A PHASE I STUDY OF FG-3019 IN SUBJECTS WITH TYPE I OR II DIABETES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项研究是关于FG-3019在1型或2型糖尿病和微量白蛋白尿(糖尿病肾病的早期阶段，也称为早期肾病)患者中的安全性、生物活性和增加剂量的效果的第一阶段研究。FG-3019是一种针对结缔组织生长因子(CTGF)蛋白的人类抗体，在1型或2型糖尿病微量白蛋白尿患者的肾小球中过量存在。本研究的主要目的是确定药物FG-3019在以微量白蛋白尿(早期肾病)为表现的糖尿病患者中的安全性、耐受性和生物活性。第二个目标是通过比较基线值和输液后的值来确定该药物是否改善了微量白蛋白尿和/或肾功能。这项研究将不会为次要结果提供动力。三个中心将参与这项研究：洛杉矶生物医学研究所、乔斯林诊所和弗吉尼亚大学。报名将是竞争性的，所有三个中心都将有20个科目报名。在获得书面知情同意后，多达20名有微量白蛋白尿的受试者将被分成两组，每组10人。前10名受试者将接受低剂量的FG-3019。假设耐受性可以接受，第二组将接受更高剂量的FG-3019。受试者将首先接受筛选，以确保符合资格。受试者将积极参与这项研究大约12个月，在此期间，在为期六周的治疗期内，每隔一周注射四次药物FG-3019，在港湾-加州大学洛杉矶分校GCRC的持续监测下进行管理，该设施配备良好，可以处理在注射过程中可能发生的任何类型的紧急情况。第一次和最后一次输液将在GCRC入院过夜期间进行。第二次和第三次入院需要在输液完成后进行6小时的观察。每次输液前后将采集血液和尿样，以评估FG-3019的效果。在整个研究过程中，受试者还将进行频繁的检查，以确定他/她是否因输液而出现任何不良反应，并通过尿液和血液样本的测量来评估肾脏功能的任何变化。研究程序只有在获得书面知情同意后才能实施，并由受试者或受试者的合法授权代表在同意时签署并注明日期。签署的知情同意书的副本将发给签署表格的人。作为本研究的一部分获得的医疗信息将是保密的，除非受试者书面要求将医疗信息提供给他/她的私人医生，否则不会向第三方披露。参加研究的受试者将获得经济补偿，以补偿交通费和用于参与研究程序的时间。参与这项研究的患者存在一定的风险。这些症状包括对药物的敏感性，以及与输液相关的事件，如发烧、寒战和僵硬。其他体征和症状可能包括头痛、恶心、头晕或低血压。出现这些风险的可能性被认为很小。21名患有肺疤痕的受试者接受了单次剂量的FG-3019，没有经历严重的副作用。如果FG-3019是安全有效的，受试者可能会受益于微量白蛋白尿或肾功能的改善，尽管可能只是暂时的。然而，这项研究的主要好处将是整个社会，因为糖尿病的患病率很高，而且全世界的发病率都在增加。如果这种药物在参与研究的人类受试者中被发现是安全的，并且可能有效，它可能是评估一流药物治疗糖尿病肾病疗效的第一步。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The research is a Phase 1 study of the safety, biologic activity and effects of escalating doses of FG-3019 in patients with Type 1 or Type 2 diabetes and microalbuminuria (an early stage of diabetic kidney disease, also known as incipient nephropathy). FG-3019 is a human antibody to a protein known as Connective Tissue Growth Factor (CTGF), present in excess in the glomeruli of subjects with microalbuminuria due to Type 1 or Type 2 diabetes mellitus. The primary objective of this study is to determine the safety, tolerability and biologic activity of the drug FG-3019 in diabetic patients whose kidney disease is manifested by microalbuminuria (incipient nephropathy). The secondary objective is to is to determine whether the drug improves microalbuminuria and/or kidney function by comparing baseline values to post-infusion values. The study will not be powered for the secondary outcomes. Three centers will participate in the study: Los Angeles Biomedical Institute, the Joslin Clinic, and the University of Virginia. Enrollment will be competitive, and 20 subjects will be entered at all 3 centers. After obtaining a written informed consent, up to 20 subjects with microalbuminuria will be enrolled in this study in two groups of ten. The first 10 subjects will receive a low dose of FG-3019. Assuming acceptable tolerability, the second group will receive a higher dose of FG-3019. Subjects will initially undergo screening to ensure eligibility. Subject will actively participate in the study for approximately 12 months, during which time a total of four infusions of the drug FG-3019, given every other week over the course of a six week treatment period, will be administered under continuous monitoring in the Harbor-UCLA GCRC, a facility that is well equipped to manage any kind of emergency that may occur during infusions. The first and last infusions will be given during an overnight admission to the GCRC. The second and third admission will involve a 6-hour period of observation after the infusion is completed. Blood and urine samples will be collected before and after each infusion to evaluate the effects of FG-3019. The subject will also come in for frequent visits during the whole length of the study to determine if he/she is experiencing any adverse effects as a result of the infusion and to assess any change in the functioning of the kidneys by measurements from urine and blood samples. The study procedure will be implemented only after obtaining written informed consent, signed and dated by the subject or the subject's legally authorized representative at the time of consent. A copy of the signed informed consent will be given to the person signing the form. Medical information obtained as part of this study will be confidential and will not be disclosed to third parties except on written request by the subject that medical information be given to his/her personal physician. The subjects enrolled in the study will be compensated financially to reimburse for transportation and to compensate for the time devoted to participate in study procedures. There are certain risks to the patients enrolled in the study. These include sensitivity to the drug, and infusion-related events like fever, chills, and rigors. Other signs and symptoms may include headache, nausea, dizziness or hypotension. The chances of these risks are thought to be small. Twenty-one subjects with lung scarring have received single doses of FG-3019 without experiencing serious side-effects. If FG-3019 is safe and effective, the subject may potentially benefit, albeit probably only transiently, by improvement in microalbuminuria or kidney function. However the major benefits of this study will be to the society at large, since the prevalence of diabetes is high and the incidence is increasing worldwide. This drug, if found safe and possibly effective in the human subjects enrolled in the study, could represent a first step in evaluating the efficacy of a first-in-class agent for the treatment of diabetic kidney disease.