Choice of Dose Level for a Randomized Clinical Trial of Low-Dose Bevacizumab vs Laser for Type 1 Retinopathy of Prematurity.
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SUBMITTER: Kraker RT
PROVIDER: S-EPMC8377606 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
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Choice of Dose Level for a Randomized Clinical Trial of Low-Dose Bevacizumab vs Laser for Type 1 Retinopathy of Prematurity.
Kraker Raymond T RT Wallace David K DK Beck Roy W RW Saunders Christina T CT Lorenzi Elizabeth E Melia B Michele BM Li Zhuokai Z
JAMA ophthalmology 20211001 10
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Project description:ImportanceIntravitreous bevacizumab (0.25 mg to 0.625 mg) is commonly used to treat type 1 retinopathy of prematurity (ROP), but there are concerns about systemic toxicity, particularly the risk of neurodevelopmental delay. A much lower dose may be effective for ROP while reducing systemic risk. Previously, after testing doses of 0.25 mg to 0.031 mg, doses as low as 0.031 mg were found to be effective in small cohorts of infants.ObjectiveTo find the lowest dose of intravitreous bevacizumab effective for severe ROP.Design, setting, and participantsBetween April 2017 and May 2019, 59 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, dose de-escalation study. In cohorts of 10 to 14 infants, 1 eye per infant received 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg of intravitreous bevacizumab. Diluted bevacizumab was prepared by individual research pharmacies and delivered using 300-µL syringes with 5/16-inch, 30-guage fixed needles. Analysis began July 2019.InterventionsBevacizumab intravitreous injections at 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg.Main outcomes and measuresSuccess was defined as improvement by 4 days postinjection and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks.ResultsFifty-five of 59 enrolled infants had 4-week outcomes completed; the mean (SD) birth weight was 664 (258) g, and the mean (SD) gestational age was 24.8 (1.6) weeks. A successful 4-week outcome was achieved for 13 of 13 eyes (100%) receiving 0.016 mg, 9 of 9 eyes (100%) receiving 0.008 mg, 9 of 10 eyes (90%) receiving 0.004 mg, but only 17 of 23 eyes (74%) receiving 0.002 mg.Conclusions and relevanceThese data suggest that 0.004 mg may be the lowest dose of bevacizumab effective for ROP. Further investigation is warranted to confirm effectiveness of very low-dose intravitreous bevacizumab and its effect on plasma vascular endothelial growth factor levels and peripheral retinal vascularization.
| S-EPMC7180729 | biostudies-literature
Project description:PurposeLow-dose and very low-dose intravitreal bevacizumab (IVB) have been reported to be successful in short-term treatment of type 1 retinopathy of prematurity (ROP), down to an initial dose of 0.004 mg. We now report 12-month outcomes for these infants.DesignMasked, multicenter, dose de-escalation study.ParticipantsOne hundred twenty prematurely born infants with type 1 ROP.MethodsA cohort of 120 infants with type 1 ROP in at least 1 eye from 2 sequential dose de-escalation studies of low-dose IVB (0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg) or very low-dose IVB (0.016 mg, 0.008 mg, 0.004 mg, and 0.002 mg) to the study eye; the fellow eye (if also type 1) received 1 dose level higher of IVB. After primary success or failure at 4 weeks, clinical management was at investigator discretion, including all additional treatment.Main outcome measuresReactivation of severe ROP by 6 months corrected age, additional treatments, retinal and other ocular structural outcomes, and refractive error at 12 months corrected age.ResultsSixty-two of 113 study eyes (55%) and 55 of 98 fellow eyes (56%) received additional treatment. Of the study eyes, 31 (27%) received additional ROP treatment, and 31 (27%) received prophylactic laser therapy for persistent avascular retina. No trend toward a higher risk of additional ROP treatment related to initial IVB doses was found. However, time to reactivation among study eyes was shorter in eyes that received very low-dose IVB (mean, 76.4 days) than in those that received low-dose IVB (mean, 85.7 days). At 12 months, poor retinal outcomes and anterior segment abnormalities both were uncommon (3% and 5%, respectively), optic atrophy was noted in 10%, median refraction was mildly myopic (-0.31 diopter), and strabismus was present in 29% of infants.ConclusionsRetinal structural outcomes were very good after low- and very low-dose IVB as initial treatment for type 1 ROP, although many eyes received additional treatment. The rate of reactivation of severe ROP was not associated with dose; however, a post hoc data-driven analysis suggested that reactivation was sooner with very low doses.
