Author: Andreas Stahl (Germany)
Co-authors: Emine Sukgen, Wei-Chi Wu, Domenico Lepore, Noriyuki Azuma, Hidehiko Nakanishi, Jan Mazela
Purpose
Retinopathy of prematurity (ROP) is a proliferative vascular disease caused by abnormal vascularization of the retina in premature infants. Laser photocoagulation is currently one of the standards of care for patients with ROP requiring treatment; however, it is associated with potential risks, such as loss of visual field and the development of high myopia, and usually requires longer sedation and breathing assistance. Currently available clinical data indicate potential advantages of anti-vascular endothelial growth factor (VEGF) agents, including intravitreal aflibercept (IVT-AFL), over laser photocoagulation. Because there is a considerable unmet need for an effective, safe, less invasive, and tolerable treatment for preterm infants with vision-threatening ROP, prospective and longer-term data on the use of IVT-AFL for the treatment of ROP are required. The aim of the FIREFLEYE study was to compare the efficacy and safety of IVT-AFL injections with laser photocoagulation for patients with ROP.
Setting/Venue
FIREFLEYE (NCT04004208) was a 24-week, randomized, controlled, open-label, multicenter, non-inferiority, Phase 3 study to assess the efficacy and safety of IVT-AFL versus laser photocoagulation in patients with ROP. The study population comprised infants born at a gestational age of ≤32 weeks or birth weight of ≤1500 g, who weighed ≥800 g at baseline and who had ROP in at least one eye classified as Zone I Stage 1+, 2+, 3, 3+; Zone II Stage 2+, 3+; or aggressive posterior (AP)-ROP.
Methods
Patients with ROP were randomized 2:1 across 63 sites in 27 countries to receive IVT-AFL (0.4 mg/0.01 mL) or laser photocoagulation. Re-treatment and/or rescue treatment (laser for the IVT-AFL arm; IVT-AFL for the laser arm) was administered if required according to pre-specified criteria. If multiple laser sessions were necessary within 1 week from baseline, they were counted as one single treatment. Up to two re-treatments with IVT-AFL per eye at minimum treatment intervals of 28 days were permitted. The primary endpoint was the proportion of patients with absence of active ROP and unfavorable structural outcomes (defined as retinal detachment, macular dragging, macular fold, or retrolental opacity) at Week 24 after baseline treatment. IVT-AFL was deemed non-inferior to laser, with a non-inferiority margin of 5%, if the lower limit of the 2-sided 90% Bayesian credible interval (CI) for the treatment difference was above −5%. Secondary endpoints included the number of IVT-AFL and laser treatments and the proportion of patients with ocular and systemic serious adverse events (SAEs).
Results
The full analysis set comprised 113 patients (IVT-AFL: n=75; laser: n=38) with mean±SD gestational age of 26 weeks and 2 days ±1.9 weeks and mean±SD birth weight of 862.1±282.9 g. ROP classification at baseline was 33.6% Zone I (including Zone I AP-ROP), 66.4% Zone II (including Zone II AP-ROP), and 16.8% AP-ROP. Bilateral treatment was performed in 71 (94.7%) IVT-AFL-group patients and 34 (89.5%) laser-group patients. The estimated success rate was 85.5% in patients treated with IVT-AFL and 82.1% in laser-treated patients. The 90% CI for treatment difference was −8.0% – +16.2%; therefore, non-inferiority could not be concluded. In the IVT-AFL group, 17.8% of eyes received one re-treatment. In the laser group, 6.9% of eyes received one re-treatment after ≥1 week, and 2.8% received two re-treatments. In the IVT-AFL group, 4.8% of eyes received rescue treatment. In the laser group, 11.1% received rescue treatment. Ocular and systemic SAEs were reported in 13.3% and 24.0% of patients in the IVT-AFL group, and 7.9% and 36.8% of patients in the laser group, respectively. No cases of endophthalmitis were reported. Three deaths were reported (2.7%), all in the IVT-AFL group, occurring 4–9 weeks after treatment and considered unrelated to the study drug.
Conlusions
FIREFLEYE is the first prospective, randomized, controlled, multicenter study to evaluate the efficacy and safety of IVT-AFL compared with laser treatment for patients with severe ROP. During this 6-month study, treatment success was numerically higher with IVT-AFL (85.5%) than with laser photocoagulation (82.1%). Non-inferiority of IVT-AFL versus laser treatment could not be formally shown, because the observed laser success rate was higher than expected based on previously published data. Most infants in the IVT-AFL group required one single injection per eye. Ocular safety of IVT-AFL in infants was consistent with the established safety profile known from adults, and no ROP population-specific safety concerns were identified. The three deaths in the IVT-AFL group occurred between 4 and 9 weeks after treatment and were considered related to complications from prematurity, not study treatment. Overall, treatment with IVT-AFL showed a favorable benefit-risk profile, indicating clinical benefit of IVT-AFL in the treatment of premature infants with severe unilateral or bilateral ROP. Patients are being followed up for ocular, neurodevelopmental, and overall clinical outcomes until 5 years of age as part of the FIREFLEYE NEXT extension study (NCT04015180).
Financial Disclosure
Andreas Stahl: Speaker: Allergan, Bayer, Novartis; Scientific advisory boards: Bayer, Novartis, Roche; Research grants: Bayer, Novartis; Participation in clinical trials: Bayer, Novartis. Emine Sukgen: Speaker: Allergan; Participation in clinical trials: Bayer, Regeneron, TR-PHARMA. Wei-Chi Wu: Participation in clinical trials: Bayer, Novartis. Domenico Lepore: Participation in clinical trials: Bayer, Novartis. Noriyuki Azuma: Participation in clinical trials: Bayer, Novartis. Hidehiko Nakanishi: None. Jan Mazela: Speaker: AbbVie, AstraZeneca, Draeger, HIPP, Maquet, Nestle, Nutricia, Roche; Clinical trials: Bayer, Merck Sharp & Dohme, WindTree. Thomas Schmelter: Employee of Bayer AG, Berlin, Germany. Sergio Leal: Employee of Bayer Consumer Care AG, Basel, Switzerland. Evra Koefuencue: Employee of Bayer AG, Berlin, Germany. Funding: The FIREFLEYE study was funded by Bayer AG, Germany. Medical writing support was provided by ApotheCom, and funded by Bayer Consumer Care AG, Pharmaceuticals, Switzerland.
Comments
Important add below co-authors: 7. - Thomas Schmelter: Bayer AG, Berlin, Germany 8. - Sergio Leal: Bayer Consumer Care AG, Basel, Switzerland 9. - Evra Koefuencue: Bayer AG, Berlin, Germany