A Phase 2, Multi-Center, Randomized, Double-Masked, Active Controlled Study of ADVM-022 (AAV.7m8-aflibercept) in Subjects With Diabetic Macular Edema [INFINITY]
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Time to Worsening of DME Disease Activity in the Study Eye.
研究概览
简要总结
A Phase 2, Multi-Center, Randomized, Double-Masked*, Active Controlled Study of ADVM-022 (AAV.7m8-aflibercept) in Subjects with Diabetic Macular Edema [INFINITY]
详细描述
ADVM-022 (also known as Ixo-vec and AAV.7m8-aflibercept) is an investigational gene therapy product developed for the treatment of serious retinal vascular diseases including Diabetic Macular Edema (DME), a vision-threatening complication of diabetic retinopathy. DME can affect up to 10% of individuals with both type 1 and type 2 diabetes mellitus. Current therapies for treating DME include anti-vascular endothelial growth factor (anti-VEGF) agents that require frequent and long-term intravitreal (IVT) injections to achieve and maintain efficacy. ADVM-022 is intended provide sustained intraocular expression of aflibercept from a single IVT injection to potentially reduce the current treatment burden and prevent disease progression and vision loss due to undertreatment.
This Phase 2, randomized, controlled study (INFINITY) enrolled 36 eligible participants with DME. The participants were randomized to receive one of the two dose levels of ADVM-022 or assigned to the control arm to receive a sham ocular injection with a preceding aflibercept injection. Participants randomized to the ADVM-022 arms were assigned to receive a preceding aflibercept or sham ocular injection. All participants were monitored regularly for disease activity and may have received supplemental aflibercept based on predefined retreatment criteria. All participants were to be followed over a 96- week follow-up period.
To enhance safety monitoring for participants in this study, the sponsor unmasked treatment assignment (in April 2021) due to the occurrence of a suspected unexpected serious adverse reaction (SUSAR) which occurred early in the study in the high dose (ADVM-022 6E11 vg/eye) arm. Interpretation of the results of this study should consider the potential confounding nature of this unmasking in the context of the observed dose-limiting events and the associated additional use of topical/intravitreal/systemic steroids, particularly in the high dose ADVM-022 arm.
In this study ADVM-022 (Ixo-vec) demonstrated improved efficacy across endpoints, reducing the need for supplemental aflibercept in DME management and demonstrating a clinically meaningful delay in DME worsening and improved outcomes across multiple endpoints compared to the control arm (sham + Aflibercept). However, the benefit of the ADVM-022 6E11 vg/eye dose was affected by dose-limiting toxicities in some participants. In terms of safety outcomes, the most common ADVM-022-related adverse events were mild-to-moderate intraocular inflammation, a known and expected side effect of ocular gene therapy, which was generally responsive to corticosteroid eye drops. No Ixo-vec-related events were reported in the fellow eye or systemically, indicating no off-target effects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
From May 2020 through April 2021: Double-masked study - participants, outcomes assessors and the designated masked study personnel were to have been masked to subject's treatment assignment throughout the study. There must have been a minimum of two physicians per site to fulfill the masking requirements of the study. A masked and unmasked investigator were required to be present for administration of the preceding dose of aflibercept or sham and following dose of ADVM-022 or sham visits, thereafter only the masked investigator was required to be present.
Starting April 2021: Open label study - study was unmasked for enhanced safety monitoring.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Type 1 or Type 2 diabetes mellitus
- •Willing and able to provide informed consent
- •Vision impairment due to center involving diabetic macular edema
排除标准
- •Uncontrolled diabetes defined as HbA1C >10%, or history of diabetic ketoacidosis within 3 months prior to randomization; or subjects who, within the last 3 months, initiated intensive insulin treatment (a pump or multiple daily injection) or plan to do so in the next 3 months.
- •Acute coronary syndrome, myocardial infarction or coronary artery revascularization, CVA, TIA in the last 6 months
- •Uncontrolled hypertension defined as average SBP ≥160 mmHg or an average DBP ≥100 mmHg
- •Known severe renal impairment
- •High risk Proliferative Diabetic Retinopathy
- •History of retinal disease in the study eye other than diabetic retinopathy
- •History of retinal detachment (with or without repair) in the study eye
- •History of vitrectomy, trabeculectomy, or other filtration surgery in the study eye
- •Any prior focal or grid laser photocoagulation or any prior PRP in the study eye
- •Current or planned pregnancy or breastfeeding
研究组 & 干预措施
1
6E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT
干预措施: 6E11 vg/eye of ADVM-022 (Biological)
1
6E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT
干预措施: Aflibercept (Biological)
2
2E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT
干预措施: 2E11 vg/eye of ADVM-022 (Biological)
2
2E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT
干预措施: Aflibercept (Biological)
3
Aflibercept 2mg IVT
干预措施: Aflibercept (Biological)
结局指标
主要结局
Time to Worsening of DME Disease Activity in the Study Eye.
时间窗: Day 1 through 96 weeks
Time to worsening of DME disease activity in the study eye through 96 weeks. Time to worsening of DME disease activity defined by either: An increase in CST \> 50 µm as assessed by SD-OCT compared to the lower of the two CST measurements recorded at Day 1 or Week 4; A loss of \> 5 letters in BCVA due to worsening DME disease activity compared to the higher of the two BCVA measurements recorded at Day 1 or Week 4. Number of weeks was relative to Day 1.
次要结局
- Incidence of 2-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time(From Day 1 through 96 weeks)
- Incidence of 3-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time(From Day 1 through 96 weeks)
- Occurrence of Any Vision Threatening Complications in the Study Eye (Anterior Segment Neovascularization, Vitreous Hemorrhage, or Any Other High-risk Proliferative DR, or Tractional Retinal Detachment) Over Time Through Week 96(From Day 1 through 96 weeks)
- Incidence of CST <300 μm Over Time Through Week 96 in the Study Eye(Day 1 through 96 weeks)
- Incidence of Ocular Adverse Events (AEs)(96 weeks)
- Incidence of Non-ocular Adverse Events (AEs)(Day 1 through 96 weeks)
- Change From Baseline Central Subfield Thickness (CST) in Study Eye(Baseline through 96 weeks)
- Change From Baseline in Best Corrected Visual Acuity (BCVA) Score Over Time in the Study Eye(96 weeks)
- Frequency of Supplemental Aflibercept Injections (2 mg IVT) in the Study Eye Over Time During the Study(Day 1 through 96 weeks)
- Incidence of 2-step Improvement in Diabetic Retinopathy Severity Score (DRSS) in the Study Eye Over Time(From Day 1 through 96 weeks)
- Incidence of 3-step Improvement in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time(From Day 1 through 96 weeks)