A Phase 2, Randomized, Controlled, Dose-escalation Study to Evaluate the Efficacy, Safety, and Tolerability of RGX-314 Gene Therapy Delivered Via a Single Suprachoroidal Space (SCS) Injections in Participants With Diabetic Retinopathy (DR) With and Without Center Involved-Diabetic Macular Edema (CI-DME)(ALTITUDE)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 139
- 试验地点
- 49
- 主要终点
- Part 2: Mean change from baseline in Best Corrected Visual Acuity (BCVA) in the study eye at Week 54.
研究概览
简要总结
ABBV-RGX-314 is being developed as a novel, potential one-time gene therapy treatment for the treatment of Diabetic Retinopathy (DR) with and without Center-Involved Diabetic Macular Edema (CI-DME). DR is a chronic and progressive complication of diabetes mellitus. It is a sight-threatening disease characterized in the early stages by neuronal and vascular dysfunction in the retina, and later by neovascularization that leads to further deterioration of functional vision. Despite the availability of current treatments, diabetic retinopathy remains the leading cause of vision loss in working-age adults, those between the ages of 20 and 74. Existing treatment with anti-VEGF agents, although shown to be effective, are limited by short therapeutic half-lives, which then require frequent intravitreal injections over the patient's lifetime, resulting in increased risk of associated adverse events and significant treatment burden. Due to the burden of treatment, patients often do not closely adhere to treatment regimens and experience sub-optimal outcomes and a decline in vision.
详细描述
This phase 2, randomized, dose-escalation study is designed to evaluate the efficacy, safety and tolerability of ABBV-RGX-314 gene therapy in subjects with DR with and without center-involved diabetic macular edema (CI-DME).
Part 1: For subjects with DR without CI-DME, approximately 100 participants who meet the inclusion/exclusion criteria will be enrolled into one of 5 cohorts. Participants will be randomized in Cohorts 1, 2, 4 and 5 to receive ABBV-RGX-314 or to be observed, and participants enrolled in Cohort 3 will receive ABBV-RGX-314. Cohort 1 will evaluate ABBV-RGX-314 Dose 1, Cohorts 2 and 3 will evaluate ABBV-RGX-314 Dose 2, and Cohorts 4 and 5 will evaluate ABBV-RGX-314 Dose 3. Following SCS ABBV-RGX-314 administration, participants in Cohorts 4 and 5 will receive a protocol-mandated post-procedure steroid regimen for 7 weeks. Participants who are randomized to be observed in Cohorts 1, 2, 4 and 5 will be offered ABBV-RGX-314 after completing the study.
Part 2: For subjects with DR with CI-DME, approximately 30 participants who meet the inclusion/exclusion criteria will be enrolled into one cohort (Cohort A). Participants will be randomized to receive ABBV-RGX-314 or Aflibercept Control. Cohort A will evaluate ABBV-RGX-314 Dose 4. Participants randomized to receive SCS ABBV-RGX-314 will receive a protocol-mandated course of steroid. Participants who are randomized to the Aflibercept Control arm will be offered ABBV-RGX-314 after completing the study.
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
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 25 Years 至 89 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Part 1 (DR without CI-DME):
- •Inclusion Criteria:
- •Patients 25-89 years of age with a diabetic retinopathy (DR) diagnosis of nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) secondary to diabetes mellitus Type 1 or 2 for which PRP or anti-VEGF injections can be safely deferred for at least 6 months
- •HbA1c < 12%.
- •Best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye of ≥69 letters (approximate Snellen equivalent of 20/40 or better).
- •Prior history of CI-DME in the study eye is acceptable.
- •Must be willing and able to provide written, signed informed consent.
排除标准
- •Neovascularization in the study eye from a cause other than DR.
- •Presence of any active CI-DME.
- •Active or history of retinal detachment in the study eye.
- •Any evidence or documented history of PRP or retinal laser in the study eye.
- •Patients who had a prior vitrectomy surgery.
- •Women of childbearing potential.
- •Part 2 (DR with CI-DME):
- •Inclusion Criteria:
- •Patients 25-89 years of age with diabetic retinopathy secondary to diabetes mellitus Type 1 or
- •HbA1c < 12%
- •Macular thickening secondary to DME involving the center of the fovea, CST on SD-OCT (≥ 325 μm)
- •Best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye of 78-25 letters (approximate Snellen equivalent of 20/32 to 20/320)
- •Participants must have demonstrated a meaningful response to anti-VEGF therapy.
- •Must be willing and able to provide written, signed informed consent
- •Exclusion Criteria:
- •Neovascularization in the study eye from a cause other than DR.
- •Active or history of retinal detachment in the study eye.
- •Any evidence or documented history of PRP or retinal laser in the study eye.
- •Patients who had a prior vitrectomy surgery.
