Diabetic Macular Edema, Diabetic Retinopathy
Conditions
Keywords
ADVM-022, ADVM-022-04, AAV.7m8, Anti-VEGF therapy, Blindness, INFINITY, Gene therapy, Aflibercept (Eylea), Retinal Diseases, Eye Diseases, AAV Vector, Adverum, DME, Diabetic macular edema, Diabetic eye disease, Diabetic retinopathy, DR, AAV.7m8-aflibercept, Ixoberogene soroparvovec, Ixo-vec
Brief summary
A Phase 2, Multi-Center, Randomized, Double-Masked\*, Active Controlled Study of ADVM-022 (AAV.7m8-aflibercept) in Subjects with Diabetic Macular Edema \[INFINITY\]
Detailed description
ADVM-022 (also known as Ixo-vec and AAV.7m8-aflibercept) is an investigational gene therapy product developed for the treatment of serious retinal vascular diseases including Diabetic Macular Edema (DME), a vision-threatening complication of diabetic retinopathy. DME can affect up to 10% of individuals with both type 1 and type 2 diabetes mellitus. Current therapies for treating DME include anti-vascular endothelial growth factor (anti-VEGF) agents that require frequent and long-term intravitreal (IVT) injections to achieve and maintain efficacy. ADVM-022 is intended provide sustained intraocular expression of aflibercept from a single IVT injection to potentially reduce the current treatment burden and prevent disease progression and vision loss due to undertreatment. This Phase 2, randomized, controlled study (INFINITY) enrolled 36 eligible participants with DME. The participants were randomized to receive one of the two dose levels of ADVM-022 or assigned to the control arm to receive a sham ocular injection with a preceding aflibercept injection. Participants randomized to the ADVM-022 arms were assigned to receive a preceding aflibercept or sham ocular injection. All participants were monitored regularly for disease activity and may have received supplemental aflibercept based on predefined retreatment criteria. All participants were to be followed over a 96- week follow-up period. To enhance safety monitoring for participants in this study, the sponsor unmasked treatment assignment (in April 2021) due to the occurrence of a suspected unexpected serious adverse reaction (SUSAR) which occurred early in the study in the high dose (ADVM-022 6E11 vg/eye) arm. Interpretation of the results of this study should consider the potential confounding nature of this unmasking in the context of the observed dose-limiting events and the associated additional use of topical/intravitreal/systemic steroids, particularly in the high dose ADVM-022 arm. In this study ADVM-022 (Ixo-vec) demonstrated improved efficacy across endpoints, reducing the need for supplemental aflibercept in DME management and demonstrating a clinically meaningful delay in DME worsening and improved outcomes across multiple endpoints compared to the control arm (sham + Aflibercept). However, the benefit of the ADVM-022 6E11 vg/eye dose was affected by dose-limiting toxicities in some participants. In terms of safety outcomes, the most common ADVM-022-related adverse events were mild-to-moderate intraocular inflammation, a known and expected side effect of ocular gene therapy, which was generally responsive to corticosteroid eye drops. No Ixo-vec-related events were reported in the fellow eye or systemically, indicating no off-target effects.
Interventions
BIOLOGICAL6E11 vg/eye of ADVM-022
ADVM-022 (AAV.7m8-aflibercept) is a recombinant, replication-incompetent adeno-associated virus (AAV.7m8) gene therapy vector carrying a coding sequence for aflibercept
BIOLOGICAL2E11 vg/eye of ADVM-022
ADVM-022 (AAV.7m8-aflibercept) is a recombinant, replication-incompetent adeno-associated virus (AAV.7m8) gene therapy vector carrying a coding sequence for aflibercept
BIOLOGICALAflibercept
Commercially available Active Comparator
Sponsors
Adverum Biotechnologies, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
From May 2020 through April 2021: Double-masked study - participants, outcomes assessors and the designated masked study personnel were to have been masked to subject's treatment assignment throughout the study. There must have been a minimum of two physicians per site to fulfill the masking requirements of the study. A masked and unmasked investigator were required to be present for administration of the preceding dose of aflibercept or sham and following dose of ADVM-022 or sham visits, thereafter only the masked investigator was required to be present. Starting April 2021: Open label study - study was unmasked for enhanced safety monitoring.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 * Type 1 or Type 2 diabetes mellitus * Willing and able to provide informed consent * Vision impairment due to center involving diabetic macular edema
Exclusion criteria
