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

 描述（由申请方提供）：溶组织内阿米巴和蓝氏贾第鞭毛虫是水和食源性疫情的主要原因。咪唑类药物，特别是甲硝唑，是世界范围内用于治疗的主要药物。贾第虫和内阿米巴对甲硝唑的耐药性越来越受到关注，因为交叉耐药性也发生在较新的药物替硝唑和硝唑尼特上。美国国立卫生研究院已将B类药物的新药鉴定作为优先事项。在UO 1资助下，我们开发了使用内阿米巴和贾第虫滋养体的高通量筛选。我们发现一种药物，金诺芬，一种1985年被FDA批准用于治疗类风湿性关节炎的口服含金化合物，对内阿米巴的IC 50显著较低，对贾第虫的IC 50与甲硝唑相当。最重要的是，口服金诺芬在体外和体内对E.溶组织菌和贾第虫甲硝哒唑敏感和耐药菌株。基于这些发现，我们将检验口服金诺芬有效治疗阿米巴病和贾第虫病的假设。我们提出的临床试验是一项IIa期、2个平行组、随机、对照、双盲、优效性治疗研究，比较短期金诺芬（贾第虫5天，内阿米巴7天）与安慰剂治疗成人阿米巴病和贾第虫病。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合作研究者Haque和Petri博士将鉴定18岁以下的无症状E.在高度流行地区，通过显微镜检查、抗原检测或粪便PCR阳性在粪便中检测到溶组织原虫或贾第虫。主要终点是治疗第7天阿米巴病消退（显微镜检查未检出包囊或滋养体）的患者比例。次要结局包括治疗第3天或第5天贾第鞭毛虫病或阿米巴病消退的患者比例，第3、5和7天粪便中通过qPCR测定的滋养体/包囊载量降低率，以及第3、5和7天粪便抗原检测阴性的患者比例。因为最初的研究表明金诺芬对囊肿也有活性，我们将跟踪患有囊肿的患者比例。 持续治愈28天，并通过菌株基因分型确定复发或再感染。这项使用重新描述的FDA药物的临床试验可能会产生第一种新药，并在52年内确定治疗阿米巴病和贾第虫病的目标。此外，金诺芬可能被证明是一种未来的广谱抗寄生虫药物，因为体外疗效也已被证明对隐孢子虫，毛滴虫，弓形虫病，T。布鲁氏菌病、丝虫病和血吸虫病。

 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.