- •Women of childbearing potential.
- •Note: Other inclusions/exclusions criteria apply.
研究组 & 干预措施
Part 1: ABBV-RGX-314 Treatment Arm (Dose 1)
ABBV-RGX-314 Dose 1
干预措施: ABBV-RGX-314 Dose 1 (Genetic)
Part 1: ABBV-RGX-314 Treatment Arm (Dose 3) and Topical Steroid
ABBV-RGX-314 Dose 3 and Topical Steroid
干预措施: Topical Steroid (Drug)
Part 2: ABBV-RGX-314 Treatment Arm (Dose 4) and Topical Steroid
ABBV-RGX-314 Dose 4 and Topical Steroid
干预措施: Topical Steroid (Drug)
Part 2: ABBV-RGX-314 Treatment Arm (Dose 4) and Topical Steroid
ABBV-RGX-314 Dose 4 and Topical Steroid
干预措施: ABBV-RGX-314 Dose 4 (Genetic)
Part 2: Aflibercept Control
Control treatment arm
干预措施: Aflibercept (Biological)
Part 1: ABBV-RGX-314 Treatment Arm (Dose 2)
ABBV-RGX-314 Dose 2
干预措施: ABBV-RGX-314 Dose 2 (Genetic)
Part 1: ABBV-RGX-314 Treatment Arm (Dose 3) and Topical Steroid
ABBV-RGX-314 Dose 3 and Topical Steroid
干预措施: ABBV-RGX-314 Dose 3 (Genetic)
结局指标
主要结局
Part 2: Mean change from baseline in Best Corrected Visual Acuity (BCVA) in the study eye at Week 54.
时间窗: At Week 54
To evaluate the effect of ABBV-RGX-314 on BCVA at Week 54.
Part 1: Proportion of participants achieving a 2-step or greater improvement in DR in the study eye per the ETDRS-DRSS on 4 widefield digital stereoscopic fundus photography at Week 48
时间窗: At Week 48
To evaluate the effect of ABBV-RGX-314 on DR by the ETDRS DRSS at Week 48.
次要结局
- Part 1: Proportion of participants achieving an improvement in DR in the study eye per the ETDRS DRSS on 4 widefield digital stereoscopic fundus photography.(At Week 4, Week 12, Week 24, and Week 36)
- Part 1:Proportion of participants achieving a 0-step (no change) or greater improvement in DR in the study eye per the ETDRS DRSS on 4 widefield digital stereoscopic fundus photography.(At Week 4, Week 12, Week 24, Week 36, and Week 48)
- Part 1:Proportion of participants with a worsening in DR in the study eye per the ETDRS-DRSS on 4 widefield digital stereoscopic fundus photography.(At Week 4, Week 12, Week 24, Week 36, and Week 48)
- Part 1: Proportion of participants in the NPDR and PDR subgroups at baseline achieving an improvement or worsening in DR in the study eye per the ETDRS-DRSS on 4 widefield digital stereoscopic fundus photography.(At Week 4, Week 12, Week 24, Week 36, and Week 48)
- Part 1: Proportion of participants graded as proliferative diabetic retinopathy (PDR) in the study eye at baseline achieving regression to nonproliferative diabetic retinopathy (NPDR) in the study eye.(At Week 24, Week 36, and Week 48)
- Part 1: Proportion of participants achieving a 0-step (no change) or greater improvement in DR in the study eye per the ETDRS-DRSS on 4-widefield digital stereoscopic fundus photography(At Week 54, Week 62, and Week 74 (Crossover (CO) participants))
- Part 1: Proportion of participants with a worsening in DR in the study eye per the ETDRS-DRSS on 4 widefield digital stereoscopic fundus photography.(At Week 54, Week 62, and Week 74 (Crossover participants))
- Part 1: Mean change from baseline in the study eye in ETDRS-DRSS severity steps at Week 12, Week 24, Week 36, and Week 48 and (CO participants) change from Week 48 at Week 54, Week 62, and Week 74(Baseline to Week 12, Week 24, Week 36, and Week 48; Week 48 to Week 54, Week 62, and Week 74 (Crossover participants))
- Part 1: Incidences of overall and ocular AEs(Through Week 48; and through Week 74 (Crossover participants))
- Part 1: Vector shedding analysis in serum, urine, and tears(Through Week 48; and through Week 74 (Crossover participants))
- Part 1: Proportion of participants who experience ocular inflammation in the study eye following Suprachoroidal Space (SCS) ABBV-RGX-314 administration.(Through Week 48; and through Week 74 (Crossover participants))
- Part 1: Proportion of participants requiring any additional intervention in the study eye for ocular diabetic complications(Through Week 48 or Week 74 (Crossover participants))
- Part 1: Proportion of participants with any sight threatening ocular diabetic complications in the study eye based on duration of time to development of sight threatening ocular conditions(Day 1 to Week 48; Week 50 to Week 74 (Crossover participants))
- Part 1:Proportion of participants developing ocular diabetic complications in the study eye requiring treatment per SOC based on number of treatments received and duration of time from intervention to first treatment per SOC(Day 1 to Week 48; Week 50 to Week 74 (Crossover participants))