* Uncontrolled diabetes defined as HbA1C \>10%, or history of diabetic ketoacidosis within 3 months prior to randomization; or subjects who, within the last 3 months, initiated intensive insulin treatment (a pump or multiple daily injection) or plan to do so in the next 3 months. * Acute coronary syndrome, myocardial infarction or coronary artery revascularization, CVA, TIA in the last 6 months * Uncontrolled hypertension defined as average SBP ≥160 mmHg or an average DBP ≥100 mmHg * Known severe renal impairment * High risk Proliferative Diabetic Retinopathy * History of retinal disease in the study eye other than diabetic retinopathy * History of retinal detachment (with or without repair) in the study eye * History of vitrectomy, trabeculectomy, or other filtration surgery in the study eye * Any prior focal or grid laser photocoagulation or any prior PRP in the study eye * Current or planned pregnancy or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Worsening of DME Disease Activity in the Study Eye. | Day 1 through 96 weeks | Time to worsening of DME disease activity in the study eye through 96 weeks. Time to worsening of DME disease activity defined by either: An increase in CST \> 50 µm as assessed by SD-OCT compared to the lower of the two CST measurements recorded at Day 1 or Week 4; A loss of \> 5 letters in BCVA due to worsening DME disease activity compared to the higher of the two BCVA measurements recorded at Day 1 or Week 4. Number of weeks was relative to Day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Ocular Adverse Events (AEs) | 96 weeks | Incidence of ocular adverse events (AEs) through 96 weeks |
| Incidence of Non-ocular Adverse Events (AEs) | Day 1 through 96 weeks | Incidence of non-ocular adverse events (AEs) through 96 weeks. |
| Change From Baseline Central Subfield Thickness (CST) in Study Eye | Baseline through 96 weeks | Central subfield thickness is a measurement of the thickness of the retina in a circular area around the fovea. Least squares mean change from Baseline in central subfield thickness at Week 96 is presented for the study eye. |
| Frequency of Supplemental Aflibercept Injections (2 mg IVT) in the Study Eye Over Time During the Study | Day 1 through 96 weeks | Frequency of supplemental aflibercept (2 mg IVT) injections was assessed in the study eye over time during the study. Participants were analyzed according to the study treatments they actually received on Days 1 and 8. The rate of supplemental aflibercept per year = Total number of supplemental aflibercept injections / Total years at-risk (at-risk duration starting at Day 8). |
| Incidence of 2-step Improvement in Diabetic Retinopathy Severity Score (DRSS) in the Study Eye Over Time | From Day 1 through 96 weeks | Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 and is divided into 13-steps used to classify increasing diabetic retinopathy severity (with higher scored indicating more advanced stages of Diabetic Retinopathy). In this endpoint a 2-step improvement indicates an improvement in a participant across 2 steps of the 13-step scale. |
| Change From Baseline in Best Corrected Visual Acuity (BCVA) Score Over Time in the Study Eye | 96 weeks | Least squares mean change from Baseline in BCVA score over time was measured over time through week 96 in the study eye by ETDRS letters. |
| Incidence of 2-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | From Day 1 through 96 weeks | Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 and is divided into 13-steps used to classify increasing diabetic retinopathy severity (with higher scored indicating more advanced stages of Diabetic Retinopathy). In this endpoint a 2-step worsening indicates a worsening across 2 steps of the 13-step scale. Note: 2-step worsening in DRSS was observed in 2 participants in both the control arm and the ADVM-022 6E11 vg/eye arm. These participants experienced ocular adverse events which may have contributed, at least in part, to the worsening in DRSS. This included one participant in the ADVM-022 6E11 vg/eye arm who had a SUSAR of Hypotony of eye (secondary to intraocular inflammation). |
| Incidence of 3-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | From Day 1 through 96 weeks | Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 with higher scored indicating more advanced stages of Diabetic Retinopathy. The incidence of 3-step worsening in DRSS score over time at Week 96 is presented. Visits with a 3-step or greater worsening in DRSS were considered separate events. Note: 3-step worsening in DRSS was observed in one participant each in the control arm and the ADVM-022 6E11 vg/eye arm. Both participants experienced ocular adverse events which may have contributed, at least in part, to the worsening in DRSS. This included one participant in the ADVM-022 6E11 vg/eye arm who had a SUSAR of Hypotony of eye (secondary to intraocular inflammation). |
