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

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

doi:10.3389/fped.2019.00180

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

Luca Filippi^*, Giacomo Cavallaro, Elettra Berti, Letizia Padrini, Gabriella Araimo, Giulia Regiroli, Genny Raffaeli, Valentina Bozzetti, Paolo Tagliabue, Barbara Tomasini, Annalisa Mori, Giuseppe Buonocore, Massimo Agosti, Angela Bossi, Gaetano Chirico, Salvatore Averse, Pina Fortunato, Silvia Osnaghi, Barbara Cavallotti, Martina SuzaniMaurizio Vanni, Giulia Borsari, Simone Donati, Giuseppe Nascimbeni, Daniel Nardo, Stefano Piermarocchi, Giancarlo la Marca, Giulia Forni, Silvano Milani, Ivan Cortinovis, Maura Calvani, Paola Bagnoli, Massimo Dal Monte, Anna Maria Calvani, Alessandra Pugi, Eduardo Villamor, Gianpaolo Donzelli, Fabio Mosca

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 beta-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results.

Original language	English
Article number	180
Pages (from-to)	1-12
Number of pages	12
Journal	Frontiers in pediatrics
Volume	7
DOIs	https://doi.org/10.3389/fped.2019.00180
Publication status	Published - 7 May 2019

Keywords

propranolol
beta blocker
proliferative retinopathy
angiogenesis
preterm newborn
OXYGEN-INDUCED RETINOPATHY
ENDOTHELIAL GROWTH-FACTOR
NITRIC-OXIDE
ORAL PROPRANOLOL
MOUSE MODEL
PREVENTION
HYPOXIA
PILOT

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Filippi, L., Cavallaro, G., Berti, E., Padrini, L., Araimo, G., Regiroli, G., Raffaeli, G., Bozzetti, V., Tagliabue, P., Tomasini, B., Mori, A., Buonocore, G., Agosti, M., Bossi, A., Chirico, G., Averse, S., Fortunato, P., Osnaghi, S., Cavallotti, B., ... Mosca, F. (2019). Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study. Frontiers in pediatrics, 7, 1-12. Article 180. https://doi.org/10.3389/fped.2019.00180

@article{cf4e6bc82fca4ba49a1552df3422d5b4,

title = "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 beta-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results.",

keywords = "propranolol, beta blocker, proliferative retinopathy, angiogenesis, preterm newborn, OXYGEN-INDUCED RETINOPATHY, ENDOTHELIAL GROWTH-FACTOR, NITRIC-OXIDE, ORAL PROPRANOLOL, MOUSE MODEL, PREVENTION, HYPOXIA, PILOT",

author = "Luca Filippi and Giacomo Cavallaro and Elettra Berti and Letizia Padrini and Gabriella Araimo and Giulia Regiroli and Genny Raffaeli and Valentina Bozzetti and Paolo Tagliabue and Barbara Tomasini and Annalisa Mori and Giuseppe Buonocore and Massimo Agosti and Angela Bossi and Gaetano Chirico and Salvatore Averse and Pina Fortunato and Silvia Osnaghi and Barbara Cavallotti and Martina Suzani and Maurizio Vanni and Giulia Borsari and Simone Donati and Giuseppe Nascimbeni and Daniel Nardo and Stefano Piermarocchi and {la Marca}, Giancarlo and Giulia Forni and Silvano Milani and Ivan Cortinovis and Maura Calvani and Paola Bagnoli and {Dal Monte}, Massimo and Calvani, {Anna Maria} and Alessandra Pugi and Eduardo Villamor and Gianpaolo Donzelli and Fabio Mosca",

note = "Funding Information: No external funding was secured for this study. The insurance for this clinical trial was financed by A. Meyer Hospital. Publisher Copyright: {\textcopyright} 2019 Filippi, Cavallaro, Berti, Padrini, Araimo, Regiroli, Raffaeli, Bozzetti, Tagliabue, Tomasini, Mori, Buonocore, Agosti, Bossi, Chirico, Aversa, Fortunato, Osnaghi, Cavallotti, Suzani, Vanni, Borsari, Donati, Nascimbeni, Nardo, Piermarocchi, la Marca, Forni, Milani, Cortinovis, Calvani, Bagnoli, Dal Monte, Calvani, Pugi, Villamor, Donzelli and Mosca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.",

