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Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial.

ABSTRACT: Importance:Anti-vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient. Objective:To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab. Design, Setting, and Participants:This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized. Interventions:All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days. Main Outcomes and Measures:The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee. Results:Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49; P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group. Conclusions and Relevance:This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab. Trial Registration:clinicaltrials.gov Identifier: NCT02134457 and clinicaltrialsregister.eu Identifier: 2013-002539-13.

SUBMITTER: Stahl A

PROVIDER: S-EPMC5840003 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRetinopathy of prematurity (ROP) is typically treated with laser photocoagulation and/or intravitreal anti-vascular endothelial growth factor (anti-VEGF). To the best of our knowledge, most systematic reviews have focused on comparing anti-VEGF against laser treatment while comparisons between different anti-VEGF agents are lacking. Thus, we conducted this meta-analysis to compare the efficacy and safety of different anti-VEGF agents or laser after primary ROP therapy.MethodsWe conducted a comprehensive search across multiple databases up to November 2022. We included studies that used anti-VEGF or laser for ROP with comparable cohorts.ResultsOverall, 44 studies were included in this meta-analysis. When comparing anti-VGEF with laser, we found that the anti-VEGF group had a significantly higher retreatment rate (RR = 1.56, 95%CI = [1.06, 2.31], p = 0.03), a longer time from treatment to retreatment (WMD = 5.99 weeks, 95%CI = [4.03, 7.95], p < 0.001), a lower retinal detachment rate (RR = 0.55, 95%CI = [0.30, 0.91], p = 0.02), higher spherical equivalent (WMD = 1.69D, 95%CI = [0.61, 2.77], p = 0.002), lower myopia rate (RR = 0.69, 95%CI = [0.50, 0.97], p = 0.03) and lower anisometropia rate (RR = 0.44, 95%CI = [0.29, 0.67], p = 0.0001). In comparisons between ranibizumab and bevacizumab, the intravitreal ranibizumab (IVR) group was associated with higher recurrence rate (RR = 2.02, 95%CI = [1.49, 2.73], p < 0.0001), higher retreatment rate (RR = 1.70, 95%CI = [1.17, 2.47], p = 0.0006), and lower high myopia rate (RR = 0.31, 95%CI = [0.12, 0.77], p = 0.01). Similarly, when compared to aflibercept and conbercept, the IVR cohort also demonstrated higher recurrence and retreatment rates. While no significant differences were observed in any of the variables included in the statistical analysis in the comparison between bevacizumab and aflibercept.ConclusionsAnti-VEGF was associated with higher retreatment and lesser incidence of myopia as compared to laser. Laser therapy was linked to more complications like retinal detachment and myopia. Ranibizumab exhibited higher recurrence and retreatment rates compared to bevacizumab, aflibercept, and conbercept.

Project description:ImportanceAnti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME) favorably affects diabetic retinopathy (DR) improvement and worsening. It is unknown whether these effects differ across anti-VEGF agents.ObjectiveTo compare changes in DR severity during aflibercept, bevacizumab, or ranibizumab treatment for DME.Design, setting, and participantsPreplanned secondary analysis of data from a comparative effectiveness trial for center-involved DME was conducted in 650 participants receiving aflibercept, bevacizumab, or ranibizumab. Retinopathy improvement and worsening were determined during 2 years of treatment. Participants were randomized in 2012 through 2013, and the trial concluded on September 23, 2015.InterventionsRandom assignment to aflibercept, 2.0 mg; bevacizumab, 1.25 mg; ranibizumab, 0.3 mg, up to every 4 weeks through 2 years following a retreatment protocol.Main outcomes and measuresPercentages with retinopathy improvement at 1 and 2 years and cumulative probabilities for retinopathy worsening through 2-year without adjustment for multiple outcomes.ResultsA total of 650 participants (495 [76.2%] nonproliferative DR [NPDR], 155 proliferative DR [PDR]) were analyzed; 302 (46.5%) were women and mean (SD) age was 61 (10) years; 425 (65.4%) were white. At 1 year, among 423 NPDR eyes, 44 of 141 (31.2%) treated with aflibercept, 29 of 131 (22.1%) with bevacizumab, and 57 of 151 (37.7%) with ranibizumab had improvement of DR severity (adjusted difference: 11.7%; 95% CI, 2.9% to 20.6%; P = .004 for aflibercept vs bevacizumab; 8.9%; 95% CI, 1.7% to 16.1%; P = .01 for ranibizumab vs bevacizumab; and 2.9%; 95% CI, -5.7% to 11.4%; P = .51 for aflibercept vs ranibizumab). At 2 years, 33 eyes (24.8%) in the aflibercept group, 25 eyes (22.1%) in the bevacizumab group, and 40 eyes (31.0%) in the ranibizumab group had DR improvement; no treatment group differences were identified. For 93 eyes with PDR at baseline, 1-year improvement rates were 75.9% for aflibercept, 31.4% for bevacizumab, and 55.2% for ranibizumab (adjusted difference: 50.4%; 95% CI, 26.8% to 74.0%; P < .001 for aflibercept vs bevacizumab; 20.4%; 95% CI, -3.1% to 44.0%; P = .09 for ranibizumab vs bevacizumab; and 30.0%; 95% CI, 4.4% to 55.6%; P = .02 for aflibercept vs ranibizumab). These rates and treatment group differences appeared to be maintained at 2 years. Despite the reduced numbers of injections in the second year, 66 (59.5%) of NPDR and 28 (70.0%) of PDR eyes that manifested improvement at 1 year maintained improvement at 2 years. Two-year cumulative rates for retinopathy worsening ranged from 7.1% to 10.2% and 17.2% to 26.4% among anti-VEGF groups for NPDR and PDR eyes, respectively. No statistically significant treatment differences were noted.Conclusions and relevanceAt 1 and 2 years, eyes with NPDR receiving anti-VEGF treatment for DME may experience improvement in DR severity. Less improvement was demonstrated with bevacizumab at 1 year than with aflibercept or ranibizumab. Aflibercept was associated with more improvement at 1 and 2 years in the smaller subgroup of participants with PDR at baseline. All 3 anti-VEGF treatments were associated with low rates of DR worsening. These data provide additional outcomes that might be considered when choosing an anti-VEGF agent to treat DME.

