Retinopathy of Prematurity
Conditions
Brief summary
The primary objective of the study is to assess the efficacy of aflibercept compared to laser in patients diagnosed with retinopathy of prematurity (ROP). The secondary objectives of the study are to assess the need for a second treatment modality, to assess the recurrence of ROP in the study and to assess the safety and tolerability of aflibercept.
Interventions
DRUGaflibercept
Administered IVT
PROCEDURElaser photocoagulation
Transpupillary conventional laser will be administered according to standard local procedures.
Sponsors
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-Label
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Gestational age at birth ≤ 32 weeks or birth weight ≤1500 g * Patients with treatment-naïve retinopathy of prematurity (ROP) classified according to the International Classification for ROP in at least one eye as: * Zone I Stage 1 plus, or 2 plus, or 3 non-plus or 3 plus, or * Zone II Stage 2 plus or 3 plus, or * Aggressive posterior retinopathy of prematurity (AP-ROP) Key
Exclusion criteria
* Known or suspected chromosomal abnormality, genetic disorder, or syndrome * Previous exposure to any Intravitreal (IVT) or systemic anti-vascular endothelial growth factor (VEGF) agent, including maternal exposure during pregnancy and/or during breastfeeding * Clinically significant neurological disease (eg, intraventricular hemorrhage grade 3 or higher, periventricular leukomalacia, congenital brain lesions significantly impairing optic nerve function, severe hydrocephalus with significantly increased intracranial pressure) * Pediatric conditions rendering the infant ineligible for study intervention at baseline or for repeated blood draws as evaluated by a neonatal intensive care unit specialist and a study ophthalmologist * Presence of active ocular infection within 5 days of the first treatment * Advanced stages of ROP with partial or complete retinal detachment (ROP stage 4 and stage 5) * ROP involving only Zone III NOTE: Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Absence of Active Retinopathy of Prematurity (ROP) and Unfavorable Structural Outcomes From Baseline to Week 52 of Chronological Age | Baseline to week 52 of chronological age | Active ROP was ROP requiring treatment and unfavorable structural outcome was defined as retinal detachment, macular dragging, macular fold, or retrolental opacity. For participants with both eyes enrolled in the study, both eyes must have met the endpoint. Participants with only one study eye enrolled were responders if the respective eye responded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Requiring Intervention With a Second Treatment Modality From Baseline to Week 52 of Chronological Age | Baseline to to week 52 of chronological age | Second treatment modality includes any treatment in addition to that assigned to the participant at baseline. This includes per-protocol rescue treatment (laser for aflibercept group, aflibercept for laser group), anti-VEGF agents not part of study protocol (e.g., bevacizumab, ranibizumab, commercially-available aflibercept not provided as study medication), or any ocular surgery for the management of any retinal pathology secondary to ROP (e.g., victrectomy, scleral buckle for retinal detachments). |
| Percentage of Participants With Recurrence of ROP Through Week 52 of Chronological Age | Baseline to week 52 of chronological age | Recurrence of disease is defined as the reappearance of the disease requiring further treatment (including retreatment or rescue), where both presence of ROP and presence of active ROP requiring treatment are marked as Yes, after initial regression. Here, the initial regression is defined as, at a particular visit, absence of ROP or ROP treatment not required for active ROP, i.e., presence of ROP is marked as No or the presence of active ROP requiring treatment is marked as No. |
| Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Baseline to Week 52 of chronological age | — |
| Percentage of Participants With Systematic (Non-ocular) TEAEs and TESAEs | Baseline to Week 52 of chronological age | — |
Countries
Bulgaria, Colombia, Czechia, Hungary, Romania, Russia, Slovakia, South Korea, Taiwan, Thailand, Turkey (Türkiye), United States, Vietnam
Participant flow
Recruitment details
137 participants were screened, 127 were randomized.
Pre-assignment details
Of the 127 participants randomized, 33 were randomized to laser and 94 were randomized to aflibercept. Six of the 33 participants randomized to laser were withdrawn before receiving any study intervention (5 due to Parent/Guardian and 1 due to Physician decision); One of the 94 participants randomized to aflibercept was withdrawn before receiving any study intervention due to Parent/Guardian. In total, 120 participants (27, laser group; 93, aflibercept group) received at least 1 study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Laser Photocoagulation Participants received laser treatment to each eligible eye at baseline (Day 1), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. If both eyes were eligible, they were assigned to the same treatment group. | 27 |
| Laser Photocoagulation Participants received laser treatment to each eligible eye at baseline (Day 1), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. If both eyes were eligible, they were assigned to the same treatment group. | 50 |
| Aflibercept 0.4 mg Participants received one intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (Day 1), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. If both eyes were eligible, they were assigned to the same treatment group. | 93 |
| Aflibercept 0.4 mg Participants received one intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (Day 1), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. If both eyes were eligible, they were assigned to the same treatment group. | 179 |
| Total | 349 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Withdrawal By Parent/Guardian | 1 | 2 |
Baseline characteristics
| Characteristic | Aflibercept 0.4 mg | Total | Laser Photocoagulation |
|---|---|---|---|
| Age, Continuous | 9.76 Weeks STANDARD_DEVIATION 3.149 | 10.06 Weeks STANDARD_DEVIATION 3.476 | 11.09 Weeks STANDARD_DEVIATION 4.338 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 20 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 72 Participants | 94 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 6 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 44 Participants | 57 Participants | 13 Participants |
| Race/Ethnicity, Customized Black or African American | 6 Participants | 8 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 5 Participants | 5 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 13 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 26 Participants | 37 Participants | 11 Participants |
| Retinopathy of prematurity (ROP) Zone, by eye Zone I | 47 Eyes | 60 Eyes | 13 Eyes |
| Retinopathy of prematurity (ROP) Zone, by eye Zone II | 132 Eyes | 169 Eyes | 37 Eyes |
| Sex: Female, Male Female | 52 Participants | 62 Participants | 10 Participants |
| Sex: Female, Male Male | 41 Participants | 58 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 1 / 93 |
| other Total, other adverse events | 12 / 27 | 40 / 93 |
| serious Total, serious adverse events | 12 / 27 | 32 / 93 |
Outcome results
Primary
Percentage of Participants With Absence of Active Retinopathy of Prematurity (ROP) and Unfavorable Structural Outcomes From Baseline to Week 52 of Chronological Age
Active ROP was ROP requiring treatment and unfavorable structural outcome was defined as retinal detachment, macular dragging, macular fold, or retrolental opacity. For participants with both eyes enrolled in the study, both eyes must have met the endpoint. Participants with only one study eye enrolled were responders if the respective eye responded.
