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

简要总结

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. Following randomization, the investigator was informed of the subject's allocated treatment (GT005 or the untreated control group) and the study eye selected. To minimize bias, all imaging endpoint assessments and grading were performed at a Central Reading Centre (CRC), in a masked fashion. For part 1, the Sponsor, subject, investigators, and study personnel performing clinical assessments remained masked to dose received for those allocated to GT005. For part 2, the Sponsor, investigators, subjects, and study personnel performing clinical assessments were unmasked to dose received, since only the low dose was administered. Subjects randomized to GT005 underwent a single time subretinal administration of the study drug. Vitreous samples were collected during surgery. Following surgery, a prophylactic steroid regimen was prescribed. The study consisted of a screening period lasting up to 8 weeks (or up to 12 weeks if agreed by the Sponsor Medical Monitor), followed by a 96-week study period. All subjects were assessed for the occurrence of adverse events (AEs) at each visit and underwent functional visual and retinal imaging,anatomical assessments, and biological sampling as per the schedule of assessments. This study was conducted in compliance with Independent ethics committees (IECs) / Institutional review board (IRBs), informed consent regulations, the Declaration of Helsinki, International Council on Harmonisation (ICH) Good Clinical Practices (GCP) Guidelines, and the Food and Drug Administration (FDA) guidance. On 24-Aug-2023, the decision was taken to terminate the study and the GT005 program. The decision was aligned with the recommendation of an independent DMC, which concluded that futility criteria had been met for the HORIZON study (GT005-03) and the overall benefit-risk ratio did not support continuation of the current development program as planned. All GT005- treated subjects, who were willing to be transferred into the long-term safety follow-up study were enrolled in the ORACLE (CPPY988A12203B / NCT05481827) study. In both Part 1 and Part 2, patients with geographic atrophy secondary to age-related macular degeneration were enrolled. In Part 1, patients with CFI rare variant genotype and low serum CFI level and in Part 2, patients were enrolled regardless of genotypes. Efficacy results were analyzed by arm and also by part. AE and disposition data were reported per arm, but the parts were combined, according to the analysis plan. Part 1 enrolled subjects with CFI rare variant; Part 2 enrolled subjects regardless of genotype. There were no subjects in the high dose arm in Part 2.

主要结局

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)