Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial.

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 confirm the findings of the original RAINBOW trial and a 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. Funding: Novartis Pharma AG.

Intravitreal Aflibercept vs Laser Therapy for Retinopathy of Prematurity: Two-Year Efficacy and Safety Outcomes in the Nonrandomized Controlled Trial FIREFLEYE next.

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.

Time Course of Retinopathy of Prematurity Regression and Reactivation After Treatment with Ranibizumab or Laser in the RAINBOW Trial.

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.

2-year outcomes of ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW extension study): prospective follow-up of an open label, randomised controlled trial.

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. FUNDING: Novartis Pharma AG.

International Classification of Retinopathy of Prematurity, Third Edition.

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., anti-vascular 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.

Ranibizumab Population Pharmacokinetics and Free VEGF Pharmacodynamics in Preterm Infants With Retinopathy of Prematurity in the RAINBOW Trial.

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.

Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial.

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 α=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. FUNDING: Novartis.

Development of a Retinopathy of Prematurity Activity Scale and Clinical Outcome Measures for Use in Clinical Trials.

Importance: To facilitate drug and device development for neonates, the International Neonatal Consortium brings together key stakeholders, including pharmaceutical companies, practitioners, regulators, funding agencies, scientists, and families, to address the need for objective, standardized clinical trial outcome measurements to fulfill regulatory requirements. Retinopathy of prematurity (ROP) is a disease that affects preterm neonates. The current International Classification of Retinopathy of Prematurity does not take into account all of the characteristics of ROP and does not adequately discriminate small changes in disease after treatment. These factors are critical for evaluating outcomes in clinical trials. Observations: There is need for an updated ROP acute disease activity and structure scale as well as end-stage structure and ophthalmologic outcome measures designed for use at different ages. The scale and measures, based on current diagnostic methods and treatments, could be used as a guideline for clinical intervention trials. The scale is intended to be validated against retrospective data and revised for use in future trials. An iterative revision process can be accomplished if new measures are added to clinical trials and evaluated at the end of each trial for prognostic value. The new measures would then be incorporated into a new version of the activity scale and the outcome measures revised. Conclusions and Relevance: An ROP activity scale and outcome measures to obtain the most robust and discriminatory data for clinical trials are needed. The scales should be dynamic and modified as knowledge and imaging modalities improve and then validated using data from well-documented clinical trials. This approach is relevant to improving clinical trial data quality.

Delay in presentation to hospital for childhood cataract surgery in India.

PURPOSE: Cataract is one of the major causes of avoidable visual disability in children and the aim of this study was to investigate the age at which children with cataract present for surgery at tertiary hospitals across India. METHODS: A prospective multicenter study collected data from 9 eye hospitals in 8 states in India. All children admitted for cataract surgery between Nov 2015 and March 2016 were considered eligible. Parents were interviewed at the hospital by trained personnel and socio demographic information, age at diagnosis and at surgery and the relevant clinical data were obtained from the medical records. Mean age, age range at surgery were used and performed logistic regression analyses. RESULTS: Parents of 751 consecutive cases were interviewed, of which 469(63%) were boys and 548 (73%) were from rural areas. Cataract was bilateral in 493 (66%) and unilateral in 258 (34%); of the unilateral cases, 179 (69%) were due to trauma. The mean age at surgery for 'congenital' and 'developmental' cataract was 48.2 ± 50.9 and 99.7 ± 46.42 months, respectively and the mean age was lower in the southern region compared to other regions. Children with 2 or more siblings at home were five times more likely to undergo surgery within 12 months (OR, 4.69; 95% CI: 2.04-10.79; p = < 0.001). CONCLUSIONS: Late surgery for childhood cataract remains a major challenge and the factors determining this issue in India are pertinent also to several other countries and need to be addressed for every child with cataract to achieve full visual potential.

Occlusion dose monitoring in amblyopia therapy: status, insights, and future directions.

Occlusion therapy remains the mainstay treatment of amblyopia, but its outcome is not assured or universally excellent. Many factors are known to influence treatment outcome, among which compliance is foremost. The occlusion dose monitor (ODM) removes one variable from the treatment equation, because it records the occlusion actually received by-rather than prescribed for-the child. Improvement observed can thus be quantitatively related to the patching received. This review summarizes the insights the ODM has provided to date particularly in elucidating the dose-response relationship. We are entering the era of personalized ophthalmology in which treatments will be tailored to the needs of the individual child and facilitated by the use of wearable monitors.

Management of children and young people with vision impairment: diagnosis, developmental challenges and outcomes.