| Occurrence of Any Vision Threatening Complications in the Study Eye (Anterior Segment Neovascularization, Vitreous Hemorrhage, or Any Other High-risk Proliferative DR, or Tractional Retinal Detachment) Over Time Through Week 96 | From Day 1 through 96 weeks | Occurrence of any vision threatening complication over time though 96 weeks. Results present the incidence of participants who experienced Any Vision Threatening Complications (defined as any Vitreous Haemorrhage adverse event (AE), Anterior Segment Neovascularization AE, High-risk proliferative DR (defined as DSSR \>= 71), or Tractional Retinal Detachment AE) in the study eye from Day 1 through 96 weeks. Note: AEs of Vitreous Haemorrhage and High-risk proliferative DR were reported in 1 participant in the control arm and in 2 separate participants in the 6E11 vg/eye arm. No AE of Tractional Retinal Detachment or Anterior Segment Neovascularization occurred. |
| Incidence of CST <300 μm Over Time Through Week 96 in the Study Eye | Day 1 through 96 weeks | Central subfield thickness is a measurement of the thickness of the retina in a circular area around the fovea. Incidence of participants with Central subfield thickness of less than 300 μm over time in the study eye through Week 96 is presented. |
| Incidence of 3-step Improvement in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | From Day 1 through 96 weeks | Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 and is divided into 13-steps used to classify increasing diabetic retinopathy severity (with higher scored indicating more advanced stages of Diabetic Retinopathy). In this endpoint a 3-step improvement indicates an improvement in a participant across 3 steps of the 13-step scale. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Two doses of ADVM-022 (Ixo-vec) were investigated, administered with or without a prior loading dose of Aflibercept. The control group received the initial loading dose of Aflibercept (Day 1) but received a Sham injection on Day 8 instead of Ixo-vec. Only one eye was selected as the study eye. After the assigned intravitreal (IVT) injections on Days 1 and 8, clinic visits were on Weeks 2, 4, and every 4 weeks up to Week 96. Consenting participants then entered a long-term follow-up study.
Pre-assignment details
Participants with initial diagnosis of DME within 6 months of screening, and who had received up to 2 prior injections of anti-VEGF therapy in the study eye (0, 1 or 2) were eligible for enrollment. If a prior anti-VEGF had been administered to the study eye, in the judgement of the Investigator, there must have been a meaningful CST response (e.g., ≥ 10% reduction) and no adverse reaction to the anti-VEGF (e.g., intraocular inflammation).
Participants by arm
| Arm | Count |
|---|---|
| ADVM-022 6E11 vg/Eye 6E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT
6E11 vg/eye of ADVM-022: ADVM-022 (AAV.7m8-aflibercept) is a recombinant, replication-incompetent adeno-associated virus (AAV.7m8) gene therapy vector carrying a coding sequence for aflibercept
Aflibercept: Commercially available Active Comparator | 13 |
| ADVM-022 2E11 vg/Eye 2E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT
2E11 vg/eye of ADVM-022: ADVM-022 (AAV.7m8-aflibercept) is a recombinant, replication-incompetent adeno-associated virus (AAV.7m8) gene therapy vector carrying a coding sequence for aflibercept
Aflibercept: Commercially available Active Comparator | 13 |
| Aflibercept + Sham Aflibercept 2mg IVT
Aflibercept: Commercially available Active Comparator | 10 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 | 2 |
| Overall Study | Pre-existing medical condition | 0 | 1 | 0 |
| Overall Study | Subject Discontinued by the Sponsor | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | ADVM-022 6E11 vg/Eye | ADVM-022 2E11 vg/Eye | Aflibercept + Sham | Total |
|---|---|---|---|---|
| Age, Continuous | 62.8 Years STANDARD_DEVIATION 5.94 | 60.5 Years STANDARD_DEVIATION 8.28 | 56.6 Years STANDARD_DEVIATION 5.68 | 60.3 Years STANDARD_DEVIATION 7.09 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 7 Participants | 6 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 4 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 10 Participants | 10 Participants | 31 Participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 5 Participants | 15 Participants |
| Sex: Female, Male Male | 7 Participants | 9 Participants | 5 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 1 / 13 | 0 / 9 |
| other Total, other adverse events | 12 / 12 | 13 / 13 | 9 / 9 |
| serious Total, serious adverse events | 9 / 12 | 8 / 13 | 4 / 9 |
Outcome results
Primary
Time to Worsening of DME Disease Activity in the Study Eye.
Time to worsening of DME disease activity in the study eye through 96 weeks. Time to worsening of DME disease activity defined by either: An increase in CST \> 50 µm as assessed by SD-OCT compared to the lower of the two CST measurements recorded at Day 1 or Week 4; A loss of \> 5 letters in BCVA due to worsening DME disease activity compared to the higher of the two BCVA measurements recorded at Day 1 or Week 4. Number of weeks was relative to Day 1.
