Introduction: FIREFLEYE next 3 years of age efficacy and safety outcomes after intravitreal aflibercept 0.4 mg injection versus laser therapy for retinopathy of prematurity (ROP) in the randomized, FIREFLEYE trial are reported. METHODS:Children born prematurely (gestational age ≤32 weeks) or with low birth weight (≤1,500 g) were treated for ROP in FIREFLEYE. Efficacy and safety end points for this prespecified interim analysis included ROP status, unfavorable structural outcomes, disease recurrence, treatment of ROP complications, vascularization completion, visual function, adverse events, and growth outcomes. RESULTS:One hundred children were enrolled (aflibercept, 66 [128 eyes]; laser, 34 [64 eyes]). Data for the 3-year analysis were available for 90 children (aflibercept, 60; laser, 30). Most children had no ROP or unfavorable structural outcomes (aflibercept, 98.3% and 93.9% vs. laser, 96.7% and 94.1%), with no ROP reactivation after age 50 weeks. Two children (aflibercept) with re-activated disease received bilateral laser treatment prior to age 50 weeks. Most children could fix and follow a 5-cm toy (aflibercept, 96.6%; laser, 98.3% of eyes). Binocular best-corrected visual acuity (Snellen equivalent) was ≥20/200 and ≥20/40 in 97.8% and 66.7% (aflibercept) versus 100% and 47.8% (laser) of children, respectively. High myopia was present in 8.9% (aflibercept) and 24.1% (laser) of eyes. Adverse events and growth outcomes were as expected for the population. CONCLUSION:Descriptive analyses of the 3-year outcomes confirm long-term, stable disease control following aflibercept 0.4 mg treatment of severe acute-phase ROP, with age-appropriate visual function, less frequent/severe myopia compared with laser, and no ocular or systemic safety concerns. .

Importance:Laser photocoagulation, which is the standard treatment for retinopathy of prematurity (ROP), can have adverse events. Studies of anti-vascular endothelial growth factor injections have suggested efficacy in the treatment of ROP, but few studies have directly compared them with laser treatments. Objective:To compare intravitreal aflibercept vs laser photocoagulation in infants with ROP requiring treatment. Design, Setting, and Participants:This noninferiority, phase 3, 24-week, randomized clinical trial was conducted in 27 countries (64 hospital sites) throughout Asia, Europe, and South America. Overall, 118 infants (gestational age ≤32 weeks at birth or birth weight ≤1500 g) with ROP severity (zone I stage 1+ [stage 1 plus increased disease activity], zone I stage 2+, zone I stage 3, zone I stage 3+, zone II stage 2+, or zone II stage 3+) requiring treatment or with aggressive posterior ROP in at least 1 eye were enrolled between September 25, 2019, and August 28, 2020 (the last visit occurred on February 12, 2021). Interventions:Infants were randomized 2:1 to receive a 0.4-mg dose of intravitreal aflibercept (n = 75) or laser photocoagulation (n = 43) at baseline. Additional treatment was allowed as prespecified. Main Outcomes and Measures:The primary outcome was the proportion of infants without active ROP and unfavorable structural outcomes 24 weeks after starting treatment (assessed by investigators). The requirement for rescue treatment was considered treatment failure. Intravitreal aflibercept was deemed noninferior if the lower limit of the 1-sided 95% bayesian credible interval for the treatment difference was greater than -5%. Results:Among 118 infants randomized, 113 were treated (mean gestational age, 26.3 [SD, 1.9] weeks; 53 [46.9%] were female; 16.8% had aggressive posterior ROP, 19.5% had zone I ROP, and 63.7% had zone II ROP) and 104 completed the study. Treatment (intravitreal aflibercept: n = 75; laser photocoagulation: n = 38) was mostly bilateral (92.9%), and 82.2% of eyes in the intravitreal aflibercept group received 1 injection per eye. Treatment success was 85.5% with intravitreal aflibercept vs 82.1% with laser photocoagulation (between-group difference, 3.4% [1-sided 95% credible interval, -8.0% to ∞]). Rescue treatment was required in 4.8% (95% CI, 1.9% to 9.6%) of eyes in the intravitreal aflibercept group vs 11.1% (95% CI, 4.9% to 20.7%) of eyes in the laser photocoagulation group. The serious adverse event rates were 13.3% (ocular) and 24.0% (systemic) in the intravitreal aflibercept group compared with 7.9% and 36.8%, respectively, in the laser photocoagulation group. Three deaths, which occurred 4 to 9 weeks after intravitreal aflibercept treatment, were considered unrelated to aflibercept by the investigators. Conclusions and Relevance:Among infants with ROP, intravitreal aflibercept compared with laser photocoagulation did not meet criteria for noninferiority with respect to the primary outcome of the proportion of infants achieving treatment success at week 24. Further data would be required for more definitive conclusions regarding the comparative effects of intravitreal aflibercept and laser photocoagulation in this population. Trial Registration:ClinicalTrials.gov Identifier: NCT04004208.

