Safety and Efficacy of Propranolol 0.2% Eye Drops in Treating Retinopathy of Premature: A Pilot Study (DROP-ROP-0.2%)

Safety and Efficacy of Propranolol 0.2% Eye Drops in Treating Newborn With Retinopathy of Premature: A Pilot Study (DROP-ROP-0.2%)

The aim of the present study is to evaluate the safety and efficacy of propranolol 0.2% eye drops in treating preterm newborns with a precocious stage of retinopathy of prematurity (ROP). Preterm newborns (gestational age 23-32 weeks) with a stage 1 ROP will receive propranolol 0.2% eye drops treatment until retinal vascularization will be completed, but no more than 90 days.

Propranolol concentrations will be measured on dried blood spots at the steady state (10th day). Cardiovascular and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions will be performed periodically, as well as cardiac function, in order to verify the treatment safety. Serial ophthalmological evaluations will be planned to monitor the efficacy of the treatment, the ROP progression and the possible complications.

Study Overview

• Status: Completed
• Conditions: Retinopathy of Prematurity
• Intervention / Treatment: Drug: Propranolol 0.2% eye drops

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Brescia, Italy
    • Neonatal Intensive Care Unit, Azienda Ospedaliera Spedali Civili di Brescia
  • Florence, Italy, 50139
    • Neonatal Intensive Care Unit, A. Meyer University Childrens' Hospital
  • Milan, Italy, 20122
    • Institute of Pediatrics and Neonatology, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan
  • Monza, Italy
    • Neonatal Intensive Care Unit, Azienda Ospedaliera San Gerardo
  • Padova, Italy, 35100
    • Piermarocchi Stefano
  • Siena, Italy
    • Neonatal Intensive Care Unit, Azienda Ospedaliera Universitaria Senese
  • Varese, Italy
    • Neonatal Intensive Care Unit, Azienda Ospedaliera Ospedale di Circolo e Fondazione Macchi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Preterm newborns (gestational age 23-32 weeks) with stage 1 ROP
• A signed parental informed consent

Exclusion Criteria:

• Newborns with heart failure
• Newborns with recurrent bradycardia (heart rate < 90 beat per minute)
• Newborns with second or third degree atrioventricular block
• Newborns with congenital cardiovascular anomalies, except for persistent ductus arteriosus, patent foramen ovale and small ventricular septal defects
• Newborns with hypotension
• Newborns with renal failure
• Newborns with actual cerebral haemorrhage
• Newborns with other diseases which contraindicate the use of beta-adrenoreceptor blockers.
• Newborns with a more severe stage of ROP than stage 1

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Propranolol 0.2% eye drops; Enrolled preterm newborns will receive propranolol as ophthalmic solution (0.2%). The treatment will be started as soon as the diagnosis of stage 1 ROP is made and will be continue until the development of retinal vascularization is completed, but no more than 90 days. Cardiovascular and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions will be performed periodically, as well as cardiac function, in order to verify the treatment safety. Propranolol concentrations will be measured on dried blood spots at the steady state (10th day). Serial ophthalmological evaluations will be planned to monitor the efficacy of the treatment, the ROP progression and the possible complications.

Drug: Propranolol 0.2% eye drops; Enrolled preterm newborns will receive propranolol as ophthalmic solution (0.2%): 3 microdrops of 6 microliters (μL) propranolol solution (= 6 μg propranolol/microdrop) will be topically applied with a calibrated pipette, in each eye, four times daily (every 6 hours). Propranolol treatment will be always associated to the conventional approach adopted by the Early Treatment for Retinopathy of Prematurity Study (ETROP) Cooperative Group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence rate of progression from stage 1 ROP to zone II stage 2 ROP with plus	participants will be followed for the duration of hospital stay, an expected average of 2 months
Incidence rate of progression from stage 1 ROP to zone II stage 3 ROP with plus	participants will be followed for the duration of hospital stay, an expected average of 2 months
Plasma concentrations of propranolol at the steady state measured by dried blood spots	10th day of treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of newborns who progress to Stage 2 without plus ROP	participants will be followed for the duration of hospital stay, an expected average of 2 months
Number of newborns who progress to Stage 3 without plus ROP	participants will be followed for the duration of hospital stay, an expected average of 2 months
Number of newborns who progress to Stage 4 with total or partial retinal detachment	participants will be followed for the duration of hospital stay, an expected average of 2 months
Number of newborns who progress to Stage 5 ROP with total or partial retinal detachment	participants will be followed for the duration of hospital stay, an expected average of 2 months
Number of newborns who need vitrectomy	participants will be followed for the duration of hospital stay, an expected average of 2 months
Collection of adverse events due to eye drop propranolol treatment	participants will be followed for the duration of hospital stay, an expected average of 2 months

