Phase IIa Clinical Trial of the Reprofiled Drug Auranofin for GI Protozoa

重新定位药物金诺芬治疗胃肠道原虫的 IIa 期临床试验

基本信息

批准号：
9063467
负责人：
SHARON L REED
金额：
$ 60.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-05 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9063467
关键词：
18 year old Address Adult Adverse effects Amebiasis Amebic colitis Animals Antigens Antiparasitic Agents Area Auranofin Award Bangladesh Cells Clinical Trials Cryptosporidium Cyst Developing Countries Development Disease Disease Outbreaks Double-Blind Method Drug Targeting Drug resistance Drug usage Drug-sensitive Enrollment Entamoeba Entamoeba histolytica Entamoeba invadens FDA approved Feces Filariasis Food Contamination Funding Future Genotype Giardia Giardia lamblia Giardiasis Gold Grant Health Imidazole In Vitro Infection Ingestion Lead Leishmania infantum Liver Abscess Metronidazole Metronidazole resistance Microscopic Microscopy Morbidity - disease rate Oral Orphan Drugs Outcome Parasites Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Placebo Control Placebos Protozoa Randomized Relapse Reporting Research Personnel Resistance Resolution Rheumatoid Arthritis Rodent Model Schistosomiasis Short Tandem Repeat Staging Testing Time Tinidazole Toxoplasma gondii Toxoplasmosis Transfer RNA Trichomonas Trichomonas Infections Triose-Phosphate Isomerase Trypanosoma brucei brucei United States National Institutes of Health Universities Virginia Water arm base clinical research site design drug standard effective therapy efficacy testing experience filaria foodborne outbreak high throughput screening in vitro testing in vivo international center killings neglect nitazoxanide novel therapeutics placebo controlled study primary outcome resistant strain screening secondary outcome targeted treatment thioredoxin reductase treatment duration trial comparing waterborne

项目摘要

DESCRIPTION (provided by applicant): Entamoeba histolytica and Giardia lamblia are major causes of water- and foodborne outbreaks. Imidazoles, particularly metronidazole, are the primary class of drugs used worldwide for treatment. Resistance to metronidazole is a growing concern in Giardia and Entamoeba as cross resistance also occurs to the newer drugs, tinidazole and nitazoxanide. The NIH has made the identification of new drugs for Class B agents a priority. Under a UO1 grant, we developed high throughput screens using Entamoeba and Giardia trophozoites. We found one drug, auranofin, an oral gold-containing compound approved by the FDA in 1985 to treat rheumatoid arthritis, had an IC50 significantly lower for Entamoeba and equivalent for Giardia to metronidazole. Most importantly, oral auranofin was effective in vitro and in vivo against E. histolytica and both metronidazole-sensitive and resistan strains of Giardia. Based on these findings, we will test the hypothesis that oral auranofin is effective treatment of amebiasis and giardiasis. Our proposed clinical trial is a Phase IIa, 2 parallel arms, randomized, controlled, double blinded, superiority treatment study comparing short course auranofin (5 days for Giardia and 7 days for Entamoeba) to placebo for treatment of amebiasis and giardiasis in adults. Our experienced co-investigators from the International Center for Diarrheal Diseases in Bangladesh and University of Virginia, Drs. Haque and Petri, will identify asymptomatic patients =18 years old with E. histolytica or Giardia detected in their stools by microscopy, antigen testing, or positive stool PCR, in a highly endemic area. The primary end-point will be the proportion of patients with resolution of amebiasis (no detectable cysts or trophozoites on microscopic examination) by day 7 of therapy. Secondary outcomes include proportion of patients with resolution of giardiasis or amebiasis by days 3 or 5 of therapy, rate of decrease of trophozoites/cyst load by qPCR in stools by Days 3, 5, and 7, and proportion of patients with negative stool antigen test by Days 3, 5, and 7. Because initial studies show auranofin is also active against cysts, we will follow the proportion of patients with sustained cure at 28 days and determine relapse or re-infection by genotyping of strains. This proposed clinical trial using a re- profiled FDA drug could result in the first new drug and define target for the treatment of amebiasis and giardiasis in 52 years. In addition, auranofin may prove to be a future broad spectrum antiparasitic drug as in vitro efficacy has also been demonstrated against Cryptosporidium, Trichomonas, toxoplasmosis, T. brucei, filariasis, and schistosomiasis.

描述（由申请人提供）：溶组织内阿米巴和蓝氏贾第虫是水源性和食源性爆发的主要原因，咪唑类药物，特别是甲硝唑，是全世界用于治疗的主要药物类别，贾第虫和肠阿米巴的耐药性日益受到关注。较新的药物替硝唑和硝唑尼特也出现交叉耐药，NIH已做出新药鉴定。在 UO1 资助下，我们使用内阿米巴和贾第鞭毛虫滋养体开发了高通量筛选，我们发现一种药物，金诺芬，一种口服含金化合物，于 1985 年被 FDA 批准用于治疗类风湿性关节炎。与甲硝唑相比，口服金诺芬对内阿米巴的作用显着降低，而对贾第鞭毛虫的作用与甲硝唑相当。我们提议的临床试验是一项 IIa 期、2 个平行组、随机、对照、双盲、优效治疗研究，比较短程金诺芬（贾第虫 5 天，内阿米巴 7 天）与安慰剂治疗阿米巴病和我们来自孟加拉国国际腹泻病中心和弗吉尼亚大学的经验丰富的联合研究人员 Haque 和 Petri 博士将通过显微镜检查在粪便中检测到溶组织内贾第虫或贾第虫的无症状患者，在高流行地区进行抗原检测或粪便 PCR 阳性的主要终点是阿米巴病消退（没有检测到包囊或）的患者比例。次要结局包括治疗第 3 天或第 5 天贾第虫病或阿米巴病消退的患者比例，第 3 天、第 5 天粪便中 qPCR 检测的滋养体/囊肿负载减少率。 7，以及第 3、5 和 7 天粪便抗原检测呈阴性的患者比例。由于初步研究表明金诺芬对囊肿也有活性，因此我们将跟踪患者的比例 28 天持续治愈，并通过菌株基因分型确定复发或再次感染。这项拟议的临床试验使用重新分析的 FDA 药物，可能会产生第一种新药，并确定 52 年来治疗阿米巴病和贾第鞭毛虫病的目标。此外，金诺芬被证明可能是未来的广谱抗寄生虫药物，因为体外对隐孢子虫、毛滴虫、弓形虫、T.布鲁氏菌病、丝虫病和血吸虫病。