Background Concerns remain over the long-term safety of vascular endothelial growth factor (VEGF) inhibitors to treat retinopathy of prematurity (ROP). RAINBOW is an open label randomised trial comparing intravitreal ranibizumab (in 0.2 mg and 0.1 mg doses) with laser therapy in very low birthweight infants (<1500 g) with ROP. Methods Of 201 infants completing RAINBOW, 180 were enrolled in the RAINBOW Extension Study. At 5 years, children underwent ophthalmic, development and health assessments. The primary outcome was visual acuity in the better-seeing eye. The study is registered with ClinicalTrial.gov, NCT02640664. Findings Between 16-6-2016 and 21-4-2022, 156 children (87%) were evaluated at 5 years. Of 32 children with no acuity test result, 25 had a preferential looking test, for 4 children investigators reported low vision for each eye, and in 3 further children no vision measurement was obtained. 124 children completed the acuity assessment, the least square mean (95% CI) letter score in the better seeing eye was similar in the three trial arms - 66.8 (62.9 - 70.7) following ranibizumab 0.2 mg, 64.6 (60.6 - 68.5) following ranibizumab 0.1 mg and 62.1 (57.8 - 66.4) following laser therapy; differences in means: ranibizumab 0.2 mg v laser: 4.7 (95% CI: - 1.1, 10.5); 0.1 mg v laser: 2.5 ( - 3.4, 8.3); 0.2 mg v 0.1 mg: 2.2 ( - 3.3, 7.8). High myopia (worse than - 5 dioptres) in at least one eye occurred in 4/52 (8%) children following ranibizumab 0.2 mg, 8/55 (15%) following ranibizumab 0.1 mg and 11/45 (24%) following laser therapy (0.2 mg versus laser: odds ratio: 3.99 (1.16 - 13.72)). Ocular and systemic secondary outcomes and adverse events were distributed similarly in each trial arm. Interpretation 5-year outcomes con fi rm the findings of the original RAINBOW trial anda planned interim analysis at 2 years, including a reduced frequency of high myopia following ranibizumab treatment. No effects of treatment on non-ocular outcomes were detected.

EDITORIAL article Front. Pediatr., 06 March 2024Sec. Neonatology Volume 12 - 2024 | https://doi.org/10.3389/fped.2024.1382858

Importance:Prospective long-term data after retinopathy of prematurity (ROP) treatment with anti-vascular endothelial growth factor injections vs laser therapy are scarce. The FIREFLEYE (Aflibercept for ROP IVT Injection vs Laser Therapy) next trial is prospectively evaluating the long-term efficacy and safety outcomes following ROP treatment with intravitreal aflibercept vs laser therapy. Objective:To evaluate 2-year ophthalmic and safety outcomes after 0.4-mg aflibercept injection or laser therapy in the 24-week randomized (2:1) FIREFLEYE trial (FIREFLEYE outcomes previously reported). Design, Setting, and Participants:This prospective nonrandomized controlled trial performed in 24 countries in Asia, Europe, and South America (2020-2025) follows up participants treated in the FIREFLEYE randomized clinical trial (2019-2021) through 5 years of age. Participants included children born very or extremely preterm (gestational age ≤32 weeks) or with very or extremely low birth weight (≤1500 g) who were previously treated with a 0.4-mg injection of aflibercept compared with laser therapy for severe acute-phase ROP. Data for the present interim analysis were acquired from March 18, 2020, to July 25, 2022. Interventions:Complications of ROP treated at investigator discretion (no study treatment). Main Outcomes and Measures:Efficacy end points included ROP status, unfavorable structural outcomes, ROP recurrence, treatment for ROP complications, completion of vascularization, and visual