Phase II Study to Compare Anti-VEGF Agents in Treatment of DME (12-EI-0134)

目的：糖尿病视网膜病变（DR）仍然是视力损害的主要原因。糖尿病性黄斑水肿（DME）是糖尿病性黄斑水肿的常见表现，激光光凝是过去几十年来唯一被证实的治疗方法。研究表明，抗血管内皮生长因子（VEGF）注射如贝伐单抗或雷尼单抗在治疗DME患者中是有效的。然而，目前还没有对这些药物进行直接比较，以确定一种治疗方法是否比另一种更有效。本研究的目的是比较雷尼单抗与贝伐单抗在眼部DME中的治疗效果。研究人群：60名患有继发于糖尿病的黄斑水肿和任何阶段DR（除了需要散射激光光凝治疗增殖性DR的患者）的参与者将被纳入这项随机研究。设计：在这项II期比较双盲研究中，受试者将被随机分配接受雷尼单抗或贝伐单抗治疗。在研究的初始阶段，参与者将参与一项为期三期、为期36周的交叉研究，在该研究中，研究眼睛将被分配到四个治疗组（即治疗序列）之一。两种药物和三个周期形成AAB/ABB/BBA/BAA模式如下：组1眼将在基线和第4、8、12、16和20周接受一系列雷尼珠单抗玻璃体内注射，然后在第24、28和32周交叉接受一系列贝伐珠单抗玻璃体内注射。组2眼将在基线和第4周和第8周接受一系列雷尼珠单抗玻璃体内注射，然后在第12、16、20、24、28和32周交叉接受一系列贝伐珠单抗玻璃体内注射。组3眼将在基线和第4、8、12、16和20周接受一系列贝伐单抗玻璃体内注射，然后在第24、28和32周交叉接受一系列雷尼单抗玻璃体内注射。第4组将在基线和第4周和第8周接受一系列贝伐单抗玻璃体内注射，然后在第12、16、20、24、28和32周交叉接受一系列雷尼单抗玻璃体内注射。将一只眼睛纳入研究的参与者将这只眼睛随机分为上述四组之一。两只眼睛都参加研究的参与者将把右眼随机分到上述四组之一。右眼被随机分到第1组或第2组的患者，左眼被随机分到第3组或第4组；相反，对于那些右眼被随机分到第3组或第4组的人，左眼将被随机分到第1组或第2组。在这个交叉阶段之后，眼睛将返回到最初分配的治疗（雷尼单抗或贝伐单抗），并在需要的基础上进行治疗，直到最后一次入组的参与者入组后三年的共同终止日期。治疗研究人员和参与者都将被掩盖到小组分配中。主要结果将在第12、24、36周以及第1、2和3年进行评估。主要观察指标为最佳矫正视力（BCVA）的平均变化。三个周期（即第12、24和36周）结束后从基线到四周以及第1、2和3年的BCVA变化将用于主要分析。次要结果（在基线和第12周、第12周和第24周、第24周和第36周以及第1年、第2年和第3年之间进行评估）将包括治疗组中央黄斑厚度和中央视网膜体积的平均变化（通过OCT测量）；BCVA、中央黄斑厚度和视网膜体积变化的斜率；视力改善大于等于10个字母的眼睛比例；视力改善大于等于15个字母的眼睛比例；logOCT损失或增益大于或等于0.1 log单位的眼睛比例；logOCT损失或增益大于或等于0.05 log单位的眼睛比例；荧光素血管造影显示黄斑液体渗漏的变化；其他次要结果将包括符合显著恶化、治疗成功或治疗失败标准的眼睛比例，研究中按需治疗阶段眼睛间再注射的频率，以及在研究过程中接受焦点/网格激光光凝或其他辅助治疗的眼睛比例。安全性结果包括不良事件的数量和严重程度。由于视力下降或不良事件而退出试验产品的眼睛数量以及被认为疾病恶化的眼睛数量也将有助于安全性评估。

Objective: Diabetic retinopathy (DR) remains a leading cause of visual impairment. A frequent manifestation of DR is diabetic macular edema (DME) for which laser photocoagulation has been the only proven treatment for the last several decades. Studies have shown that anti-vascular endothelial growth factor (VEGF) injections such as bevacizumab or ranibizumab have been efficacious in treating patients with DME. However, there has been no direct comparison of these agents to determine whether one treatment is more effective than the other. The objective of this study is to compare the treatment efficacy of ranibizumab versus bevacizumab in eyes with DME. Study Population: Sixty (60) participants with macular edema secondary to diabetes and any stage of DR (other than those requiring scatter laser photocoagulation for proliferative DR) in one or both eyes will be enrolled in this randomized study. Design: In this Phase II, comparative, double-masked study, eyes will be randomly assigned to receive ranibizumab or bevacizumab. During the initial phase of the study participants will participate in a three-period, 36-week, cross-over study in which study eyes will be assigned to one of four treatment groups (i.e., treatment sequences). The two drugs and three periods form an AAB/ABB/BBA/BAA pattern as follows: Group 1 eyes will receive a series of intravitreal injections of ranibizumab at baseline and Weeks 4, 8, 12, 16 and 20, then cross-over to receive a series of intravitreal injections of bevacizumab at Weeks 24, 28 and 32. Group 2 eyes will receive a series of intravitreal injections of ranibizumab at baseline and Weeks 4 and 8, then cross-over to receive a series of intravitreal injections of bevacizumab