Project description:IMPORTANCE:Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME). OBJECTIVE:To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy. DESIGN, SETTING, AND PARTICIPANTS:Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015. INTERVENTIONS:Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n?=?203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n?=?191 eyes). Eyes in both treatment groups could receive ranibizumab for DME. MAIN OUTCOMES AND MEASURES:The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization. RESULTS:Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P?<?.001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P?<?.001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P?<?.001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P?<?.001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P?<?.001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P?=?.58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified. CONCLUSIONS AND RELEVANCE:Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT01489189.

Project description:Objective: To perform a meta-analysis of randomized controlled trials verifying clinical efficacy and safety of propranolol in pre-term newborns with retinopathy of prematurity (ROP). Methods: We searched the literature databases (Pubmed, Embase, The Cochrane Library, Web of Science, CNKI, WanFang, VIP, CBM) for publications before August 10, 2020, and the World Health Organization's International Clinical Trials Registry and ClinicalTrials.gov for ongoing trials. Randomized controlled trials (RCTs) of propranolol for the prevention or treatment of ROP were included. The quality of the included studies was primarily assessed by the RCT tool of the Cochrane Collaboration. The included studies were quantified using a meta-analysis of relative risk (RR) estimated with a random effect model. Results: Our original search identified 171 articles, and five studies met our criteria. A meta-analysis was performed that showed that infants orally treated with propranolol had a decreased risk of disease progression: stage progression had an RR = 0.65 [95% confidence interval (CI), 0.47-0.88]), plus disease had an RR = 0.43 [95% CI, 0.22-0.82]. The demands for additional treatments had similar protective results: laser photocoagulations had an RR = 0.55 [95% CI, 0.35-0.86]), and intravitreal injection of anti-vascular endothelial growth factor had an RR = 0.45 [95% CI, 0.22-0.90]). The oral administration of propranolol was associated with an increased risk of adverse events (RR = 2.01 [95% CI, 1.02-3.97]). High-risk adverse events included bradycardia, hypotension, not gaining enough weight, bronchospasm, hypoglycemia, apnea, and increasing ventilator need. Subgroup analysis of ROP phases and stages found that the risk in stage 2 ROP of the second phase and the individual risk factors (stage progression, RR = 0.42 [95% CI, 0.27-0.65]; plus disease, RR = 0.40 [95% CI, 0.17-0.93]; laser photocoagulation, RR = 0.31 [95% CI, 0.14-0.68]) have statistically significant differences compared with other phases and stages. Conclusions: Pre-term newborns with ROP, especially in stage 2 ROP of the second phase, who were orally given propranolol have a reduced risk of disease progression and demand for additional treatments, but the safety needs more attention.

Project description:Despite new therapeutic approaches have improved the prognosis of newborns with retinopathy of prematurity (ROP), an unfavourable structural and functional outcome still remains high. There is high pressure to develop new drugs to prevent and treat ROP. There is increasing enthusiasm for anti-VEGF drugs, but angiogenic inhibitors selective for abnormal blood vessels would be considered as an optimal treatment.In an animal experimental model of proliferative retinopathy, we have recently demonstrated that the pharmacological blockade of beta-adrenoreceptors improves retinal neovascularization and blood retinal barrier breakdown consequent to hypoxia. The purpose of this study is to evaluate the propranolol administration in preterm newborns suffering from a precocious phase of ROP in terms of safety and efficacy in counteracting the progression of retinopathy.Preterm newborns (gestational age at birth lower than 32 weeks) with stage 2 ROP (zone II-III without plus) will be randomized, according to their gestational age, to receive propranolol added to standard treatment (treatment adopted by the ETROP Cooperative Group) or standard treatment alone. Propranolol will be administered until retinal vascularization will be completely developed, but not more than 90 days. Forty-four participants will be recruited into the study. To evaluate the safety of propranolol administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of propranolol, the progression of the disease, the number of laser treatments or vitrectomies, the incidence of retinal detachment or blindness, will be evaluated by serial ophthalmologic examinations. Visual function will be evaluated by means of behavioural standardized tests.This pilot study is the first research that explores the possible therapeutic role of beta blockers in ROP. The objective of this research is highly ambitious: to find a treatment simple, inexpensive, well tolerated and with few adverse effects, able to counteract one of the major complications of the prematurity. Any favourable results of this research could open new perspectives and original scenarios about the treatment or the prevention of this and other proliferative retinopathies.Current Controlled Trials ISRCTN18523491; ClinicalTrials.gov Identifier NCT01079715; EudraCT Number 2010-018737-21.

Project description:ImportanceLack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP).ObjectiveTo determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants.Design, setting, and participantsThe Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020.InterventionsInfants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age.Main outcomes and measuresThe primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth.ResultsA total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died.Conclusions and relevanceThis study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants.Trial registrationClinicalTrials.gov Identifier: NCT03201588.

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Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial.

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