function. Safety end points included adverse events and growth and neurodevelopmental outcomes. Results:Overall, 100 children were enrolled (median gestational age, 26 [range, 23-31] weeks; 53 boys and 47 girls). Of these, 21 were Asian, 2 were Black, 75 were White, and 2 were of more than 1 race. At 2 years of age, 61 of 63 children (96.8%) in the aflibercept group vs 30 of 32 (93.8%) in the laser group had no ROP. Through 2 years of age, 62 of 66 (93.9%) in the aflibercept group and 32 of 34 (94.1%) in the laser group had no unfavorable structural outcomes. No new retinal detachment occurred during the study. Four children in the aflibercept group (6.1%) were treated for ROP complications before 1 year of age (2 had preexisting end-stage disease and total retinal detachment; 1 had reactivated plus disease; and 1 had recurrent retinal neovascularization not further specified). Most children were able to fix and follow a 5-cm toy (aflibercept group, 118 of 122 eyes [96.7%] among 63 children; laser group, 62 of 63 eyes [98.4%] among 33 children). High myopia was present in 9 of 115 eyes (7.8%) among 5 children in the aflibercept group and 13 of 60 eyes (21.7%) among 9 children in the laser group. No relevant differences in growth and neurodevelopmental outcomes by Bayley Scales of Infant and Toddler Development, Third Edition and Vineland Adaptive Behavior Scales, Second Edition were identified. Conclusions and Relevance:In this nonrandomized follow-up of a randomized clinical trial comparing treatment of severe acute-phase ROP with 0.4-mg injection of aflibercept and laser, disease control was stable and visual function was appropriate in children through 2 years of age. No adverse effects on safety, including growth and neurodevelopment, were identified. These findings provide clinically relevant long-term information on intravitreal aflibercept injection therapy for ROP. Trial Registration:ClinicalTrials.gov Identifier: NCT04015180.

To compare a novel, model-based personalised dosing strategy (PDS) with a standardised (best practice) occlusion dosing strategy (SDS) for the treatment of childhood amblyopia. We have utilised archived clinical trial data sets to develop a statistical model that aims to optimise the prescription of occlusion therapy. This approach, whose effectiveness has not previously been evaluated, incorporates within its underlying model: patient age, severity and type of amblyopia. Randomised, parallel group design with PDS and SDS arms each having within or pre-trial optical treatment. Actual worn occlusion for both PDS and SDS dosing strategies was objectively recorded using occlusion dose monitors (ODMs). Of the 94 initially enrolled participants, 50 were male, 44 female, mean [IQR] age 5.53 [4.79-6.02] years. The improvement in logMAR acuity In the 68 participants remaining in the trial subsequent to optical treatment and not having withdrawn did not differ (p = 0.641) between the PDS and SDS groups: median [IQR] improvement 0.250 [0.13-0.39] in the PDS group, 0.225 [0.14-0.32] in the SDS group. A subset (n = 28) of participants were objectively observed to have occluded for every day prescribed. In these, we found that, after allowing for slightly higher prescribed doses of occlusion in the SDS group, adherence in the PDS group to be ∼20% greater than in the SDS group. Whilst the PDS and SDS dosing strategies demonstrated equivalent visual performance and temporal outcomes, there is evidence that PDS results in improved adherence with therapy likely to have arisen due to increased patient engagement with this novel regimen.