year = "2019",

month = may,

day = "7",

doi = "10.3389/fped.2019.00180",

language = "English",

volume = "7",

pages = "1--12",

journal = "Frontiers in pediatrics",

issn = "2296-2360",

publisher = "Frontiers Media S.A.",

}

Filippi, L, Cavallaro, G, Berti, E, Padrini, L, Araimo, G, Regiroli, G, Raffaeli, G, Bozzetti, V, Tagliabue, P, Tomasini, B, Mori, A, Buonocore, G, Agosti, M, Bossi, A, Chirico, G, Averse, S, Fortunato, P, Osnaghi, S, Cavallotti, B, Suzani, M, Vanni, M, Borsari, G, Donati, S, Nascimbeni, G, Nardo, D, Piermarocchi, S, la Marca, G, Forni, G, Milani, S, Cortinovis, I, Calvani, M, Bagnoli, P, Dal Monte, M, Calvani, AM, Pugi, A, Villamor, E, Donzelli, G & Mosca, F 2019, 'Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study', Frontiers in pediatrics, vol. 7, 180, pp. 1-12. https://doi.org/10.3389/fped.2019.00180

TY - JOUR

T1 - Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity

T2 - A Prospective Phase IIB Study

AU - Filippi, Luca

AU - Cavallaro, Giacomo

AU - Berti, Elettra

AU - Padrini, Letizia

AU - Araimo, Gabriella

AU - Regiroli, Giulia

AU - Raffaeli, Genny

AU - Bozzetti, Valentina

AU - Tagliabue, Paolo

AU - Tomasini, Barbara

AU - Mori, Annalisa

AU - Buonocore, Giuseppe

AU - Agosti, Massimo

AU - Bossi, Angela

AU - Chirico, Gaetano

AU - Averse, Salvatore

AU - Fortunato, Pina

AU - Osnaghi, Silvia

AU - Cavallotti, Barbara

AU - Suzani, Martina

AU - Vanni, Maurizio

AU - Borsari, Giulia

AU - Donati, Simone

AU - Nascimbeni, Giuseppe

AU - Nardo, Daniel

AU - Piermarocchi, Stefano

AU - la Marca, Giancarlo

AU - Forni, Giulia

AU - Milani, Silvano

AU - Cortinovis, Ivan

AU - Calvani, Maura

AU - Bagnoli, Paola

AU - Dal Monte, Massimo

AU - Calvani, Anna Maria

AU - Pugi, Alessandra

AU - Villamor, Eduardo

AU - Donzelli, Gianpaolo

AU - Mosca, Fabio

N1 - Funding Information: No external funding was secured for this study. The insurance for this clinical trial was financed by A. Meyer Hospital. Publisher Copyright: © 2019 Filippi, Cavallaro, Berti, Padrini, Araimo, Regiroli, Raffaeli, Bozzetti, Tagliabue, Tomasini, Mori, Buonocore, Agosti, Bossi, Chirico, Aversa, Fortunato, Osnaghi, Cavallotti, Suzani, Vanni, Borsari, Donati, Nascimbeni, Nardo, Piermarocchi, la Marca, Forni, Milani, Cortinovis, Calvani, Bagnoli, Dal Monte, Calvani, Pugi, Villamor, Donzelli and Mosca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

PY - 2019/5/7

Y1 - 2019/5/7

N2 - 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 beta-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results.

AB - 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 beta-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results.

KW - propranolol

KW - beta blocker

KW - proliferative retinopathy

KW - angiogenesis

KW - preterm newborn

KW - OXYGEN-INDUCED RETINOPATHY

KW - ENDOTHELIAL GROWTH-FACTOR

KW - NITRIC-OXIDE

KW - ORAL PROPRANOLOL

KW - MOUSE MODEL

KW - PREVENTION

KW - HYPOXIA

KW - PILOT

U2 - 10.3389/fped.2019.00180

DO - 10.3389/fped.2019.00180

M3 - Article

C2 - 31134171

SN - 2296-2360

VL - 7

SP - 1

EP - 12

JO - Frontiers in pediatrics

JF - Frontiers in pediatrics

M1 - 180

ER -