Vision impairment (VI) has a significant impact on an individual's ability to engage with everyday tasks. Severe early-onset VI presents different challenges to adult onset visual loss since reduced visual input presents a major obstacle to the acquisition and development of fundamental developmental skills in early and later childhood. Early referral of the child with reduced vision is vital to ensure accurate diagnosis and prompt treatment of any modifiable aspects of the condition. Guidance to ensure optimisation of developmental opportunity through adaptation of play and care is vital from the earliest stages. Cognitive and social challenges occur throughout education and need to be understood and addressed through skilled support. Multiagency input, particularly from health and education, is vital to minimise the risk of adverse outcomes and promote successful transition to independent adulthood. VI may also arise in a variety of neurological disorders, and diagnosis and assessment to ensure appropriate adaptations are made is also crucial for this group of children. This review provides the paediatrician with information on diagnosis, assessment, long-term support needs and outcomes.

Treatment of Amblyopia Using Personalized Dosing Strategies: Statistical Modelling and Clinical Implementation.

PURPOSE: To generate a statistical model for personalizing a patient's occlusion therapy regimen. METHODS: Statistical modelling was undertaken on a combined data set of the Monitored Occlusion Treatment of Amblyopia Study (MOTAS) and the Randomized Occlusion Treatment of Amblyopia Study (ROTAS). This exercise permits the calculation of future patients' total effective dose (TED)-that predicted to achieve their best attainable visual acuity. Daily patching regimens (hours/day) can be calculated from the TED. RESULTS: Occlusion data for 149 study participants with amblyopia (anisometropic in 50, strabismic in 43, and mixed in 56) were analyzed. Median time to best observed visual acuity was 63 days (25% and 75% quartiles; 28 and 91 days). Median visual acuity in the amblyopic eye at start of occlusion was 0.40 logMAR (quartiles 0.22 and 0.68 logMAR) and at end of occlusion was 0.12 (quartiles 0.025 and 0.32 logMAR). Median lower and upper estimates of TED were 120 hours (quartiles 34 and 242 hours), and 176 hours (quartiles 84 and 316 hours). The data suggest a piecewise linear relationship (P = 0.008) between patching dose-rate (hours/day) and TED with a single breakpoint estimated at 2.16 (standard error 0.51) hours/day, suggesting doses below 2.16 hours/day are less effective. CONCLUSION: We introduce the concept of TED of occlusion. Predictors for TED are visual acuity deficit, amblyopia type, and age at start of occlusion therapy. Dose-rates prescribed within the model range from 2.5 to 12 hours/day and can be revised dynamically throughout treatment in response to recorded patient compliance: a personalized dosing strategy.

Outcomes of Two Trials of Oxygen-Saturation Targets in Preterm Infants.

BACKGROUND: The safest ranges of oxygen saturation in preterm infants have been the subject of debate. METHODS: In two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial. RESULTS: After 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P=0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P=0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P=0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P=0.001). CONCLUSIONS: Use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.).

Personalized versus standardized dosing strategies for the treatment of childhood amblyopia: study protocol for a randomized controlled trial.

BACKGROUND: Amblyopia is the commonest visual disorder of childhood in Western societies, affecting, predominantly, spatial visual function. Treatment typically requires a period of refractive correction ('optical treatment') followed by occlusion: covering the nonamblyopic eye with a fabric patch for varying daily durations. Recent studies have provided insight into the optimal amount of patching ('dose'), leading to the adoption of standardized dosing strategies, which, though an advance on previous ad-hoc regimens, take little account of individual patient characteristics. This trial compares the effectiveness of a standardized dosing strategy (that is, a fixed daily occlusion dose based on disease severity) with a personalized dosing strategy (derived from known treatment dose-response functions), in which an initially prescribed occlusion dose is modulated, in a systematic manner, dependent on treatment compliance. METHODS/DESIGN: A total of 120 children aged between 3 and 8 years of age diagnosed with amblyopia in association with either anisometropia or strabismus, or both, will be randomized to receive either a standardized or a personalized occlusion dose regimen. To avoid confounding by the known benefits of refractive correction, participants will not be randomized until they have completed an optical treatment phase. The primary study objective is to determine whether, at trial endpoint, participants receiving a personalized dosing strategy require fewer hours of occlusion than those in receipt of a standardized dosing strategy. Secondary objectives are to quantify the relationship between observed changes in visual acuity (logMAR, logarithm of the Minimum Angle of Resolution) with age, amblyopia type, and severity of amblyopic visual acuity deficit. DISCUSSION: This is the first randomized controlled trial of occlusion therapy for amblyopia to compare a treatment arm representative of current best practice with an arm representative of an entirely novel treatment regimen based on statistical modelling of previous trial outcome data. Should the personalized dosing strategy demonstrate superiority over the standardized dosing strategy, then its adoption into routine practice could bring practical benefits in reducing the duration of treatment needed to achieve an optimal outcome. TRIAL REGISTRATION: ISRCTN ISRCTN12292232.