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

 描述(申请人提供)：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，是全世界用于治疗的主要药物类别。甲硝唑耐药性是贾第鞭毛虫和内阿米巴的一个日益严重的问题，因为对新药替硝唑和硝唑尼特也会产生交叉耐药。NIH已将为B类特工识别新药作为优先事项。在UO1的资助下，我们开发了使用内阿米巴和贾第虫滋养体的高通量筛查。我们发现一种名为Auranofin的药物，它是FDA于1985年批准用于治疗类风湿性关节炎的含金口服化合物，对阿米巴的IC50显著低于阿米巴，对贾第虫的IC50与甲硝唑相当。最重要的是，口服金诺芬在体外和体内对溶组织肠杆菌和甲硝唑敏感株和耐药株贾第鞭毛虫都有有效的抑制作用。基于这些发现，我们将检验口服金诺芬对阿米巴病和贾第鞭毛虫病有效治疗的假设。我们建议的临床试验是一项IIa期、2个平行对照的随机、对照、双盲、优势治疗研究，比较短程金诺芬(贾第鞭毛虫5天，内阿米巴7天)与安慰剂治疗成人阿米巴病和贾第鞭毛虫病的疗效。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人员Haque博士和Petri博士将在高度流行的地区通过显微镜、抗原测试或粪便PCR阳性检测到18岁的无症状患者的粪便中检测到溶组织埃希菌或贾第鞭毛虫。主要终点将是治疗第7天阿米巴病(显微镜检查未发现包囊或滋养体)消退的患者比例。次要结果包括治疗3天或5天后贾第鞭毛虫病或阿米巴病消失的患者比例，3天、5天和7天qPCR检测粪便滋养体/包囊负荷的减少率，以及3天、5天和7天大便抗原试验阴性患者的比例。由于初步研究表明金诺芬对囊性疾病也有效，我们将跟踪观察以下患者的比例 持续治愈28天，通过菌株的基因分型确定复发或再感染。这项拟议的临床试验使用的是FDA重新设计的药物，可能会产生第一个新药，并确定52年内治疗阿米巴病和贾第鞭毛虫病的目标。此外，金诺芬可能被证明是一种未来的广谱抗寄生虫药物，因为体外实验也证明了它对隐孢子虫、滴虫、弓形虫病、布氏毛滴虫、丝虫病和血吸虫病的疗效。

 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.