Purpose: To study the time course of retinopathy of prematurity (ROP) regression and reactivation after treatment with intravitreal ranibizumab or laser in the ranibizumab compared with laser therapy for the treatment of infants born prematurely with ROP trial.Design: Post hoc analysis of a randomized, clinical trial.Subjects: A total of 225 infants (448 eyes) were randomized to ranibizumab 0.2 mg (n = 74, 148 eyes), ranibizumab 0.1 mg (n = 77, 152 eyes), and laser (n = 74, 148 eyes).Methods: Features of disease regression were measured using time-to-event analysis per eye, corrected for within-subject association. Analyses of disease reactivation and additional treatments were descriptive.Main Outcome Measures: Median time to regression of plus disease, stage 3 ROP, aggressive posterior (AP)-ROP to 24-week follow-up and disease reactivation and first additional treatment to 2-year follow-up.Results: The median times to regression after ranibizumab 0.2 mg vs. laser were as follows: plus disease, 4 vs. 16 days (P < 0.001); stage 3 ROP, 8 vs. 16 days (P = 0.004); and AP-ROP, 7.3 vs. 22 days (P = 0.03). Results for ranibizumab 0.1 mg were similar to those for 0.2 mg, with a median of 4, 9, and 8 days, respectively. Additional treatments were given in 34 (25%) of 138 eyes after laser and 40 (27%) of 146 and 42 (28%) of 152 eyes after 0.2 mg and 0.1 mg ranibizumab, respectively. Incomplete disease regression requiring additional treatment occurred in 30 (22%) of 138 eyes after laser after a median interval of 15 days compared with 11 (8%) of 146 and 9 (6%) of 152 after 0.2 mg and 0.1 mg ranibizumab after a median interval of 21 and 13 days, respectively. Retinopathy of prematurity reactivation requiring additional treatment occurred in 3 (2%) of 138 eyes after laser after a median interval of 43 days compared with 22 (15%) of 146 and 26 (17%) of 152 after 0.2 and 0.1 mg ranibizumab after a median interval of 53.5 (maximum, 105) and 54.5 days (maximum, 128), respectively. Conclusions: Intravitreal 0.2 or 0.1 mg ranibizumab induced a faster regression of plus disease, stage 3 ROP, and AP-ROP than laser did. Ranibizumab was associated with fewer additional treatments for incomplete disease regression but more for disease reactivation. Ophthalmology Retina 2022;6:628-637 (c) 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

It seems indisputable that the treatment for a condition should be based on the current description and classification of the condition. But here, we ask: is this always so for treatment of severe retinopathy of prematurity (ROP)? The current indications for ROP treatment were defined in 2003 by the Early Treatment for ROP (ETROP) trial, as type 1 ROP, which includes stages 1 or 2 with plus disease in zone I, stage 3 with or without plus in zone I, and stages 2 or 3 with plus in zone II. 1 Early Treatment for Retinopathy of Prematurity Cooperative GroupRevised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003; 121: 1684-1694 Crossref PubMed Scopus (1499) Google Scholar ETROP also defined type 2 ROP that is somewhat less severe but requires increased surveillance. Since then, the International Classification of ROP (ICROP) has been updated twice (in 2005 2 International Committee for the Classification of Retinopathy of PrematurityThe International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005; 123: 991-999 Crossref PubMed Scopus (2099) Google Scholar and 2021 3 Chiang MF, Quinn GE, Fielder AR, et al. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology 2021;128:e51-e68. Google Scholar ), and critically new treatment modalities, such as antivascular endothelial growth factor agents, have been developed. 4 Mintz-Hittner H.A. Kennedy K.A. Chuang A.Z. BEAT-ROP Cooperative GroupEfficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011; 364: 603-615 Crossref PubMed Scopus (987) Google Scholar , 5 Stahl A. Lepore D. Fielder A. et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial. Lancet. 2019; 394: 1551-1559 Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar , 6 Wallace D.K. Kraker R.T. Freedman S.F. et al. Short-term outcomes after very low-dose intravitreous bevacizumab for retinopathy of prematurity. JAMA Ophthalmol. 2020; 138: 698-701 Crossref PubMed Scopus (29) Google Scholar Yet clinical practice and research are still based on earlier iterations of the ICROP, 2 International Committee for the Classification of Retinopathy of PrematurityThe International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005; 123: 991-999 Crossref PubMed Scopus (2099) Google Scholar ,7 Committee for the Classification of Retinopathy of PrematurityAn international classification of retinopathy of prematurity. Arch Ophthalmol. 1984; 102: 1130-1134 Crossref PubMed Scopus (1125) Google Scholar and there is evidence that some clinicians are treating severe disease more aggressively than recommended by ETROP. 8 Gupta M.P. Chan R.V.P. Anzures R. et al. Practice patterns in retinopathy of prematurity treatment for disease milder than recommended by guidelines. Am J Ophthalmol. 2016; 163: 1-10 Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar , 9 Adams G.G.W. Bunce C. Xing W. et al. Treatment trends for retinopathy of prematurity in the UK: active surveillance study of infants at risk. BMJ Open. 2017; 7e013366 Crossref Scopus (42) Google Scholar , 10 Liu T. Tomlinson L.A. Ying G.S. Yang M.B. Binenbaum G. G-ROP Study GroupTreatment of non-type 1 retinopathy of prematurity in the Postnatal Growth and Retinopathy of Prematurity (G-ROP) study. J AAPOS. 2019; 23: 332.e1-332.e6 Abstract Full Text Full Text PDF Scopus (7) Google Scholar , 11 Rajan R.P. Kohli P. Babu N. Dakshayini C. Tandon M. Ramasamy K. Treatment of retinopathy of prematurity (ROP) outside International Classification of ROP (ICROP) guidelines. Graefes Arch Clin Exp Ophthalmol. 2020; 258: 1205-1210 Crossref PubMed Scopus (6) Google Scholar Our purpose here is to open a discussion on how the ROP classification updates might affect the indications for ROP treatment, and whether potential changes require collaborative research and/or expert consensus opinion.

