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

Frontiers in Pediatrics

article

Luca Filippi¹  Barbara Tomasini²  Annalisa Mori³  Giuseppe Buonocore³  Massimo Agosti⁴  Angela Bossi⁴  Gaetano Chirico⁵  Salvatore Aversa⁵  Pina Fortunato¹  Silvia Osnaghi⁶  Barbara Cavallotti⁷  Giacomo Cavallaro⁸  Martina Suzani⁷  Maurizio Vanni²  Giulia Borsari²  Simone Donati^1,10  Giuseppe Nascimbeni^1,11  Daniel Nardo^1,12  Stefano Piermarocchi^1,13  Giancarlo la Marca^1,14  Giulia Forni^1,14  Silvano Milani^1,15  Elettra Berti¹  Ivan Cortinovis^1,15  Maura Calvani^1,16  Paola Bagnoli^1,17  Massimo Dal Monte^1,17  Anna Maria Calvani^1,18  Alessandra Pugi^1,19  Eduardo Villamor^2,20  Gianpaolo Donzelli¹  Fabio Mosca⁸  Letizia Padrini¹  Gabriella Araimo⁸  Giulia Regiroli⁸  Genny Raffaeli⁸  Valentina Bozzetti^2,21  Paolo Tagliabue^2,21 

[1] Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, “A. Meyer” University Children's Hospital;Neonatal Intensive Care Unit, University Hospital of Siena;Department of Molecular and Developmental Medicine, University of Siena;Neonatal Intensive Care Unit, Del Ponte Hospital;Neonatal Intensive Care Unit, Children's Hospital, University Hospital “Spedali Civili” of Brescia;Department of Ophthalmology, Ospedale Maggiore Policlinico, Università degli Studi di Milan;Department of Ophthalmology, San Gerardo Hospital;Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico;Department of Clinical Sciences and Community Health, University of Milan;Department of Surgical and Morphological Sciences, Section of Ophthalmology, University of Insubria;Department of Ophthalmology, University Hospital “Spedali Civili” of Brescia;Department of Women's and Children's Health, Azienda Ospedaliera di Padova, University of Padua;Department of Ophthalmology, University of Padua;Biochemistry and Pharmacology Laboratory, Meyer Children's University Hospital;Laboratory “G.A. Maccacro, ” Department of Clinical Sciences and Community Health, University of Milan;Oncohematology Unit, Department of Pediatric Oncology, “A. Meyer” University Children's Hospital;Department of Biology, Unit of General Physiology, University of Pisa;Department of Pharmacy, “A. Meyer” University Children's Hospital;Clinical Trial Office, “A. Meyer” University Children's Hospital;Department of Pediatrics, Maastricht University Medical Center, School for Oncology and Developmental Biology;Neonatal Intensive Care Unit, MBBM Foundation, San Gerardo Hospital

关键词: propranolol;    beta blocker;    proliferative retinopathy;    angiogenesis;    preterm newborn;   

DOI  :  10.3389/fped.2019.00180

学科分类：社会科学、人文和艺术（综合）

来源: Frontiers

【 摘 要 】

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 β-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 {"type":"clinical-trial","attrs":{"text":"NCT02504944","term_id":"NCT02504944"}} NCT02504944 and with EudraCT Number 2014-005472-29.

【 授权许可】

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