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)仍然是导致视力损害的主要原因。糖尿病黄斑水肿(DME)是DR的常见表现，在过去的几十年里，激光光凝一直是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，如贝伐单抗或雷尼贝珠单抗，在治疗DME患者方面是有效的。然而，目前还没有对这些药物进行直接比较来确定其中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比珠单抗和贝伐单抗治疗DME的疗效。研究人群：60(60)名患有糖尿病继发黄斑水肿的患者和任何阶段的糖尿病视网膜病变(除了需要散射激光光凝治疗增殖性糖尿病视网膜病变的患者)都将参加这项随机研究。设计：在这项第二阶段的双盲对照研究中，眼睛将被随机分配接受雷尼比珠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个周期、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中的一个(即治疗序列)。这两种药物和三个周期形成了如下AAB/ABB/BBA/BAA模式：第一组在基线和第4、8、12、16和20周接受一系列雷尼比单抗玻璃体内注射，然后在24、28和32周交叉接受一系列玻璃体内注射贝伐单抗。第2组在基线、第4周和第8周接受一系列的雷尼比单抗玻璃体内注射，然后在第12、16、20、24、28和32周接受一系列的贝伐单抗玻璃体内注射。第3组在基线、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24、28和32周交叉接受一系列雷尼比单抗玻璃体内注射。第4组在基线、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比单抗玻璃体内注射。只有一只眼睛参与研究的参与者将这只眼睛随机分配到上述四组中的一组。两只眼睛都参与研究的参与者将右眼随机分配到上述四组中的一组。对于那些右眼被随机分到组1或2的人，左眼将被随机分到组3或组4；相反，对于右眼被随机分到组3或组4的人，左眼将被随机分到组1或组2。在这个交叉阶段之后，眼睛将返回到它们最初被分配到的治疗(雷尼比单抗或贝伐单抗)，并根据需要进行治疗，直到最后一名参与者登记后三年的共同终止日期。治疗调查人员和参与者都将被蒙面到小组任务中。主要结果将在12周、24周、36周以及1、2和3岁时进行评估。结果测量：主要结果测量是最佳矫正视力(BCVA)的平均变化。在三个时期(即第12、24和36周)结束后，以及在第1、第2和第3年，BCVA从基线到四周的变化将用于初步分析。次要结果(在基线到第12周、第12和24周、第24和36周以及1年、2年和3年之间进行评估)将包括治疗组的中心黄斑厚度和中心视网膜体积的平均变化，如OCT测量；BCVA、中心黄斑厚度和视网膜体积变化的斜率；视力改善大于或等于10个字母的眼睛的比例；视力改善大于或等于15个字母的眼睛的比例；在LOGOCT中，大于或等于0.1个对数单位损失或增加的眼睛的比例；LogOCT中大于或等于0.05个对数单位损失或增加的眼的比例；荧光素血管造影术显示的黄斑液体渗漏的变化；以及OCT测量的黄斑结构改善(即囊性变化的分辨率)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的比例，在研究的按需治疗阶段眼睛中再次注射的频率，以及在研究过程中接受焦点/栅格激光光凝或其他辅助治疗的眼睛的比例。安全结果包括不良事件的数量和严重程度。由于视力丧失或不良事件而退出研究产品的眼睛数量以及被认为患有恶化疾病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.