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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。该研究是一项I期研究，旨在评估FG-3019剂量递增对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，也称为初期肾病）患者的安全性、生物活性和影响。FG-3019是一种抗结缔组织生长因子（CTGF）蛋白的人抗体，CTGF蛋白在1型或2型糖尿病所致微量白蛋白尿受试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在肾脏疾病表现为微量白蛋白尿（早期肾病）的糖尿病患者中的安全性、耐受性和生物活性。次要目的是通过比较基线值与输注后值，确定药物是否改善微量白蛋白尿和/或肾功能。本研究对次要结局没有把握度。 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。招募将是竞争性的，所有3家中心将入组20例受试者。 在获得书面知情同意书后，最多20例微量白蛋白尿受试者将分两组入组本研究，每组10例。前10例受试者将接受低剂量FG-3019。假设耐受性可接受，第二组将接受更高剂量的FG-3019。受试者将首先接受筛选，以确保合格性。受试者将积极参与本研究约12个月，在此期间，将在Harbor-UCLA GCRC（一家设备齐全的机构，可管理输注期间可能发生的任何类型的紧急情况）的连续监测下，在6周治疗期间每隔一周输注一次FG-3019，共输注4次。第一次和最后一次输注将在GCRC过夜住院期间进行。第二次和第三次入院将包括输注完成后的6小时观察期。 将在每次输注前后采集血液和尿液样本，以评价FG-3019的作用。受试者还将在整个研究期间进行频繁访视，以确定他/她是否因输注而出现任何不良反应，并通过尿液和血液样本的测量值评估肾脏功能的任何变化。 仅在获得书面知情同意书后方可实施研究程序，并在知情同意时由受试者或受试者的法定授权代表签名并注明日期。将向签署知情同意书的人员提供一份已签署知情同意书的副本。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其私人医生，否则不会向第三方披露。 将对入组研究的受试者进行经济补偿，以报销交通费用并补偿参与研究程序的时间。入组研究的患者存在一定风险。这些包括对药物的敏感性和输注相关事件，如发热、寒战和寒战。其他体征和症状可能包括头痛、恶心、头晕或低血压。这些风险的可能性被认为是很小的。21例肺瘢痕形成受试者接受了FG-3019单次给药，未发生严重副作用。如果FG-3019安全有效，则受试者可能通过改善微量白蛋白尿或肾功能而获益，尽管可能只是短暂的。然而，由于糖尿病的患病率很高，并且全球范围内的发病率正在增加，因此本研究的主要益处将是整个社会。如果发现该药物在入组研究的人类受试者中安全且可能有效，则可能代表评估用于治疗糖尿病肾病的一流药物的疗效的第一步。

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.