A Phase 1/2 Dose-Escalation and Randomized, Controlled, Masked Expansion Trial of Intravitreal 4D-150 Gene Therapy in Adults With Neovascular (Wet) Age-Related Macular Degeneration
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 215
- 试验地点
- 46
- 主要终点
- Incidence and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs), including clinically significant changes in safety parameters
研究概览
简要总结
Phase 1/2 dose-escalation and randomized, controlled, masked expansion trial in adults with wet AMD undergoing active anti-VEGF treatment.
Substudies will evaluate the safety and tolerability of 4D-150 contralateral eye dosing and characterize vector shedding.
详细描述
This Phase 1/2 trial is a prospective, multicenter, Phase 1/2 dose-escalation and randomized, controlled, masked expansion trial in adults with wet AMD undergoing active anti-VEGF treatment who have demonstrated a clinical response consistent with anti-VEGF activity. The trial consists of Dose Escalation, Dose Expansion, Steroid Optimization, and Population Extension Cohorts.
After receiving one time administration of 4D-150 by intravitreal injection (IVT), subjects will undergo assessments at monthly intervals for 24 months to assess safety and efficacy outcomes. Only subjects that received 4D-150 will then enter a long-term follow-up (LTFU) period to assess long-term safety of 4D-150 gene therapy and duration of clinical activity through year 5 (60 months).
Eligible subjects who received 4D-150 in the study eye may participate in a sub-study to evaluate one-time IVT administration of 4D-150 to the contralateral ("fellow") eye.
Additional subjects will be enrolled in a separate sub-study to characterize the vector shedding profile of one-time administration of IVT 4D-150.
In both sub-studies, subjects will undergo regular assessments to assess safety and tolerability through Week 52 and then will enter long-term follow-up for safety evaluation through year 5 (60 months).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
Dose Escalation will be open-label. During Dose Expansion, outcome assessors will be masked to treatment assignment. Other site personnel (including investigator) and subjects will be unmasked to treatment assignment but will be masked to 4D-150 dose level. The Sponsor and its representatives and the site dose preparer/pharmacist will be unmasked to treatment assignment. Steroid Optimization and Population Extension will be open-label.
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •≥50 years of age
- •Diagnosed with CNV secondary to AMD (confirmed by reading center)
- •BCVA ≥34 ETDRS letters (~20/200) in the contralateral eye, and BCVA in the study eye:
- •Central subfield thickness (CST) and/or presence of subretinal or intraretinal fluid requiring continued anti-VEGF therapy in the study eye, as assessed by SD-OCT; and confirmed by a reading center):
- •Study eye amenable to IVT injection
- •Ability to perform tests of visual and retinal function and structure, and ability to comply with other protocol-specified procedures
- •Currently receiving anti-VEGF treatment (e.g. ranibizumab, aflibercept, faricimab or bevacizumab) in the study eye AND has demonstrated a clinical response consistent with anti-VEGF activity within 12 months prior to screening:
- •Note: Day -7 aflibercept will be administered ≥ 4 weeks from last IVT anti-VEGF
- •Subjects receiving 4D-150 agree to use a barrier method (e.g. condom) during intercourse for 6 months after administration of 4D-150 to prevent fluid transmission; sexually active males should not father a child or donate sperm during this period
- •Medical records available to document history of anti-VEGF therapy (dates, drugs, and dosage) for a minimum of 12 months prior to Screening
- •Provide written informed consent.