Time frame: Day 1 through 96 weeks
Population: The Modified Intent to Treat population (mITT) was analyzed for this endpoint (mITT population includes all randomized participants who received study treatment at both Day 1 \[Aflibercept or Sham\] and Day 8 \[Ixo-vec or Sham\]).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Time to Worsening of DME Disease Activity in the Study Eye. | 82.1 Weeks |
| ADVM-022 2E11 vg/Eye | Time to Worsening of DME Disease Activity in the Study Eye. | 96.1 Weeks |
| Aflibercept + Sham | Time to Worsening of DME Disease Activity in the Study Eye. | 19.1 Weeks |
Secondary
Change From Baseline Central Subfield Thickness (CST) in Study Eye
Central subfield thickness is a measurement of the thickness of the retina in a circular area around the fovea. Least squares mean change from Baseline in central subfield thickness at Week 96 is presented for the study eye.
Time frame: Baseline through 96 weeks
Population: The Modified Intent to Treat population (mITT) was analyzed for this endpoint (mITT population includes all randomized participants who received study treatment at both Day 1 \[Aflibercept or Sham\] and Day 8 \[Ixo-vec or Sham\]).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Change From Baseline Central Subfield Thickness (CST) in Study Eye | -84.4 micrometers |
| ADVM-022 2E11 vg/Eye | Change From Baseline Central Subfield Thickness (CST) in Study Eye | -129.7 micrometers |
| Aflibercept + Sham | Change From Baseline Central Subfield Thickness (CST) in Study Eye | -129.7 micrometers |
Secondary
Change From Baseline in Best Corrected Visual Acuity (BCVA) Score Over Time in the Study Eye
Least squares mean change from Baseline in BCVA score over time was measured over time through week 96 in the study eye by ETDRS letters.
Time frame: 96 weeks
Population: The Modified Intent to Treat population (mITT) was analyzed for this endpoint (mITT population includes all randomized participants who received study treatment at both Day 1 \[Aflibercept or Sham\] and Day 8 \[Ixo-vec or Sham\]).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Change From Baseline in Best Corrected Visual Acuity (BCVA) Score Over Time in the Study Eye | -11.9 ETDRS letters |
| ADVM-022 2E11 vg/Eye | Change From Baseline in Best Corrected Visual Acuity (BCVA) Score Over Time in the Study Eye | 10.1 ETDRS letters |
| Aflibercept + Sham | Change From Baseline in Best Corrected Visual Acuity (BCVA) Score Over Time in the Study Eye | 17.1 ETDRS letters |
Secondary
Frequency of Supplemental Aflibercept Injections (2 mg IVT) in the Study Eye Over Time During the Study
Frequency of supplemental aflibercept (2 mg IVT) injections was assessed in the study eye over time during the study. Participants were analyzed according to the study treatments they actually received on Days 1 and 8. The rate of supplemental aflibercept per year = Total number of supplemental aflibercept injections / Total years at-risk (at-risk duration starting at Day 8).
Time frame: Day 1 through 96 weeks
Population: The Modified Intent to Treat population (mITT) was analyzed for this endpoint (mITT population includes all randomized participants who received study treatment at both Day 1 \[Aflibercept or Sham\] and Day 8 \[Ixo-vec or Sham\]).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Frequency of Supplemental Aflibercept Injections (2 mg IVT) in the Study Eye Over Time During the Study | 1.001 Injections/year |
| ADVM-022 2E11 vg/Eye | Frequency of Supplemental Aflibercept Injections (2 mg IVT) in the Study Eye Over Time During the Study | 0.423 Injections/year |
| Aflibercept + Sham | Frequency of Supplemental Aflibercept Injections (2 mg IVT) in the Study Eye Over Time During the Study | 5.54 Injections/year |
Secondary
Incidence of 2-step Improvement in Diabetic Retinopathy Severity Score (DRSS) in the Study Eye Over Time
Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 and is divided into 13-steps used to classify increasing diabetic retinopathy severity (with higher scored indicating more advanced stages of Diabetic Retinopathy). In this endpoint a 2-step improvement indicates an improvement in a participant across 2 steps of the 13-step scale.