| S-EPMC9509410 | biostudies-literature
Project description:BackgroundInfants with stage 3+ retinopathy of prematurity (ROP) in zone I or zone II posterior were randomized to initial treatment with bevacizumab or laser in a multicenter trial (BEAT-ROP). The purpose of this study was to assess the effects of bevacizumab on nonophthalmologic outcomes.MethodsAt one study site, inborn infants of <27 weeks' gestational age underwent medical and standardized neurologic and developmental assessments at 18-22 months' corrected age (age after expected date of full-term delivery).ResultsOf the 18 infants enrolled at our site, 16 (7 bevacizumab, 9 laser) were evaluated for medical and neurodevelopmental outcomes at 18-28 months' corrected age. For each of the groups, the medians and ranges of growth percentiles were low compared with norms for healthy infants. The ranges for Bayley III developmental scores were also low relative to expected norms for healthy infants. There were no significant differences between the bevacizumab and laser therapy groups in weight (median percentile: bevacizumab, 18; laser, 7), length, head circumference, cerebral palsy, or Bayley scores (median Cognitive Composite Score: bevacizumab, 85; laser, 65). There was a significant difference in length of hospital stay (median days, 98 vs 140 days) favoring the bevacizumab group.ConclusionsIn this patient cohort 2-year follow-up evaluation of infants treated with bevacizumab versus laser therapy for retinopathy of prematurity showed no adverse effects on medical or neurodevelopmental outcomes.
| S-EPMC5826862 | biostudies-literature
Project description:ImportanceIntravitreal bevacizumab effectively treats severe retinopathy of prematurity (ROP), but it enters the bloodstream and may reduce serum vascular endothelial growth factor (VEGF), potentially causing detrimental effects on developing organs in the premature infant.ObjectiveTo evaluate the association of intravitreal bevacizumab with plasma bevacizumab and VEGF concentrations at 2 and 4 weeks after predefined, de-escalating doses of intravitreal bevacizumab were administered to infants with severe ROP.Design, setting, and participantsThis phase 1 dose de-escalation case series study was conducted at 10 US hospitals of ophthalmology institutions from May 21, 2015, to May 7, 2019. Blood samples were collected 2 and 4 weeks after intravitreal bevacizumab injection. Participants included 83 premature infants with type 1 ROP in 1 or both eyes and no previous ROP treatment. Data were analyzed from April 2017 to August 2021.InterventionsStudy eyes received a single bevacizumab injection of 0.250 mg, 0.125 mg, 0.063 mg, 0.031 mg, 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg. When the fellow eye required treatment, one dose higher was administered. Total dose administered at baseline was defined as the sum of doses given to each eye within 3 days of initial study-eye injection.Main outcomes and measuresPlasma bevacizumab concentration at 2 and 4 weeks after injection and the percentage change in plasma VEGF concentrations from pretreatment levels.ResultsA total of 83 infants (mean [SD] age, 25 [2] weeks; 48 boys [58%]) were included in this study. Higher doses of bevacizumab administered at baseline were associated with higher plasma bevacizumab concentrations at 2 weeks (ρ, 0.53; 95% CI, 0.31-0.70) and 4 weeks (ρ, 0.44; 95% CI, 0.18-0.64). Plasma VEGF concentrations decreased by 50% or more from pretreatment levels in 40 of 66 infants (61%) at 2 weeks and 31 of 61 infants (51%) at 4 weeks, but no association was observed between the total dose of bevacizumab administered at baseline and percentage change in plasma VEGF concentrations 2 weeks (ρ, -0.04; 95% CI, -0.28 to 0.20) or 4 weeks (ρ, -0.17; 95% CI, -0.41 to 0.08) after injection.Conclusions and relevanceResults of this phase 1 dose de-escalation case series study revealed that bevacizumab doses as low as 0.002 mg were associated with reduced plasma VEGF levels for most infants at 2 and 4 weeks after intravitreal administration; however, no association was observed between total bevacizumab dose administered and reductions in plasma VEGF levels from preinjection to 2 weeks or 4 weeks. Additional studies are needed to evaluate the long-term effects of low-dose bevacizumab on neurodevelopment and retinal structure.