at Weeks 12, 16, 20, 24, 28 and 32. Group 3 eyes will receive a series of intravitreal injections of bevacizumab at baseline and Weeks 4, 8, 12, 16 and 20, then cross-over to receive a series of intravitreal injections of ranibizumab at Weeks 24, 28 and 32. Group 4 eyes will receive a series of intravitreal injections of bevacizumab at baseline and Weeks 4 and 8, then cross-over to receive a series of intravitreal injections of ranibizumab at Weeks 12, 16, 20, 24, 28 and 32. Participants for whom one eye is enrolled in the study will have this eye randomized to one of the four groups above. Participants for whom both eyes are enrolled in the study will have the right eye randomized to one of the four groups above. For those whose right eye is randomized to Group 1 or 2, the left eye will be randomized to Group 3 or 4; conversely, for those whose right eye is randomized to Group 3 or 4, the left eye will be randomized to Group 1 or 2. Following this cross-over phase, eyes will be returned to the treatment (ranibizumab or bevacizumab) to which they were originally assigned and treated on an as-needed basis through a common termination date three years from enrollment of the last-enrolled participant. Both the treating investigators and participants will be masked to the group assignments. The primary outcome will be assessed at Weeks 12, 24, 36 and at Years 1, 2 and 3. Outcome Measures: The primary outcome measure is the mean change in best-corrected visual acuity (BCVA). Changes in BCVA from baseline to four weeks following the end of each of the three periods (i.e., Weeks 12, 24 and 36) and at Years 1, 2 and 3 will be used for the primary analysis. Secondary outcomes (assessed between the baseline and Week 12 visits, Weeks 12 and 24 visits and Weeks 24 and 36 visits and at Years 1, 2 and 3) will include the mean changes in central macular thickness and central retinal volume by treatment group as measured by OCT; the slope of the changes in BCVA, central macular thickness and retinal volume; the proportion of eyes with visual improvement greater than or equal to 10 letters; the proportion of eyes with visual improvement greater than or equal to 15 letters; the proportion of eyes with greater than or equal to 0.1 log unit loss or gain in logOCT; the proportion of eyes with greater than or equal to 0.05 log unit loss or gain in logOCT; changes in fluid leakage in the macula as demonstrated by fluorescein angiography; and changes in macular structural improvement (i.e., resolution of cystic changes) as measured by OCT. Other secondary outcomes will include the proportion of eyes meeting criteria for significant worsening, treatment success, or treatment failure, the frequency of re-injection among eyes in the treatment-as-needed phase of the study, and the proportion of eyes receiving focal/grid laser photocoagulation or other adjuvant treatment during the course of the study. Safety outcomes include the number and severity of adverse events. The number of eyes withdrawn from the investigational product due to vision loss or adverse events and the number of eyes deemed to have worsening disease will also contribute to the assessment of safety.