Time frame: From Day 1 through 96 weeks
Population: The Modified Intent to Treat population (mITT) was analyzed for this endpoint (mITT population includes all randomized participants treated on both Day 1 \[Aflibercept or Sham\] and Day 8 \[Ixo-vec or Sham\]). Only mITT participants whose Baseline Score permitted a ≥ 2 step DRSS improvement were eligible for this analysis. The incidence of 2-step improvement in DRSS score over time at Week 96 is presented.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Incidence of 2-step Improvement in Diabetic Retinopathy Severity Score (DRSS) in the Study Eye Over Time | 8 Participants |
| ADVM-022 2E11 vg/Eye | Incidence of 2-step Improvement in Diabetic Retinopathy Severity Score (DRSS) in the Study Eye Over Time | 8 Participants |
| Aflibercept + Sham | Incidence of 2-step Improvement in Diabetic Retinopathy Severity Score (DRSS) in the Study Eye Over Time | 4 Participants |
Secondary
Incidence of 2-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time
Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 and is divided into 13-steps used to classify increasing diabetic retinopathy severity (with higher scored indicating more advanced stages of Diabetic Retinopathy). In this endpoint a 2-step worsening indicates a worsening across 2 steps of the 13-step scale. Note: 2-step worsening in DRSS was observed in 2 participants in both the control arm and the ADVM-022 6E11 vg/eye arm. These participants experienced ocular adverse events which may have contributed, at least in part, to the worsening in DRSS. This included one participant in the ADVM-022 6E11 vg/eye arm who had a SUSAR of Hypotony of eye (secondary to intraocular inflammation).
Time frame: From Day 1 through 96 weeks
Population: The Modified Intent to Treat population (mITT) was analyzed for this endpoint (mITT population includes all randomized participants who received study treatment at both Day 1 \[Aflibercept or Sham\] and Day 8 \[Ixo-vec or Sham\]). The incidence of 2-step worsening in DRSS score over time at Week 96 is presented. Visits with a 2-step or greater worsening in DRSS were considered separate events.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Incidence of 2-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | 2 Participants |
| ADVM-022 2E11 vg/Eye | Incidence of 2-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | 0 Participants |
| Aflibercept + Sham | Incidence of 2-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | 2 Participants |
Secondary
Incidence of 3-step Improvement in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time
Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 and is divided into 13-steps used to classify increasing diabetic retinopathy severity (with higher scored indicating more advanced stages of Diabetic Retinopathy). In this endpoint a 3-step improvement indicates an improvement in a participant across 3 steps of the 13-step scale.
Time frame: From Day 1 through 96 weeks
Population: The Modified Intent to Treat population (mITT) was analyzed for this endpoint (mITT population includes all randomized participants treated on both Day 1 \[Aflibercept or Sham\] and Day 8 \[Ixo-vec or Sham\]). Only mITT participants whose Baseline Score permitted a ≥3 step DRSS improvement were eligible for this analysis. The incidence of 3-step improvement in DRSS score over time at Week 96 is presented. Visits with a 3-step or greater improvement in DRSS were considered separate events.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Incidence of 3-step Improvement in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | 3 Participants |
| ADVM-022 2E11 vg/Eye | Incidence of 3-step Improvement in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | 4 Participants |
| Aflibercept + Sham | Incidence of 3-step Improvement in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | 0 Participants |
Secondary
Incidence of 3-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time
Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 with higher scored indicating more advanced stages of Diabetic Retinopathy. The incidence of 3-step worsening in DRSS score over time at Week 96 is presented. Visits with a 3-step or greater worsening in DRSS were considered separate events. Note: 3-step worsening in DRSS was observed in one participant each in the control arm and the ADVM-022 6E11 vg/eye arm. Both participants experienced ocular adverse events which may have contributed, at least in part, to the worsening in DRSS. This included one participant in the ADVM-022 6E11 vg/eye arm who had a SUSAR of Hypotony of eye (secondary to intraocular inflammation).
Time frame: From Day 1 through 96 weeks
Population: The Modified Intent to Treat population (mITT) was analyzed for this endpoint (mITT population includes all randomized participants who received study treatment at both Day 1 \[Aflibercept or Sham\] and Day 8 \[Ixo-vec or Sham\]).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Incidence of 3-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | 1 Participants |
| ADVM-022 2E11 vg/Eye | Incidence of 3-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | 0 Participants |
| Aflibercept + Sham | Incidence of 3-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time | 1 Participants |
Secondary
Incidence of CST <300 μm Over Time Through Week 96 in the Study Eye
Central subfield thickness is a measurement of the thickness of the retina in a circular area around the fovea. Incidence of participants with Central subfield thickness of less than 300 μm over time in the study eye through Week 96 is presented.
