EXPLORE: A Phase II, Outcomes Assessor-masked, Multicentre, Randomised Study to Evaluate the Safety and Efficacy of Two Doses of GT005 Administered as a Single Subretinal Injection in Subjects With Geographic Atrophy Secondary to Age-related Macular Degeneration
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 98
- 试验地点
- 73
- 主要终点
- The Change From Baseline to Week 48 in Geographic Atrophy (GA) - Part 1
研究概览
简要总结
The purpose of this clinical study was to evaluate the safety and efficacy of two doses of GT005 administered as a single subretinal injection in subjects with geographic atrophy secondary to age-related macular degeneration (AMD).
详细描述
This was a Phase II, outcomes assessor-masked, multicentre, randomized study to assess the safety and efficacy of two doses of GT005 administered as a single-time subretinal injection in subjects with Geographic Atrophy (GA) secondary to age-related macular degeneration (AMD). Approximately 202 subjects were planned to be randomized to GT005 or the untreated control group.
Subjects entered the study had genotyping and serum complement factor I(CFI) levels assessed. Assessments were either performed at a sponsor-approved laboratory during the EXPLORE screening period or provided through participation in a previous Gyroscope sponsored study. If subjects failed to meet the eligibility criteria for EXPLORE, they were classified as screen failures for this study and could be considered for entry into another Novartis/Gyroscope sponsored study.
After providing the informed consent, subjects underwent ophthalmic and clinical assessments to determine eligibility for inclusion in the study.
Upon confirmation of eligibility, subjects in part 1 were randomized to one of two groups: low dose [2E10 vg], or high dose [2E11 vg]. Within each group, subjects were allocated to GT005 or untreated control based on a 2:1 ratio. Once part 1 enrolment was completed, and the last active subject completed screening and either was screen-failed or randomized, then Part 2 could commence. In part 2, subjects were randomized to the low dose [2E10] group or untreated control based on a 2:1 ratio. The study eye was identified for all subjects.
Subjects were stratified by GA lesion size on fundus autofluorescence (FAF) (≤10 mm2 or >10 mm2) and presence of choroidal neovascularisation (CNV) in the fellow eye (Yes or No). Randomization of study eyes in the GA lesion size upper stratum of >10 mm2 to 17.5 mm2 was capped at 20% of total subjects randomized. Once enrolment capping at 20% based on the upper GA lesion size was reached, eyes that fulfilled the cap criteria were no longer eligible, unless the subject had a CFI rare variant genotype (minor allele frequency ≤1%) previously associated with normal or low serum CFI or had an unreported CFI rare variant genotype. Of all subjects enrolled and randomized in the study, the presence of CNV in the fellow eye was capped at 25% per stratum. A permuted-block randomization method was used to obtain an approximately 2:1 ratio between GT005 and the untreated control groups for each dose group within each stratum.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The overall objectives of the study are to evaluate the safety and efficacy (anatomical and functional visual outcomes) of two doses of GT005 in genetically defined subjects with GA due to AMD.
入排标准
- 年龄范围
- 55 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able and willing to give written informed consent
- •Age ≥55 years
- •Have a clinical diagnosis of GA secondary to AMD in the study eye, as determined by the Investigator, and a diagnosis of AMD in the contralateral eye (except if the subject is monocular)
- •Have GA lesion(s) total size between or equal to 1.25mm2 to 17.5mm2 in the study eye
- •The GA lesion(s) in the study eye must reside completely within the FAF image
- •Up to 25% of the enrolled study population are permitted to have CNV in the fellow eye, defined as either:
- •Non-exudative/sub-clinical fellow eye CNV identified at Screening, or
- •Known history of fellow eye CNV with either ≥2 years since diagnosis or with no active treatment required in 6 months prior to Screening
- •Have a BCVA of 24 letters (6/95 and 20/320 Snellen acuity equivalent) or better, using ETDRS charts, in the study eye
- •Part 1 Only: Subjects carrying a CFI rare variant genotype (minor allele frequency of ≤1%) previously associated with low serum CFI or subjects carrying an unreported CFI rare variant genotype that have tested to have a low serum CFI
- •Able to attend all study visits and complete the study procedures
- •Women of child-bearing potential must have a negative pregnancy test within 2 weeks prior to randomisation. A pregnancy test is not required for postmenopausal women (defined as being at least 12 consecutive months without menses) or those surgically sterilised (those having a bilateral tubal ligation/bilateral salpingectomy, bilateral tubal occlusive procedure, hysterectomy, or bilateral oophorectomy)
排除标准