Purpose: The International Classification of Retinopathy of Prematurity is a consensus statement that creates a standard nomenclature for classification of retinopathy of prematurity (ROP). It was initially published in 1984, expanded in 1987, and revisited in 2005. This article presents a third revision, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), which is now required because of challenges such as: (1) concerns about subjectivity in critical elements of disease classification; (2) innovations in ophthalmic imaging; (3) novel pharmacologic therapies (e.g., antievascular endothelial growth factor agents) with unique regression and reactivation features after treatment compared with ablative therapies; and (4) recognition that patterns of ROP in some regions of the world do not fit neatly into the current classification system. Design: Review of evidence-based literature, along with expert consensus opinion. Participants: International ROP expert committee assembled in March 2019 representing 17 countries and comprising 14 pediatric ophthalmologists and 20 retinal specialists, as well as 12 women and 22 men. Methods: The committee was initially divided into 3 subcommittees-acute phase, regression or reactivation, and imaging-each of which used iterative videoconferences and an online message board to identify key challenges and approaches. Subsequently, the entire committee used iterative videoconferences, 2 in-person multiday meetings, and an online message board to develop consensus on classification. Main Outcome Measures: Consensus statement. Results: The ICROP3 retains current definitions such as zone (location of disease), stage (appearance of disease at the avascular-vascular junction), and circumferential extent of disease. Major updates in the ICROP3 include refined classification metrics (e.g., posterior zone II, notch, subcategorization of stage 5, and recognition that a continuous spectrum of vascular abnormality exists from normal to plus disease). Updates also include the definition of aggressive ROP to replace aggressive-posterior ROP because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources. ROP regression and reactivation are described in detail, with additional description of long-term sequelae. Conclusions: These principles may improve the quality and standardization of ROP care worldwide and may provide a foundation to improve research and clinical care. Published by Elsevier on behalf of the American Academy of Ophthalmology

Retinopathy of prematurity (ROP) blindness is largely preventable, with many countries having already established programs for its timely identification. However, ∼93% of infants screened do not develop ROP severe enough to require treatment.1 As reported in this issue of Pediatrics by Coyner et al.2 artificial intelligence (AI) is innovative methodology to optimize the timing of ROP examinations. For example, it can predict whether an eye will not require treatment, reducing the number of examinations needed while also predicting which eyes need closer surveillance. This is an important development because it would make ROP programs more effective and efficient, thus reducing the burden on infants, families, and the health care team.From the earliest descriptions, congestion and tortuosity of the posterior retinal vessels were recognized as prominent features of serious ROP.3 In the first international classification of ROP in 1984,4 the term “plus disease” was included to describe progressive vascular incompetence. Two decades later, after the recommendations of the Early Treatment for Retinopathy of Prematurity trial,5 plus disease became the major driver for treatment. With focus now directed to the timely identification of plus disease, the historical dichotomous categorization of normal versus plus disease was deemed inadequate and led to the introduction of an intermediate level, “preplus disease,” in 20056 and the subsequent critical acknowledgment in the 2021 classification7 that the vascular changes associated with ROP do not progress stepwise but are a continuous spectrum.However, categorizing the plus spectrum is subjective and subject to significant variation.8–10 In the late 1990s, the introduction of digital imaging into the NICU provided the opportunity to objectively measure what had long been seen, and this development spawned several methods of retinal vessel measurement.11,12 Despite revealing great early promise, these methods have yet to be incorporated into routine ROP screening worldwide.AI has recently been used to help interpret the complex images captured to monitor for ROP and other patient-specific risk factors. Coyner et al1 report the use of this technology to explore the spectrum of ROP-related vascular changes, and using deep learning (a type of machine learning that