Time frame: Day 1 through 96 weeks
Population: The Modified Intent to Treat population (mITT) was analyzed for this endpoint (mITT population includes all randomized participants who received study treatment at both Day 1 \[Aflibercept or Sham\] and Day 8 \[Ixo-vec or Sham\]). Incidence through last visit represent the last visit through Week 96 with non-missing CST data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Incidence of CST <300 μm Over Time Through Week 96 in the Study Eye | 8 Participants |
| ADVM-022 2E11 vg/Eye | Incidence of CST <300 μm Over Time Through Week 96 in the Study Eye | 6 Participants |
| Aflibercept + Sham | Incidence of CST <300 μm Over Time Through Week 96 in the Study Eye | 4 Participants |
Secondary
Incidence of Non-ocular Adverse Events (AEs)
Incidence of non-ocular adverse events (AEs) through 96 weeks.
Time frame: Day 1 through 96 weeks
Population: mITT population: participants who received treatment on Day 1 (aflibercept or Sham) and Day 8 (Ixo-vec or Sham) analyzed based on treatments they received on Days 1 and 8.~Note: two participants who were discontinued prior to Day 8 are not included in the mITT population. These two participants reported no adverse events.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Incidence of Non-ocular Adverse Events (AEs) | 9 Participants |
| ADVM-022 2E11 vg/Eye | Incidence of Non-ocular Adverse Events (AEs) | 9 Participants |
| Aflibercept + Sham | Incidence of Non-ocular Adverse Events (AEs) | 7 Participants |
Secondary
Incidence of Ocular Adverse Events (AEs)
Incidence of ocular adverse events (AEs) through 96 weeks
Time frame: 96 weeks
Population: mITT population: participants who received treatment on Day 1 (aflibercept or Sham) and Day 8 (Ixo-vec or Sham) analyzed based on treatments they received on Days 1 and 8. Ocular adverse events are presented for the Study Eye only.~Note: two participants who were discontinued prior to Day 8 are not included in the mITT population. These two participants reported no adverse events.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Incidence of Ocular Adverse Events (AEs) | 12 Participants |
| ADVM-022 2E11 vg/Eye | Incidence of Ocular Adverse Events (AEs) | 13 Participants |
| Aflibercept + Sham | Incidence of Ocular Adverse Events (AEs) | 9 Participants |
Secondary
Occurrence of Any Vision Threatening Complications in the Study Eye (Anterior Segment Neovascularization, Vitreous Hemorrhage, or Any Other High-risk Proliferative DR, or Tractional Retinal Detachment) Over Time Through Week 96
Occurrence of any vision threatening complication over time though 96 weeks. Results present the incidence of participants who experienced Any Vision Threatening Complications (defined as any Vitreous Haemorrhage adverse event (AE), Anterior Segment Neovascularization AE, High-risk proliferative DR (defined as DSSR \>= 71), or Tractional Retinal Detachment AE) in the study eye from Day 1 through 96 weeks. Note: AEs of Vitreous Haemorrhage and High-risk proliferative DR were reported in 1 participant in the control arm and in 2 separate participants in the 6E11 vg/eye arm. No AE of Tractional Retinal Detachment or Anterior Segment Neovascularization occurred.
Time frame: From Day 1 through 96 weeks
Population: The Modified Intent to Treat population (mITT) was analyzed for this endpoint (mITT population includes all randomized participants who received study treatment at both Day 1 \[Aflibercept or Sham\] and Day 8 \[Ixo-vec or Sham\]).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADVM-022 6E11 vg/Eye | Occurrence of Any Vision Threatening Complications in the Study Eye (Anterior Segment Neovascularization, Vitreous Hemorrhage, or Any Other High-risk Proliferative DR, or Tractional Retinal Detachment) Over Time Through Week 96 | 2 Participants |
| ADVM-022 2E11 vg/Eye | Occurrence of Any Vision Threatening Complications in the Study Eye (Anterior Segment Neovascularization, Vitreous Hemorrhage, or Any Other High-risk Proliferative DR, or Tractional Retinal Detachment) Over Time Through Week 96 | 0 Participants |
| Aflibercept + Sham | Occurrence of Any Vision Threatening Complications in the Study Eye (Anterior Segment Neovascularization, Vitreous Hemorrhage, or Any Other High-risk Proliferative DR, or Tractional Retinal Detachment) Over Time Through Week 96 | 1 Participants |