- •Subjects who have a clinical diagnosis of Stargardt Disease or other retinal dystrophies, confirmed by the central reading centre
- •Have a history, or evidence, of CNV in the study eye
- •Presence of moderate/severe or worse non-proliferative diabetic retinopathy in the study eye
- •Have history of vitrectomy, sub-macular surgery, or macular photocoagulation in the study eye
- •History of intraocular surgery in the study eye within 12 weeks prior to Screening (Visit 1). Yttrium aluminium garnet capsulotomy is permitted if performed >10 weeks prior to Visit 1
- •Have clinically significant cataract that may require surgery during the study period in the study eye
- •Presence of moderate to severe glaucomatous optic neuropathy in the study eye; uncontrolled IOP despite the use of two or more topical agents; a history of glaucoma-filtering or valve surgery is also excluded
- •Axial myopia of greater than -8 dioptres in the study eye
- •Have any other significant ocular or non-ocular medical or psychiatric condition which, in the opinion of the Investigator, may either put the subject at risk or may influence the results of the study
- •Have a contraindication to specified protocol corticosteroid regimen
- •Have received any investigational and/or approved product(s) for the treatment of GA within the past 6 months, or 5 half-lives (whichever is longer) other than nutritional supplements such as the age-related eye disease study (AREDS) formula in the study eye or systemically
- •Have received a gene or cell therapy at any time
- •Are unwilling to use two forms of contraception (one of which being a barrier method) for 90 days post-dosing, if relevant
- •Active malignancy within the past 12 months, except for: appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or prostate cancer with a stable prostate-specific antigen (PSA) ≥12 months
研究组 & 干预措施
GT005 Low dose [2E10 vg]
GT005 Low dose [2E10 vg] (Parts 1 and 2)
干预措施: GT005 (Drug)
GT005 High dose [2E11 vg]
GT005 High dose [2E11 vg] (Part 1)
干预措施: GT005 (Drug)
Untreated control
Untreated control (Parts 1 and 2)
结局指标
主要结局
The Change From Baseline to Week 48 in Geographic Atrophy (GA) - Part 1
时间窗: Baseline, Weeks 12, 24, 36, and 48
The change from baseline to Week 48 in GA area as measured by fundus autofluorescence (FAF)
次要结局
- The Change From Baseline in Geographic Atrophy (GA) at Week 72 and Week 96 - Part 1(Baseline, Weeks 72 and 96)
- Summary of Adverse Events - Parts 1 and 2 Combined(Adverse events are reported from randomization up to end of study, for a maximum timeframe of approximately 96 weeks.)
- Ocular Adverse Events by Primary System Organ Class and Preferred Term for the Study Eye - Parts 1 and 2 Combined(Adverse events are reported from randomization up to end of study, for a maximum timeframe of approximately 96 weeks.)
- Non-ocular Adverse Events - Summary - Parts 1 and 2 Combined(Adverse events are reported from randomization up to end of study, for a maximum timeframe of approximately 96 weeks.)
- Change in GA Morphology From Baseline to Week 96 on Colour Fundus Photography (CFP) - Number of Participants With Increase in Fundus Autofluorescence (FAF) - Part 1(Baseline, Weeks 5,12,24,36,48,72,96)
- Change From Baseline to Week 48 in GA Morphology on Colour Fundus Photography (CFP) - Number of Participants With Increase in Fundus Autofluorescence - Part 2(Baseline, Weeks 5,12,24,36,48)
- Change in Best Corrected Visual Acuity (BCVA) Score From Baseline Through Week 96 Via the Early Treatment for Diabetic Retinopathy (ETDRS) Chart - Part 1(Baseline, Weeks 1, 5, 8, 12, 24, 36, 48, 72 and 96)
- Change in Low Luminance Difference (LLD) Letter Count From Baseline at Weeks 12, 24, 36, 48, 72 and 96, Via Early Treatment for Diabetic Retinopathy (ETDRS) Chart - Part 1(Baseline, Weeks 12, 24, 36, 48, 72 and 96)
- Change in Low Luminance Difference (LLD) Letter Count From Baseline at Weeks 12, 24, 36, and 48, Via Early Treatment for Diabetic Retinopathy (ETDRS) Chart - Part 2(Baseline, Weeks 12, 24, 36, and 48)
- Change From Baseline at Weeks 24, 36, 48, 72 and 96 in Reading Performance, Measured as the Maximum Reading Speed (Words Per Minute), as Assessed by Minnesota Low-vision Reading Test (MNRead) Chart - Part 1(Baseline, Weeks 24, 36, 48, 72 and 96)
- Change From Baseline at Weeks 24, 36 and 48 in Reading Performance, Measured as the Maximum Reading Speed (Words Per Minute), as Assessed by Minnesota Low-vision Reading Test (MNRead) Chart - Part 2(Baseline, Weeks 24, 36 and 48)
- Change From Baseline at Weeks 24, 36, 48, 72 and 96 in Functional Reading Independence (FRI) Index - Part 1(Baseline, Weeks 24, 36, 48, 72 and 96)
- Change From Baseline at Weeks 24, 36 and 48 in Functional Reading Independence (FRI) Index - Part 2(Baseline, Weeks 24, 36 and 48)
- Change From Baseline at Weeks 24, 36, 48, 72 and 96 in Patient Reported Outcomes (Visual Function Questionnaire-25) - Composite Score - Part 1(Baseline, Weeks 24, 36, 48, 72 and 96)
- Change From Baseline at Weeks 24, 36 and 48 in Patient Reported Outcomes (Visual Function Questionnaire-25) - Composite Score - Part 2(Baseline, Weeks 24, 36, and 48)