can be used to develop predictive rules), the Oregon team developed i-ROP (an algorithm to detect plus disease),13 from which a vascular severity score (VSS) was derived from zone I (the area closest to the optic disc).13,14 Coyner et al1 have devised a risk model to predict ROP requiring treatment using 2 components: gestational age and VSS. Based on images obtained at 32 to 33 weeks’ postmenstrual age, the model had 100% sensitivity and 80.8% negative predictive value to predict (on average, >1 month in advance of the diagnosis) an eye which would later require treatment. This is an exciting and important development. As a result, instead of a stepwise progression through normal, preplus, and plus disease, VSS permits a sliding scale and detailed analysis of the entire plus spectrum, which hopefully will permit fine tuning of the model in the future.To paraphrase Lord Kelvin (1883), when you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot measure it, your knowledge is of a meager and unsatisfactory kind. Herein lies a dilemma: Terms such as AI and deep learning are now in common parlance, so much so that few of us are brave enough to express ignorance. By expressing it (VSS) in numbers, it is not clear that, currently, we fully understand what is being measured or if it has advanced our scientific understanding. Hopefully, this will become apparent in the future. Pragmatically, however, there is no doubt that AI-related techniques, including deep learning–derived VSS, are effective and will likely be important in ROP screening. For this to be incorporated into routine clinical practice, some challenges need to be overcome: a short processing time will be essential preferably within the time span of the NICU ward rounds. In addition, this research is North America based and needs to be validated in other countries in which neonatal care may well be more variable and larger infants develop sight-threatening ROP over a shorter time period. Coyner et al1 have introduced us to a new and exciting era of efficient ROP identification.

Background Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors is increasingly used to treat retinopathy of prematurity (ROP) in the absence of evidence about long-term efficacy or safety. In this prespecified interim analysis of the RAINBOW extension study, we aimed to prospectively assess outcomes at age 2 years. Methods RAINBOW was an open-label, randomised trial that compared intravitreal ranibizumab (at 0.1 mg and 0.2 mg doses) with laser therapy for the treatment of ROP in very low birthweight infants (<1500 g). Families of the 201 infants that completed the RAINBOW core study were approached for consent to enter the extension study, which evaluates treatment outcomes prospectively through to 5 years of age. At age 20-28 months corrected for prematurity, participants had ophthalmic, development, and health assessments. The primary outcome was the absence of structural ocular abnormalities; secondary outcomes included vision-related quality of life (reported by parents using the Children's Visual Function Questionnaire), development (assessed with the Mullen Scales of Early Learning), motor function, and health status. Investigator-determined ocular and non-ocular serious and other adverse events were recorded. This study is registered with ClinicalTrials.gov, NCT02640664. Findings Between June 16, 2016, and Jan 22, 2018, 180 infants were enrolled in the RAINBOW extension study, and 153 (85%) were evaluated at 20-28 months of age. No child developed new ocular structural abnormalities. Structural abnormalities were present in one (2%) of 56 infants in the ranibizumab 0.2 mg group, one (2%) of 51 infants in the 0.1 mg group, and four (9%) of 44 infants in the laser therapy group. The odds ratio of no structural abnormality was 5.68 (95% CI 0.60-54.0; p=0.10) for ranibizumab 0.2 mg versus laser therapy, 4.82 (0.52-45.0; p=0.14) for ranibizumab 0.1 mg versus laser therapy, and 1.21 (0.07-20; p=0.90) for ranibizumab 0.2 mg vs 0.1 mg. High myopia (-5 dioptres or worse) was less frequent after 0.2 mg ranibizumab (five [5%] of 110 eyes) than with laser therapy (16 [20%] of 82; odds ratio 0.19, 95% CI 0.05-0.69; p=0.012). Composite vision-related quality of life scores seemed higher among the ranibizumab 0.2 mg group (mean 84, 95% CI 80-88) compared with laser therapy (77, 72-83; p=0.063). Mullen Scales T-scores for visual reception, receptive and expressive language were distributed similarly between the three trial groups and there were similar proportions of infants with motor and hearing problems among treatment groups. The proportion of infants with respiratory symptoms and Z scores of standing height, weight, and head circumference were similarly distributed in the treatment groups. There were no adverse events considered by the investigator to be related to the study intervention. Interpretation 2-year outcomes following ranibizumab 0.2 mg for the treatment of ROP confirm the ocular outcomes of the original RAINBOW trial and show reduced high myopia, with possibly better vision-related quality of life. This treatment did not appear to affect non-ocular infant development. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

