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 Aversa, 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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 cutoff 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.

Original languageEnglish
Article number180
JournalFrontiers in Pediatrics
Volume7
Issue numberMAY
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Retinopathy of Prematurity
Ophthalmic Solutions
Propranolol
Control Groups
Incidence
Safety
Apgar Score
Light Coagulation
Surface-Active Agents
Disease Progression
Lasers
Randomized Controlled Trials
Hemodynamics
Odds Ratio
Placebos
Demography
Oxygen
Morbidity

Keywords

  • Angiogenesis
  • Beta blocker
  • Preterm newborn
  • Proliferative retinopathy
  • Propranolol

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Propranolol 0.2% eye micro-drops for retinopathy of prematurity : A prospective phase IIb study. / Filippi, Luca; Cavallaro, Giacomo; Berti, Elettra; Padrini, Letizia; Araimo, Gabriella; Regiroli, Giulia; Raffaeli, Genny; Bozzetti, Valentina; Tagliabue, Paolo; Tomasini, Barbara; Mori, Annalisa; Buonocore, Giuseppe; Agosti, Massimo; Bossi, Angela; Chirico, Gaetano; Aversa, Salvatore; Fortunato, Pina; Osnaghi, Silvia; Cavallotti, Barbara; Suzani, Martina; Vanni, Maurizio; Borsari, Giulia; Donati, Simone; Nascimbeni, Giuseppe; Nardo, Daniel; Piermarocchi, Stefano; La Marca, Giancarlo; Forni, Giulia; Milani, Silvano; Cortinovis, Ivan; Calvani, Maura; Bagnoli, Paola; Monte, Massimo Dal; Calvani, Anna Maria; Pugi, Alessandra; Villamor, Eduardo; Donzelli, Gianpaolo; Mosca, Fabio.

In: Frontiers in Pediatrics, Vol. 7, No. MAY, 180, 01.01.2019.

Research output: Contribution to journalArticle

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, Aversa, 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, Monte, MD, 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, no. MAY, 180. https://doi.org/10.3389/fped.2019.00180
Filippi, Luca ; Cavallaro, Giacomo ; Berti, Elettra ; Padrini, Letizia ; Araimo, Gabriella ; Regiroli, Giulia ; Raffaeli, Genny ; Bozzetti, Valentina ; Tagliabue, Paolo ; Tomasini, Barbara ; Mori, Annalisa ; Buonocore, Giuseppe ; Agosti, Massimo ; Bossi, Angela ; Chirico, Gaetano ; Aversa, Salvatore ; Fortunato, Pina ; Osnaghi, Silvia ; Cavallotti, Barbara ; Suzani, Martina ; Vanni, Maurizio ; Borsari, Giulia ; Donati, Simone ; Nascimbeni, Giuseppe ; Nardo, Daniel ; Piermarocchi, Stefano ; La Marca, Giancarlo ; Forni, Giulia ; Milani, Silvano ; Cortinovis, Ivan ; Calvani, Maura ; Bagnoli, Paola ; Monte, Massimo Dal ; Calvani, Anna Maria ; Pugi, Alessandra ; Villamor, Eduardo ; Donzelli, Gianpaolo ; Mosca, Fabio. / Propranolol 0.2% eye micro-drops for retinopathy of prematurity : A prospective phase IIb study. In: Frontiers in Pediatrics. 2019 ; Vol. 7, No. MAY.
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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 cutoff 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.",
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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 Aversa 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 Monte, {Massimo Dal} and Calvani, {Anna Maria} and Alessandra Pugi and Eduardo Villamor and Gianpaolo Donzelli and Fabio Mosca",
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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 - Aversa, 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 - Monte, Massimo Dal

AU - Calvani, Anna Maria

AU - Pugi, Alessandra

AU - Villamor, Eduardo

AU - Donzelli, Gianpaolo

AU - Mosca, Fabio

PY - 2019/1/1

Y1 - 2019/1/1

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 cutoff 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.

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 cutoff 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.

KW - Angiogenesis

KW - Beta blocker

KW - Preterm newborn

KW - Proliferative retinopathy

KW - Propranolol

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