Aflibercept for Retinopathy of Prematurity - Intravitreal Injection Versus Laser Therapy

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate how well aflibercept works in babies with ROP, comparing it with laser therapy. The study also has the objective to demonstrate how safe aflibercept is when used in babies, and describe how the drug moves into, through and out of the body.

Official Title
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Open-label, Randomized, Two-Arm, Controlled Study to Assess the Efficacy, Safety, and Tolerability of Intravitreal (IVT) Aflibercept Compared to Laser Photocoagulation in Patients With Retinopathy of Prematurity (ROP)

Conditions
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Retinopathy of Prematurity (ROP)

Intervention / Treatment
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* Drug: Eylea (Aflibercept, BAY86-5321)
* Procedure: Laser photocoagulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age at birth ≤ 32 weeks or birth weight ≤ 1500 g Subjects with treatment-naïve 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) Weight at baseline (day of treatment) ≥ 800 g Signed informed consent from parent(s)/legally authorized representative(s), which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Exclusion Criteria: Known or suspected chromosomal abnormality, genetic disorder or syndrome Previous exposure to any 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 NICU 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 Stages 4 and 5) ROP involving only Zone III Ocular abnormalities that may interfere with the administration of study intervention or assessment of the study primary endpoint Postnatal treatment with oral or intravenous corticosteroids at an equivalent dose of prednisone ≥ 1 mg/kg/day for > 2 weeks within 14 days of the first study intervention Previous surgical or nonsurgical treatment for ROP (IVT anti-VEGF injection, ablative laser therapy, cryotherapy, and vitrectomy) Participation of the subject or the mother in other clinical trials requiring administration of investigational treatments (other than vitamins and minerals) at the time of screening, or within 30 days or 5 half-lives of administration of the previous study drug, whichever is longer

Ages Eligible for Study
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Maximum Age: 32 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aflibercept arm<br>Subjects randomized to aflibercept will receive a intravitreal (IVT) injection of Dose A aflibercept per eligible eye at baseline and, if needed, up to a defined number of additional injections in each eye. | Drug: Eylea (Aflibercept, BAY86-5321)<br>* Solution in a sterile glass vial, Dose A, IVT injection.<br>|
| Active Comparator: Laser photocoagulation arm<br>Subjects randomized to laser photocoagulation will receive treatment in each eligible eye at baseline. Retreatments may be administered if needed. | Procedure: Laser photocoagulation<br>* Transpupillary conventional laser ablative therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Absence of Active ROP and Unfavorable Structural Outcomes | Active ROP was defined as ROP requiring treatment. Unfavorable structural outcomes included retinal detachment, macular dragging, macular fold, or retrolental opacity. | At 24 weeks after starting study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Requiring Intervention With a Second Treatment Modality | A second treatment modality for ROP was either rescue treatment or any other surgical or nonsurgical treatment for ROP (e.g. IVT anti-VEGF injection, ablative laser therapy, cryotherapy, or vitrectomy) captured as concomitant medication or surgery after study start. | From baseline (treatment) up to week 24. | 
| Proportion of Participants With Recurrence of ROP | Participants with recurrence of ROP were defined as subjects requiring re-treatment or rescue treatment after in the past the absence of treatment-requiring active ROP had been confirmed by the investigator. | From baseline (treatment) up to week 24. | 
| Exploration of ROP Activity Scale Proposed by the International Neonatal Consortium | Eyes were evaluated for change in ROP activity scale proposed by the International Neonatal Consortium (2018). ROP Activity Scale value range is from 0 to 22. Value 0 to 7 are considered mild, 8 to 12 are moderate, and 13 to 22 are severe. Value 0 means the best and value 22 means the worst. Eyes evaluation was done at baseline and each visit. | From baseline (treatment) up to week 24. | 
| Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs) | A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that was observed or reported after the first and not later than 30 days after the last administration of study treatment. Participants treated after week 21 were followed-up for adverse events up to week 28. Ocular TEAEs in treated eyes only were reported | From baseline (treatment) up to week 24 | 
| Percentage of Participants With Ocular Serious Adverse Events (SAEs) | Participants treated after week 21 were followed-up for adverse events up to week 28. Ocular SAEs in treated eyes only were reported. | From baseline (treatment) up to week 24 | 
| Percentage of Participants With Systemic TEAEs | A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that was observed or reported after the first and not later than 30 days after the last administration of study treatment. Participants treated after week 21 were followed-up for adverse events up to week 28. Systemic TEAEs only were reported. | From baseline (treatment) up to week 24 | 
| Percentage of Participants With Systemic SAEs | Participants treated after week 21 were followed-up for adverse events up to week 28. Systemic SAEs only were reported. | From baseline (treatment) up to week 24 | 
| Concentrations of Free Aflibercept in Plasma | Blood samples for determination of aflibercept concentrations in plasma were collected in the aflibercept 0.4 mg arm at Day 1 (within 24 hours after injection), and at weeks 2 and 4, and if feasible also at weeks 8, 12 and 24. Statistics for week 8, 12, 24 not calculated as > 1/3 of the concentrations were below the lower limit of quantification. Free Aflibercept Concentrations in Plasma were only measured in the Aflibercept 0.4 mg treatment arm. | From Day 1 up to week 24. | 
| Number of Participants With Anti-drug Antibodies (ADA) | Immunogenicity was characterized by anti-drug antibody (ADA) responses in patients in the aflibercept 0.4 mg arm. Serum samples were taken at baseline prior to the injection and at 12 weeks after injection. ADA titers were summarized for 3 categories: Low (titer <1,000); Moderate (1,000 ≤ titer ≤ 10,000); High (titer >10,000). ADA in serum were only measured in the Aflibercept 0.4 mg treatment arm. | Baseline (treatment) and 12 weeks after aflibercept injection | 
| Number of Participants With Potential Neutralizing Antibodies (NAb) | NAb status was evaluated for the samples that were positive in the ADA assay and had sufficient volume to analyze. NAb were only measured in participants with positive ADA in the Aflibercept 0.4 mg treatment arm | At 12 weeks after aflibercept injection | 
| Number of Aflibercept Administrations | Total number of injections in both eyes. | From baseline (treatment) up to week 24. | 
| Number of Laser Treatments | Total number of laser treatment in both eyes. If multiple sessions of laser treatment were necessary within 1 week from baseline, they were counted as a single treatment. | From baseline (treatment) up to week 24. |