Purpose: To develop a population pharmacokinetic (PK) model for intravitreal ranibizumab in infants with retinopathy of prematurity (ROP) and assess plasma free vascular endothelial growth factor (VEGF) pharmacodynamics (PD). Methods: The RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) trial enrolled 225 infants to receive a bilateral intravitreal injection of ranibizumab 0.1 mg, ranibizumab 0.2 mg, or laser in a 1:1:1 ratio and included sparse sampling of blood for population PK and PD analysis. An adult PK model using infant body weight as a fixed allometric covariate was re-estimated using the ranibizumab concentrations in the preterm population. Different variability, assumptions, and covariate relationships were explored. Model-based individual predicted concentrations of ranibizumab were plotted against observed free VEGF concentrations. Results: Elimination of ranibizumab had a median half-life of 5.6 days from the eye and 0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach maximum concentration was rapid (median: 1.3 days). Maximum concentration (median 24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No differences in plasma free VEGF concentrations were apparent between the groups or over time. Plotted individual predicted concentrations of ranibizumab against observed free VEGF concentrations showed no relationship. Conclusions: In preterm infants with ROP, elimination of ranibizumab from the eye was the rate-limiting step and was faster compared with adults. No reduction in plasma free VEGF was observed. The five-year clinical safety follow-up from RAINBOW is ongoing. Translational Relevance: Our population PK and VEGF PD findings suggest a favorable ocular efficacy: systemic safety profile for ranibizumab in preterm infants.

Background Despite increasing worldwide use of anti-vascular endothelial growth factor agents for treatment of retinopathy of prematurity (ROP), there are few data on their ocular efficacy, the appropriate drug and dose, the need for retreatment, and the possibility of long-term systemic effects. We evaluated the efficacy and safety of intravitreal ranibizumab compared with laser therapy in treatment of ROP. Methods This randomised, open-label, superiority multicentre, three-arm, parallel group trial was done in 87 neonatal and ophthalmic centres in 26 countries. We screened infants with birthweight less than 1500 g who met criteria for treatment for retinopathy, and randomised patients equally (1:1:1) to receive a single bilateral intravitreal dose of ranibizumab 0.2 mg or ranibizumab 0.1 mg, or laser therapy. Individuals were stratified by disease zone and geographical region using computer interactive response technology. The primary outcome was survival with no active retinopathy, no unfavourable structural outcomes, or need for a different treatment modality at or before 24 weeks (two-sided alpha=0.05 for superiority of ranibizumab 0.2 mg against laser therapy). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02375971. Interpretation Between Dec 31, 2015, and June 29, 2017, 225 participants (ranibizumab 0.2 mg n=74, ranibizumab 0.1 mg n=77, laser therapy n=74) were randomly assigned. Seven were withdrawn before treatment (n=1, n=1, n=5, respectively) and 17 did not complete follow-up to 24 weeks, including four deaths in each group. 214 infants were assessed for the primary outcome (n=70, n=76, n=68, respectively). Treatment success occurred in 56 (80%) of 70 infants receiving ranibizumab 0.2 mg compared with 57 (75%) of 76 infants receiving ranibizumab 0.1 mg and 45 (66%) of 68 infants after laser therapy. Using a hierarchical testing strategy, compared with laser therapy the odds ratio (OR) of treatment success following ranibizumab 0.2 mg was 2.19 (95% Cl 0.99-4.82, p=0.051), and following ranibizumab 0.1 mg was 1.57 (95% Cl 0.76-3.26); for ranibizumab 0.2 mg compared with 0.1 mg the OR was 1.35 (95% Cl 0.61-2.98). One infant had an unfavourable structural outcome following ranibizumab 0.2 mg, compared with five following ranibizumab 0.1 mg and seven after laser therapy. Death, serious and non-serious systemic adverse events, and ocular adverse events were evenly distributed between the three groups. Findings In the treatment of ROP, ranibizumab 0.2 mg might be superior to laser therapy, with fewer unfavourable ocular outcomes than laser therapy and with an acceptable 24-week safety profile.