- •Contralateral Eye Sub-study-Specific Criteria:
- •Received 4D-150 in study eye-1 at least 6 months prior to Contralateral Substudy Screening Visit NOTE: Subjects who received 4D-150 in study eye-1 as part of the Shedding Substudy are also eligible to participate in the Contralateral Eye Substudy only after biological samples from all matrices were at or below the limit of quantitation for vector genomes in at least 3 consecutive measurements AND at least 6 months has passed since 4D-150 administration to study eye-
- •Macular neovascularization (MNV) secondary to AMD in study eye-2 as assessed on historical images at any time by SD-OCT (required) and FA when available or fundus photography when available or at screening based on SD-OCT, FA and fundus photography (confirmed by the reading center)
- •History of at least 1 anti-VEGF injection in study eye-2 within 6 months prior to Screening (last anti-VEGF injection must be at least 28 days prior to Day 7) AND has demonstrated a clinical response consistent with anti-VEGF activity by historical OCT at any time point prior to screening with confirmed response by the reading center (Screening OCT can be confirmatory)
- •BCVA between 25 and 83 ETDRS letters, inclusive (20/320 20/25 Snellen) in study eye-2
- •Study eye-2 amenable to IVT injection
- •BCVA ≥34 ETDRS letters (~20/200) in the previously treated study eye-1
- •Ability to comply with protocol-specified procedures and visits, in the Investigator's judgment
- •Agree to use a barrier method (e.g. condom) during intercourse for 6 months after administration of 4D-150 to study eye-2 to prevent fluid transmission; sexually active males should not father a child or donate sperm during this period
- •Provide written informed consent.
- •Shedding Substudy-specific Inclusion Criteria:
- •≥50 years of age
- •Diagnosed with MNV secondary to AMD as assessed on historical images at any time by spectral domain optical coherence tomography (SD-OCT) (required) and fluorescein angiography when available or fundus photography when available or at screening based on SD-OCT, FA and fundus photography (confirmed by Reading Center)
- •Best corrected visual acuity (BCVA) between 10 and 83 ETDRS letters, inclusive (~20/640 and 20/25, respectively) in the study eye at Screening
- •BCVA ≥34 ETDRS letters (~20/200) in the contralateral eye
- •Currently receiving anti-VEGF treatment (e.g. ranibizumab, aflibercept, faricimab or bevacizumab) in the study eye; minimum of 1 injection within the last 6 months (last anti-VEGF injection must be at least 28 days prior to Day 7) AND has demonstrated a clinical response consistent with anti-VEGF activity by historical OCT at any time prior to screening with confirmed response by the reading center (Screening OCT can be confirmatory)
- •Study eye amenable to IVT injection
- •Ability to perform tests of visual and retinal function and structure, and ability to comply with other protocol-specified procedures, in the Investigator's judgment
- •Agree to use a barrier method (e.g. condom) during intercourse for 6 months after administration of 4D-150 to prevent fluid transmission; sexually active males should not father a child or donate sperm during this period
- •Provide written informed consent.
排除标准
- 未提供
研究组 & 干预措施
4D-150 Dose Escalation up to 4 dose levels
4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1.
干预措施: 4D-150 IVT (Biological)
4D-150 Dose Expansion Dose 1
4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1.
干预措施: 4D-150 IVT (Biological)
4D-150 Population Extension Dose 2
4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1.
干预措施: 4D-150 IVT (Biological)
4D-150 Population Extension Dose 3
4D-150 will be administered at the assigned dose
干预措施: 4D-150 IVT (Biological)
4D-150 Dose Expansion Dose 2
4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1.
干预措施: 4D-150 IVT (Biological)
4D-150 Steroid Optimization
4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1.
干预措施: 4D-150 IVT (Biological)
4D-150 Population Extension Dose 1
4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1.
干预措施: 4D-150 IVT (Biological)
4D-150 Dose Expansion Control
Aflibercept at a fixed regimen will be administered.
干预措施: Aflibercept IVT (Biological)
4D-150 Contralateral Eye Dose
4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1.
干预措施: 4D-150 IVT (Biological)
4D-150 Vector Shedding Dose
4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1.
干预措施: 4D-150 IVT (Biological)
结局指标
主要结局
Incidence and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs), including clinically significant changes in safety parameters
时间窗: 52 weeks
次要结局
- Percentage of subjects requiring supplemental aflibercept injections over 52 weeks(52 weeks)
- Number of supplemental aflibercept injections over 52 weeks(52 weeks)
- Change from baseline in BCVA over time (up to 52 weeks) as assessed using the ETDRS Visual Acuity Chart(52 weeks)
- Time to receiving the first supplemental aflibercept injection(52 weeks)
- Change from baseline in central subfield thickness (CST) over time (up to 52 weeks) measured by spectral domain optical coherence tomography (SD-OCT)(52 weeks)
- Percent Change in Annualized Mean Number of anti-VEGF IVT injections before and after the 4D-150 injection(Before and after the 4D-150 injection (or Day 1 for the aflibercept only arm))