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：
9477452
负责人：
SHARON L REED
金额：
$ 60.04万
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 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9477452
关键词：
18 year old Address Adult Adverse effects Amebiasis Amebic colitis Animals Antigens Antiparasitic Agents Area Auranofin Award Bangladesh Cells Clinical 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 Ethics FDA approved Feces Filariasis Food Contamination Funding Future Genotype Giardia Giardia lamblia Giardiasis Gold Grant 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 Placebos Protozoa Randomized Relapse Reporting Research Personnel Resistance Resolution Rheumatoid Arthritis Rodent Model Schistosomiasis Short Tandem Repeat 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 carcinogenicity clinical research site design drug standard effective therapy efficacy testing experience filaria foodborne outbreak high throughput screening in vitro testing in vivo international center neglect new therapeutic target nitazoxanide novel drug class novel therapeutics placebo controlled study primary endpoint primary outcome public health relevance resistant strain routine screening 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（由适用提供）：antamoeba Histolictica和Lamblia是造成水和食源性爆发的主要原因。咪唑，特别是甲硝唑，是全球用于治疗的主要药物。甲硝唑的耐药性在贾第烷和Entamoeba越来越关注，因为跨耐药性也会发生在较新的药物，替诺唑唑和硝酸氮杂。 NIH已将确定为B类代理的新药作为优先事项。在UO1赠款下，我们使用Entamoeba和Giardia滋养体开发了高通量屏幕。我们发现一种药物，Auranofin，一种由FDA批准的口服金化合物，用于治疗类风湿关节炎，IC50的IC50明显低于Entamoeba，而贾第二唑则与甲硝唑相当。最重要的是，口服auranofin在体外和体内抗菌E. histoltica和甲硝唑敏感和抗性的贾第氏菌菌株是有效的。基于这些发现，我们将检验以下假设：口服苏拉芬是对amebiasis和贾第鞭毛疾病的有效治疗。我们提出的临床试验是IIA期，2个平行臂，随机，受控，双盲，优越的治疗研究，比较了短期丙氨酸（贾第霉菌为5天，Entamoeba的7天），以治疗成人的amebiasis和giardiasis。我们从孟加拉国国际腹泻疾病中心和弗吉尼亚大学博士的经验丰富的共同投资者。 Haque和Petri将在高度内粒区域通过显微镜，抗原测试或阳性粪便PCR在其粪便中检测到的渐近患者= 18岁，在其粪便中检测到渐近性大肠杆菌或贾第鞭毛菌患者。主要的终点是在治疗第7天，在微观检查中分辨出Amebiasis（无可检测的囊肿或滋养体）患者的比例。次要结局包括在治疗的第3或第5天通过QPCR在第3、5和7天通过QPCR在粪便中降低粮食症或第5天的患者的比例，以及第3、5和7天的患者的比例。持续的治疗在28天后通过菌株的基因分型确定释放或重新感染。该提出的使用重新封建的FDA药物的临床试验可能会导致第一种新药物，并在52年内定义了治疗Amebiasis和Giardiasis的靶标。此外，Auranofin可能被证明是一种未来的广泛抗寄生虫药物，因为还证明了对隐孢子虫，毛孢菌，毒素，弓形虫病，T。Brucei，Filarariasis和schistosomisis的体外效率。