- Part 1: Proportion of participants developing ocular diabetic complications in the study eye requiring treatment per SOC based on duration of time from study intervention to first treatment and proportion of participants requiring more than 1 treatment(Day 1 to Week 48; or Week 50 to Week 74 (Crossover participants))
- Part 1: Proportion of participants developing ocular diabetic complications in the study eye requiring surgical intervention per SOC based on duration of time from study intervention to surgical intervention(Day 1 to Week 48; or Week 50 to Week 74 (Crossover participants))
- Part 1: Aqueous ABBV-RGX-314 TP concentration at assessed time points(Through Week 48 or Week 74 (Crossover participants))
- Part 1: Serum ABBV-RGX-314 TP concentration at assessed time points(Through Week 48 or Week 74 (Crossover participants))
- Part 2: Mean change from baseline in BCVA in the study eye over time(Through Week 54)
- Part 2: Proportion of participants with improved BCVA in the study eye over time(Through Week 54)
- Part 2: Proportion of participants with a worsening in DR in the study eye per the ETDRS-DRSS on 4 widefield digital stereoscopic fundus photography(At Week 14, Week 30, Week 38, and Week 54)
- Part 2: Proportion of participants achieving an improvement in DR in the study eye per the ETDRS-DRSS on 4 widefield digital stereoscopic fundus photography(At Week 14, Week 30, Week 38, and Week 54)
- Part 2: Proportion of participants achieving a 0-step (no change) or greater improvement in DR in the study eye per the ETDRS-DRSS on 4 widefield digital stereoscopic fundus photography(At Week 66 and Week 82 (Crossover participants))
- Part 2: Proportion of participants with a worsening in DR in the study eye per the ETDRS-DRSS on 4-widefield digital stereoscopic fundus photography(At Week 66 and Week 82 (Crossover participants))
- Part 2: Mean change from baseline in the study eye in ETDRS-DRSS severity steps at Week 22, Week 38, and Week 54 and (CO participants) change from Week 56 at Week 74 and Week 82(Baseline to Week 22, Week 38, and Week 54; Week 56 to Week 74 and Week 82 (Crossover participants))
- Part 2: Proportion of participants with an absence of CI-DME in the study eye(At Week 54)
- Part 2: Incidences of overall and ocular AEs(Through Week 54 or Week 82 (Crossover participants))
- Part 2: Vector shedding analysis in serum, urine, and tears(Through Week 54 or Week 82 (Crossover participants))
- Part 2: Proportion of participants who experience ocular inflammation in the study eye following SCS ABBV-RGX-314 administration(Through Week 54 or Week 82 (Crossover participants))
- Part 2: Proportion of participants requiring any additional intervention in the study eye for ocular diabetic complications to Week 54 and (CO participants) Week 82(Through Week 54 or Week 82 (Crossover participants))
- Part 2: Proportion of participants with any sight threatening ocular diabetic complications in the study eye based on duration of time to development of sight-threatening ocular conditions(Day 1 to Week 54; Week 56 to Week 82 (Crossover participants))
- Part 2: Proportion of participants developing ocular diabetic complications in the study eye requiring treatment per SOC based on number of treatments received and duration of time from study intervention to first treatment per SOC(Day 1 to Week 54; Week 56 to Week 82 (Crossover participants))
- Part 2: Proportion of participants developing ocular diabetic complications in the study eye requiring treatment per SOC based on duration of time from study intervention to first treatment and proportion of participants requiring more than 1 treatment(Day 1 to Week 54; Week 56 to Week 82 (Crossover participants))
- Part 2: Proportion of participants developing ocular diabetic complications in the study eye requiring surgical intervention per SOC(Day 1 to Week 54; Week 56 to Week 82 (Crossover participants))
- Part 2: Mean change from baseline in CST in the study eye on SD OCT at Week 30 and Week 54(At Week 30 and Week 54)
- Part 2: Mean change from Week 54 in CST in the study eye on SD OCT at Week 82 (Crossover participants)(At Week 82)
- Part 2: Proportion of participants achieving a reduction in CST in the study eye on SD-OCT at Week 30 and Week 54(At Week 30 and Week 54)
- Part 2: Aqueous ABBV-RGX-314 TP concentration at assessed time points(Through Week 54 or Week 82 (Crossover participants))
- Part 2: Serum ABBV-RGX-314 TP concentration at assessed time points(Through Week 54 or Week 82 (Crossover participants))