| S-EPMC8895318 | biostudies-literature
Project description:ImportanceLaser 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.ObjectiveTo compare intravitreal aflibercept vs laser photocoagulation in infants with ROP requiring treatment.Design, setting, and participantsThis 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).InterventionsInfants 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 measuresThe 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%.ResultsAmong 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 relevanceAmong 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 registrationClinicalTrials.gov Identifier: NCT04004208.
| S-EPMC9327573 | biostudies-literature
Project description:Current therapies for treatment-indicated (type 1) retinopathy of prematurity mainly consist of laser photocoagulation and intravitreal anti-vascular endothelial growth factor (eg, bevacizumab) injection. The first visible signs of acute-phase regression are typically vascular, including decreased plus disease. Using a semiautomated computer program, we quantitatively compared posterior pole vascular changes following treatment with laser versus bevacizumab and found that in the first month following treatment, vascular dilation and tortuosity significantly decreased following either treatment modality, but tortuosity decreased earlier and faster after bevacizumab.
| S-EPMC9772077 | biostudies-literature
Project description:PurposeTo compare progression of myopia and refractive error in former premature infants with retinopathy of prematurity (ROP) treated using intravitreal bevacizumab (IVB) or laser.DesignRetrospective clinical cohort study.MethodsWe identified premature infants with ROP treated using IVB from 2011 to 2020 and compared their longitudinal cycloplegic refraction data to that of infants with ROP treated using laser during the same timeframe. A subset of infants treated using IVB also underwent additional treatment using laser. We included cycloplegic refractions from 789 cumulative visits over a median 3.2 years. We used a linear mixed-effects model with a log decay function to evaluate how refraction changed with age after treatment.ResultsIn aggregate, the model estimated a significant (P < .001) trend in refraction-from slight hyperopia to relatively more myopic states. However, progression in laser-treated eyes was significantly (P < .001) more rapid, regardless of treatment with IVB. The number of laser spots resulted in increased myopic progression by approximately 0.16 diopters per 100 laser spots. Both ROP stage and zone had a significant effect on myopic progression, with more severe disease resulting in faster myopic progression. Random effects, including individual subject variation with nested variance for left and right eye, accounted for 86.4% of the remaining variance not explained by age and treatment.ConclusionsLaser treatment for severe ROP increases the trend to severe myopia. In our sample, IVB did not affect myopic progression but did substantially reduce the amount of consequent laser required to treat ROP. The effect of laser persists after accounting for differences in ROP stage and zone.
| S-EPMC9308642 | biostudies-literature
Project description:PurposeTo compare the patterns of longitudinal refractive error development during the first 3.5 years in children with severe retinopathy of prematurity (ROP) treated with intravitreal bevacizumab (IVB) or laser photocoagulation.MethodsThis prospective cohort study enrolled extremely preterm infants (birth weight < 1000 g, gestational age 23-27 weeks) with type 1 ROP from multiple hospitals in Dallas between 1999 and 2017; IVB group (N = 22); laser group (N = 26). Cycloplegic retinoscopy was conducted from 0.04 years corrected age and every 0.5 to 1.0 years thereafter until 3.5 years old. Right eye spherical equivalent (SEQ) and astigmatism, anisometropia, and better-eye visual acuity were analyzed over time.ResultsIn all children, both eyes were treated with the same modality. At the final visit, the prevalence of myopia (SEQ ≤ -1D) was 82.7% in the laser group and 47.7% in the IVB group (P < 0.05) with a mean SEQ of -8.0D ± 5.8D in the laser group versus -2.3D ± 4.2D in the IVB group (P < 0.001). Longitudinal SEQ were best fit with a bilinear model. Before one year, the rate of SEQ change was -5.0D/year in the laser group, but only -3.5D/year in the IVB group (T = -5.14, P < 0.001); after one year, there was a significant flattening of these slopes (T = 6.23, P < 0.001). Anisometropia in the IVB group was significantly less than in the laser group (P < 0.05). Final visual acuity in both groups was similar at 0.47 logMAR (∼ 20/60).ConclusionsChildren with severe ROP treated with IVB developed less myopic refractive error than those treated with laser largely because of a slower rate of refractive change during the first year of life.Translational relevanceThese findings may inform decisions regarding ROP treatment timing and modality.
