减少。这项研究将提供有关与氟康唑使用相关的功效，安全性和神经发育结果的指导。