FOCUS: An Open Label First in Human Phase I/II Multicentre Study to Evaluate the Safety, Dose Response and Efficacy of GT005 Administered as a Single Subretinal Injection in Subjects With Macular Atrophy Due to AMD
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 56
- 试验地点
- 13
- 主要终点
- Ocular Treatment Emergent Adverse Events by Primary System Organ Class and Preferred Term for the Study Eye
研究概览
简要总结
This was an open label first in human Phase I/II multicentre study of GT005 in subjects with Macular Atrophy due to Age-related macular degeneration (AMD).
详细描述
This was an open label first-in-human Phase I/II multicenter study to evaluate the safety, dose response and efficacy of GT005 in participants with Geographic atrophy (GA) due to Age-related macular degeneration (AMD).
The study treatment GT005 consists of an Adeno-associated virus serotype 2 (AAV2) expressing human complement factor I (hCFI). The treatment was administered as a single subretinal administration in one eye - the "study eye". Both eyes were assessed at the screening visit. If both eyes meet the eligibility criteria, the study eye will be the worse seeing eye, or the eye with the largest geographic atrophy (GA) lesion area for eyes with equivalent visual acuity, unless the participant (in consultation with the surgeon) expresses an alternative preference.
The study was conducted in 4 parts: in Part 1 and Part 2 GT005 was administered subretinally via transvitreal procedure; in Part 3 and 4 GT005 was delivered subretinally via a suprachoroidal cannulation with the Orbit Subretinal delivery system (SDS). The Orbit SDS is a 510(k) cleared device in the US, whereby Parts 3 and 4 were only conducted at US sites. The treatment consisted in 3 dose levels: low dose, 2E10 vector genomes (vg); medium dose, 5E10 vg; and high dose, 2E11 vg.
The study consisted of up to 13 visits over a 5-year period. All participants were assessed for the occurrence of treatment emergent adverse events (AE)s at each visit and underwent visual function and retinal imaging assessments and biological sampling as per the schedule of assessments.
This study was conducted in compliance with Independent ethics committees (IECs) / Institutional review boards (IRBs), informed consent regulations, the Declaration of Helsinki, nternational Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and the Food and Drug Administration (FDA) guidance.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
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 consent to study participation
- •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)
- •Cohorts 1 to 6: GA lesion(s) total size in the study eye must be ≥1.25mm2 and ≤17.5mm
- •Cohort 7: GA lesion(s) total size in the study eye must be ≥1.25mm2
- •GA lesion(s) in the study eye must reside completely within the FAF fundus image
- •Cohorts 1 to 3: BCVA of ≤50 letters (6/36 Snellen acuity equivalent or worse) using ETDRS charts in the study eye Cohorts 4 to 7: BCVA of ≥24 letters (6/95 and 20/320 Snellen acuity equivalent or better) using ETDRS charts in the study eye
- •Aged ≥55 years
- •Able to attend all study visits and complete the study procedures
- •Women of child-bearing potential need to have a negative urine pregnancy test within two weeks prior to receiving the drug. 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
- •Have evidence or history of Choroidal Neovascularisation (CNV) in the study eye. Subjects 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
- •Presence of moderate/severe non-proliferative diabetic retinopathy or worse 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 aluminum 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 more than two topical agents; a history of glaucoma-filtering or valve surgery is also excluded
- •Axial myopia of greater than -8 diopters in the study eye
- •Have received any investigational product 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
- •Have received a gene or cell therapy at any time
- •Have a contraindication to the specified protocol corticosteroid regimen
- •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
- •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
- •Cohorts 5 to 7 only: presence of metallic objects or implanted stimulator devices in or near the head, including cochlear implants, deep brain stimulators, vagus nerve stimulators, and other implanted electrodes or stimulators
研究组 & 干预措施
GT005 2E10 vg via Transvitreal Procedure
GT005 2E10 vg via Transvitreal Procedure
干预措施: GT005 (Biological)
GT005 5E10 vg via Transvitreal Procedure
GT005 5E10 vg via Transvitreal Procedure
干预措施: GT005 (Biological)
GT005 2E11 vg via Transvitreal Procedure
GT005 2E11 vg via Transvitreal Procedure
干预措施: GT005 (Biological)
GT005 5E10 vg with Orbit Subretinal Delivery System
GT005 5E10 vg with Orbit Subretinal Delivery System
干预措施: GT005 / Device: Orbit™ Subretinal Delivery System (Device)
GT005 2E11 vg with Orbit Subretinal Delivery System
GT005 2E11 vg with Orbit Subretinal Delivery System
干预措施: GT005 / Device: Orbit™ Subretinal Delivery System (Device)
结局指标
主要结局
Ocular Treatment Emergent Adverse Events by Primary System Organ Class and Preferred Term for the Study Eye
时间窗: Adverse events are reported from the single dose of study medication administration until end of study treatment plus 240 weeks post treatment, up to a maximum timeframe of approximately 240 weeks.