| S-EPMC8054622 | biostudies-literature
Project description:BackgroundRetinopathy of prematurity is a leading cause of childhood blindness worldwide. Peripheral retinal ablation with conventional (confluent) laser therapy is destructive, causes complications, and does not prevent all vision loss, especially in cases of retinopathy of prematurity affecting zone I of the eye. Case series in which patients were treated with vascular endothelial growth factor inhibitors suggest that these agents may be useful in treating retinopathy of prematurity.MethodsWe conducted a prospective, controlled, randomized, stratified, multicenter trial to assess intravitreal bevacizumab monotherapy for zone I or zone II posterior stage 3+ (i.e., stage 3 with plus disease) retinopathy of prematurity. Infants were randomly assigned to receive intravitreal bevacizumab (0.625 mg in 0.025 ml of solution) or conventional laser therapy, bilaterally. The primary ocular outcome was recurrence of retinopathy of prematurity in one or both eyes requiring retreatment before 54 weeks' postmenstrual age.ResultsWe enrolled 150 infants (total sample of 300 eyes); 143 infants survived to 54 weeks' postmenstrual age, and the 7 infants who died were not included in the primary-outcome analyses. Retinopathy of prematurity recurred in 4 infants in the bevacizumab group (6 of 140 eyes [4%]) and 19 infants in the laser-therapy group (32 of 146 eyes [22%], P=0.002). A significant treatment effect was found for zone I retinopathy of prematurity (P=0.003) but not for zone II disease (P=0.27).ConclusionsIntravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease. Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina. This trial was too small to assess safety. (Funded by Research to Prevent Blindness and others; ClinicalTrials.gov number, NCT00622726.).
| S-EPMC3119530 | biostudies-literature
Project description:PurposeTo determine incidence, risk factors, risk period, and characteristics of recurrent retinopathy of prematurity (ROP) treated by intravitreal bevacizumab (IVB) monotherapy.DesignRetrospective case series.ParticipantsPremature infants with type 1 ROP (subdivided into stage 3+ ROP and aggressive posterior ROP [APROP]) in zone I or zone II posterior who received IVB monotherapy and were followed up for at least 65 weeks adjusted age (AA).MethodsRetrospective review of infants who demonstrated recurrence of type 1 ROP after IVB monotherapy, including examination of RetCam fundus photographs and fluorescein angiograms.Main outcomes measuresIncidence, risk factors, risk period, and characteristics of recurrent ROP.ResultsIntravitreal bevacizumab monotherapy in 241 infants (471 eyes) was reviewed. Recurrence incidence was 8.3% (20/241) for infants and 7.2% (34/471) for eyes. Recurrence risk factors of greatest significance were appearance of neovascularization as APROP (P = 0.006), extended duration of hospitalization (P = 0.01), and lower birth weight (P = 0.024). Recurrence risk period was between approximately 45 and 55 weeks AA (90.0% [18/20] for infants and 94.1% [32/34] for eyes), with mean recurrence of 51.2 weeks AA (±4.6 weeks; range, 45.7-64.9 weeks) and mean interval of 16.2 weeks (±4.4 weeks) between treatments. Recurrence characteristics included plus disease (20/20 infants [100%]) and neovascularization, which appeared at the following sites: stage 3+ ROP with confluent neovascularization recurred both at the advancing edge and at the initial ridge and extraretinal fibrovascular proliferative complex (12/14 infants [85.7%]). However, APROP (6/6 infants [100%]) and stage 3+ ROP with nonconfluent neovascularization (2/14 infants [14.3%]) recurred only at the advancing edge. Also, the anterior extent of retinal vascularization was decreased (mean, 1.76 disc diameters [DD] vs. 4.48 DD), and the rate of retinal vascularization was delayed (mean, 0.11 DD/week vs. 0.23 DD/week) in those with versus without recurrence, respectively. After retreatment with IVB, retinal vascularization proceeded minimally and slowly.ConclusionsPremature children with severe ROP are being treated successfully with IVB monotherapy. However, recurrence is not uncommon, so vigilant follow-up is necessary to ensure timely re-treatment. Knowledge of recurrence incidence, risk factors, risk period, and characteristics allows for tailored clinical management.
| S-EPMC4995132 | biostudies-literature