Time frame: Baseline to week 52 of chronological age
Population: Full analysis set (FAS): All randomized participants who received any study treatment. Analysis on the FAS was performed according to the treatment assigned at baseline (as randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Laser Photocoagulation | Percentage of Participants With Absence of Active Retinopathy of Prematurity (ROP) and Unfavorable Structural Outcomes From Baseline to Week 52 of Chronological Age | 77.8 Percentage of participants |
| Aflibercept 0.4 mg | Percentage of Participants With Absence of Active Retinopathy of Prematurity (ROP) and Unfavorable Structural Outcomes From Baseline to Week 52 of Chronological Age | 79.6 Percentage of participants |
Comparison: Difference with confidence interval (CI) is calculated using Mantel-Haenszel weighting scheme adjusted by baseline ROP status.95.1% CI: [-15.71, 19.33]
Secondary
Percentage of Participants Requiring Intervention With a Second Treatment Modality From Baseline to Week 52 of Chronological Age
Second treatment modality includes any treatment in addition to that assigned to the participant at baseline. This includes per-protocol rescue treatment (laser for aflibercept group, aflibercept for laser group), anti-VEGF agents not part of study protocol (e.g., bevacizumab, ranibizumab, commercially-available aflibercept not provided as study medication), or any ocular surgery for the management of any retinal pathology secondary to ROP (e.g., victrectomy, scleral buckle for retinal detachments).
Time frame: Baseline to to week 52 of chronological age
Population: Full analysis set (FAS): All randomized participants who received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Laser Photocoagulation | Percentage of Participants Requiring Intervention With a Second Treatment Modality From Baseline to Week 52 of Chronological Age | 18.5 Percentage of participants |
| Aflibercept 0.4 mg | Percentage of Participants Requiring Intervention With a Second Treatment Modality From Baseline to Week 52 of Chronological Age | 15.1 Percentage of participants |
Comparison: Difference with confidence interval (CI) is calculated using Mantel-Haenszel weighting scheme adjusted by baseline ROP status.95.1% CI: [-19.86, 12.54]
Secondary
Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Time frame: Baseline to Week 52 of chronological age
Population: Safety analysis set (SAF): All randomized participants who received any study treatment (active or laser); it is based on the treatment actually received (as treated).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Laser Photocoagulation | Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | % Ocular TEAEs | 25.9 Percentage of participants |
| Laser Photocoagulation | Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | % Ocular TESAEs | 11.1 Percentage of participants |
| Aflibercept 0.4 mg | Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | % Ocular TEAEs | 18.3 Percentage of participants |
| Aflibercept 0.4 mg | Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | % Ocular TESAEs | 6.5 Percentage of participants |
Secondary
Percentage of Participants With Recurrence of ROP Through Week 52 of Chronological Age
Recurrence of disease is defined as the reappearance of the disease requiring further treatment (including retreatment or rescue), where both presence of ROP and presence of active ROP requiring treatment are marked as Yes, after initial regression. Here, the initial regression is defined as, at a particular visit, absence of ROP or ROP treatment not required for active ROP, i.e., presence of ROP is marked as No or the presence of active ROP requiring treatment is marked as No.
Time frame: Baseline to week 52 of chronological age
Population: Full analysis set (FAS): All randomized participants who received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Laser Photocoagulation | Percentage of Participants With Recurrence of ROP Through Week 52 of Chronological Age | 29.6 Percentage of participants |
| Aflibercept 0.4 mg | Percentage of Participants With Recurrence of ROP Through Week 52 of Chronological Age | 39.8 Percentage of participants |
Comparison: Difference with confidence interval (CI) is calculated using Mantel-Haenszel weighting scheme adjusted by baseline ROP status95.1% CI: [-9.83, 30.02]
Secondary
Percentage of Participants With Systematic (Non-ocular) TEAEs and TESAEs
Time frame: Baseline to Week 52 of chronological age
Population: Safety analysis set (SAF): All randomized participants who received any study treatment (active or laser); it is based on the treatment actually received (as treated).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Laser Photocoagulation | Percentage of Participants With Systematic (Non-ocular) TEAEs and TESAEs | % Systematic TEAEs | 51.9 Percentage of participants |
| Laser Photocoagulation | Percentage of Participants With Systematic (Non-ocular) TEAEs and TESAEs | % Systematic TESAEs | 7.4 Percentage of participants |
| Aflibercept 0.4 mg | Percentage of Participants With Systematic (Non-ocular) TEAEs and TESAEs | % Systematic TEAEs | 47.3 Percentage of participants |
| Aflibercept 0.4 mg | Percentage of Participants With Systematic (Non-ocular) TEAEs and TESAEs | % Systematic TESAEs | 12.9 Percentage of participants |