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject. A TEAE is defined as any AE that develops after randomization or any AE already present that worsens following randomization. The primary summaries of AEs are based on TEAEs. System organ classes are sorted alphabetically, and preferred terms are sorted by decreasing overall frequency within system organ class.
Summary of Non-Ocular Treatment Emergent Adverse Events
时间窗: Adverse events are reported from the single dose of study medication administration until end of study treatment plus 240 weeks post treatment, up to a maximum timeframe of approximately 240 weeks.
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject. A TEAE is defined as any AE that develops after randomization or any AE already present that worsens following randomization. The primary summaries of AEs are based on TEAEs.
Summary of Ocular Serious Treatment-Emergent Adverse Events in the Study Eye by System Organ Class and Preferred
时间窗: Adverse events are reported from the single dose of study medication administration until end of study treatment plus 240 weeks post treatment, up to a maximum timeframe of approximately 240 weeks.
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject. A TEAE is defined as any AE that develops after randomization or any AE already present that worsens following randomization. The primary summaries of AEs are based on TEAEs.
次要结局
- Best Corrected Visual Acuity (BCVA) (in Early Treatment Diabetic Retinopathy Study (ETDRS) Letters) in the Study Eye(Up to Week 240)
- Low-Luminance Deficit Best Corrected Visual Acuity (BCVA-LLVA) (in Early Treatment Diabetic Retinopathy Study (ETDRS) Letters) in the Study Eye(Up to Week 240)
- Macular Sensitivity Parameters by Mesopic Microperimetry (MP) Over Time in the Study Eye - MP Bivariate Contour Ellipse Area (BCEA) 63 Area (deg2)(Up to Week 240)
- Macular Sensitivity Parameters by Mesopic Microperimetry (MP) Over Time in the Study Eye - MP Bivariate Contour Ellipse Area (BCEA) 95 Area (deg2)(Up to Week 240)
- Macular Sensitivity Parameters by Mesopic Microperimetry (MP) Over Time in the Study Eye - MP Mean Sensitivity Decibel (dB)(Up to Week 240)
- Macular Sensitivity Parameters by Mesopic Microperimetry (MP) Over Time in the Study Eye - MP Number of Scotomatous Points(Up to Week 240)
- Macular Sensitivity Parameters by Mesopic Microperimetry (MP) Over Time in the Study Eye - MP Percent Fixation Loss (%)(Up to Week 240)
- Change From Baseline Over Time in Square Root of Geographic Atrophy Area Size (mm) Via FAF in the Study Eye(Up to Week 240)
- Delivery of GT005 to the Subretinal Space - Rate of Successful Delivery, % (US Only) Via the Orbit Subretinal Delivery System (SDS) Device(Day 1)
- Delivery of Balanced Salt Solution (BSS) or BSS PLUS (BSS+) to the Subretinal Space - Rate of Successful Delivery, % (US Only) Via the Orbit Subretinal Delivery System (SDS) Device(Day 1)
- Summary of Ocular Treatment-Emergent Adverse Events Related to Surgical Procedure in the Study Eye(Day 1)
- Summary of Non-Ocular Treatment-Emergent Adverse Events Related to Surgical Procedure(Day 1)
- Summary of Ocular Serious Treatment-Emergent Adverse Events Related to Surgical Procedure in the Study Eye(Day 1)
- Summary of Non-Ocular Serious Treatment-Emergent Adverse Events Related to Surgical Procedure(Day 1)