Dataset Information

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

ABSTRACT: Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297- 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a ?-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results. Clinical Trial Registration The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

SUBMITTER: Filippi L

PROVIDER: S-EPMC6514240 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

Filippi Luca L Cavallaro Giacomo G Berti Elettra E Padrini Letizia L Araimo Gabriella G Regiroli Giulia G Raffaeli Genny G Bozzetti Valentina V Tagliabue Paolo P Tomasini Barbara B Mori Annalisa A Buonocore Giuseppe G Agosti Massimo M Bossi Angela A Chirico Gaetano G Aversa Salvatore S Fortunato Pina P Osnaghi Silvia S Cavallotti Barbara B Suzani Martina M Vanni Maurizio M Borsari Giulia G Donati Simone S Nascimbeni Giuseppe G Nardo Daniel D Piermarocchi Stefano S la Marca Giancarlo G Forni Giulia G Milani Silvano S Cortinovis Ivan I Calvani Maura M Bagnoli Paola P Dal Monte Massimo M Calvani Anna Maria AM Pugi Alessandra A Villamor Eduardo E Donzelli Gianpaolo G Mosca Fabio F

Frontiers in pediatrics 20190507

<b>Background:</b> Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. <b>Methods:</b> A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, r ...[more]

PMID: 31134171

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Project description:Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1).A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations.Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue.ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.

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:ObjectiveThe efficacy and safety of propranolol for retinopathy of prematurity (ROP) remain under debate. This network meta-analysis (NMA) focuses on whether a ranking may be established for different dose levels of propranolol as treatment of ROP in terms of stage progression as the primary outcome, with appearance of plus disease and need for anti-vascular endothelial growth factors (anti-VEGFs) or laser therapy as secondary endpoints.MethodsFourteen studies (10 randomised controlled trials, three single-arm trials and one retrospective observational study) of 474 patients treated with oral or ocular propranolol were retrieved from databases up to April 2024. Meta-insight and model-based NMA were undertaken to evaluate the propranolol dose-response relationship. Studies were evaluated for model fit, risk of bias and Confidence of evidence In Network Meta-Analysis (CINeMA). Effect sizes were determined as odds ratio (OR) with 95% credible interval (CrI).ResultsBayesian analysis showed a trend towards improved effects for propranolol given at late stages (stages 2-3; S23) of ROP progression compared with its administration at earlier stages (stages 0-1; S01). OR values for oral propranolol 1.5 and 2 mg/kg/day given at S23 were 0.13 (95% CrI 0.04-0.37) and 0.16 (95% CrI 0.04-0.61), respectively, while given at S01 were 0.28 (95% CrI 0.02-2.96) and 0.78 (95% CrI 0.14-4.43), respectively. Similarly, OR of eye propranolol 0.2% at S23 was 0.37 (95% CrI 0.09-1.00) versus an S01 OR of 0.64 (95% CrI 0.21-2.04). Surface under the cumulative ranking curve (SUCRA) analyses confirmed best probability values for oral propranolol 1.5-2 mg/kg followed by eye propranolol 0.2%, all at S23. Model-based NMA showed nonlinearity in the dose-response for oral propranolol with a trend to greater maximal effect for its administration at late versus early stages. For secondary endpoints, lower risk values were found with oral propranolol 1.5 mg/kg/day at S23 for progression to plus disease (OR 0.14; 95% CrI 0.02-0.84) and need for anti-VEGFs (OR 0.23; 95% CrI 0.05-0.93) and laser (OR 0.16; 95% CrI 0.02-1.10) therapies also followed by eye propranolol 0.2%, and a similar profile was obtained with SUCRA analysis. Lower doses (0.5-1.0 mg/kg/day) of oral propranolol retained efficacy. Threat of adverse events was estimated as risk difference versus control with no difference for eye propranolol 0.2% and oral propranolol 0.5 mg/kg/day, modest increases of risk for oral propranolol 1.0 and 1.5 mg/kg/day and the highest risk difference for oral propranolol 2.0 mg/kg/day (0.06; 95% CI -0.01 to 0.13).ConclusionA diminished risk of disease progression and need for additional treatment was obtained with propranolol in ROP, but safety is a potential concern. Propranolol eye micro-drops (0.2%) can be as efficacious as oral propranolol. Nonetheless, the evidence is limited due to the paucity and quality of the available studies.

Project description:PurposeTo describe the clinical characteristics of intraocular hemorrhages (IOHs) in infants in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study and to evaluate their potential use for prediction of disease severity.DesignSecondary data analysis from a prospective study.ParticipantsPreterm infants with birth weight (BW) ≤1250 g.MethodsInfants underwent serial digital retinal imaging in both eyes starting at 32 weeks' postmenstrual age. Nonphysician trained readers (TRs) evaluated all image sets from eyes that ever had IOHs documented on image evaluation or eye examination for the presence, location, type, area, and relation of the IOH to the junction between vascularized and avascular retina. Associations of IOH with demographic and neonatal factors, and with the presence and severity of retinopathy of prematurity (ROP) were investigated by univariate and multivariate analyses. Sensitivity and specificity of the telemedicine system for detecting referral-warranted ROP (RW-ROP) were calculated with and without incorporating hemorrhage into the standardized grading protocol.Main outcome measuresRetinal and vitreous hemorrhage.ResultsAmong 1239 infants (mean [standard deviation] BW = 864 [212] g; gestational age [GA] = 27 [2.2] weeks) who underwent an average of 3.2 imaging sessions, 22% had an IOH in an eye on at least 1 of the e-ROP visits. Classification of IOH was preretinal (57%), blot (57%), dot (38%), flame-shaped (16%), and vitreous (8%); most IOHs were unilateral (70%). The IOH resolved in 35% of eyes by the next imaging session and in the majority (76%) of cases by 8 weeks after initial detection. Presence of IOH was inversely associated with BW and GA and significantly associated (P < 0.0001) with the presence and severity of ROP (BW and GA adjusted odds ratios [ORs] of 2.46 for any ROP, 2.88 for stage 3, and 3.19 for RW-ROP). Incorporating IOH into the grading protocol minimally altered the sensitivity of the system (94% vs. 95%).ConclusionsApproximately 1 in 5 preterm infants examined had IOHs, generally unilateral. The presence of hemorrhage was directly correlated with both presence and severity of ROP and inversely correlated with BW and GA, although including hemorrhage in the grading algorithm only minimally improved the sensitivity of the telemedicine system to detect RW-ROP.

Project description:ImportanceMeasurable competence derived from comprehensive and advanced training in grading digital images is critical in studies using a reading center to evaluate retinal fundus images from infants at risk for retinopathy of prematurity (ROP). Details of certification for nonphysician trained readers (TRs) have not yet been described.ObjectiveTo describe a centralized system for grading ROP digital images by TRs in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study.Design, setting, and participantsMulticenter observational cohort study conducted from July 1, 2010, to June 30, 2014. The TRs were trained by experienced ROP specialists and certified to detect ROP morphology in digital retinal images under supervision of an ophthalmologist reading center director. An ROP reading center was developed with standard hardware, secure Internet access, and customized image viewing software with an electronic grading form. A detailed protocol for grading was developed. Based on results of TR gradings, a computerized algorithm determined whether referral-warranted ROP (RW-ROP; defined as presence of plus disease, zone I ROP, and stage 3 or worse ROP) was present in digital images from infants with birth weight less than 1251 g enrolled from May 25, 2011, through October 31, 2013. Independent double grading was done by the TRs with adjudication of discrepant fields performed by the reading center director.ExposureDigital retinal images.Main outcomes and measuresIntragrader and intergrader variability and monitoring for temporal drift.ResultsFour TRs underwent rigorous training and certification. A total of 5520 image sets were double graded, with 24.5% requiring adjudication for at least 1 component of RW-ROP. For individual RW-ROP components, the adjudication rate was 3.9% for plus disease, 12.4% for zone I ROP, and 16.9% for stage 3 or worse ROP. The weighted κ for intergrader agreement (n = 80 image sets) was 0.72 (95% CI, 0.52-0.93) for RW-ROP, 0.57 (95% CI, 0.37-0.77) for plus disease, 0.43 (95% CI, 0.24-0.63) for zone I ROP, and 0.67 (95% CI, 0.47-0.88) for stage 3 or worse ROP. The weighted κ for grade-regrade agreement was 0.77 (95% CI, 0.57-0.97) for RW-ROP, 0.87 (95% CI, 0.67-1.00) for plus disease, 0.70 (95% CI, 0.51-0.90) for zone I ROP, and 0.77 (95% CI, 0.57-0.97) for stage 3 or worse ROP.Conclusions and relevanceThese data suggest that the e-ROP system for training and certifying nonphysicians to grade ROP images under the supervision of a reading center director reliably detects potentially serious ROP with good intragrader and intergrader consistency and minimal temporal drift.

Dataset Information

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

Publications

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

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