Collaborators and Investigators

• Sponsor: Azienda Ospedaliero, Universitaria Meyer
• Investigators: Principal Investigator: Luca Filippi, MD, A. Meyer University Childrens' Hospital

Publications and helpful links

General Publications

• Padrini L, Isacchi B, Bilia AR, Pini A, Lanzi C, Masini E, Della Bona ML, Calvani AM, Ceccantini R, la Marca G, Filippi L. Pharmacokinetics and local safety profile of propranolol eye drops in rabbits. Pediatr Res. 2014 Oct;76(4):378-85. doi: 10.1038/pr.2014.108. Epub 2014 Jul 16.
• Filippi L, Cavallaro G, Bagnoli P, Dal Monte M, Fiorini P, Donzelli G, Tinelli F, Araimo G, Cristofori G, la Marca G, Della Bona ML, La Torre A, Fortunato P, Furlanetto S, Osnaghi S, Mosca F. Oral propranolol for retinopathy of prematurity: risks, safety concerns, and perspectives. J Pediatr. 2013 Dec;163(6):1570-1577.e6. doi: 10.1016/j.jpeds.2013.07.049. Epub 2013 Sep 18.
• Dal Monte M, Casini G, la Marca G, Isacchi B, Filippi L, Bagnoli P. Eye drop propranolol administration promotes the recovery of oxygen-induced retinopathy in mice. Exp Eye Res. 2013 Jun;111:27-35. doi: 10.1016/j.exer.2013.03.013. Epub 2013 Mar 23.
• Filippi L, Cavallaro G, Fiorini P, Malvagia S, Della Bona ML, Giocaliere E, Bagnoli P, Dal Monte M, Mosca F, Donzelli G, la Marca G. Propranolol concentrations after oral administration in term and preterm neonates. J Matern Fetal Neonatal Med. 2013 May;26(8):833-40. doi: 10.3109/14767058.2012.755169. Epub 2013 Jan 31.
• Della Bona ML, Malvagia S, Villanelli F, Giocaliere E, Ombrone D, Funghini S, Filippi L, Cavallaro G, Bagnoli P, Guerrini R, la Marca G. A rapid liquid chromatography tandem mass spectrometry-based method for measuring propranolol on dried blood spots. J Pharm Biomed Anal. 2013 May 5;78-79:34-8. doi: 10.1016/j.jpba.2013.01.034. Epub 2013 Feb 4.
• 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, Dal Monte M, Calvani AM, Pugi A, Villamor E, Donzelli G, Mosca F. Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study. Front Pediatr. 2019 May 7;7:180. doi: 10.3389/fped.2019.00180. eCollection 2019.
• Filippi L, Cavallaro G, Berti E, Padrini L, Araimo G, Regiroli G, Bozzetti V, De Angelis C, Tagliabue P, Tomasini B, Buonocore G, Agosti M, Bossi A, Chirico G, Aversa S, Pasqualetti R, Fortunato P, Osnaghi S, Cavallotti B, Vanni M, Borsari G, Donati S, Nascimbeni G, la Marca G, Forni G, Milani S, Cortinovis I, Bagnoli P, Dal Monte M, Calvani AM, Pugi A, Villamor E, Donzelli G, Mosca F. Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial. BMC Pediatr. 2017 Jul 14;17(1):165. doi: 10.1186/s12887-017-0923-8.

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (Actual): August 1, 2018
• Study Completion (Actual): August 1, 2018

Study Registration Dates

• First Submitted: July 19, 2015
• First Submitted That Met QC Criteria: July 21, 2015
• First Posted (Estimate): July 22, 2015

Study Record Updates

• Last Update Posted (Actual): August 31, 2018
• Last Update Submitted That Met QC Criteria: August 29, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Newborn; Propranolol; Eye Drops; Retinopathy of prematurity; Retinal neovascularization; Retinal angiogenesis
• Additional Relevant MeSH Terms: Eye Diseases; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Infant, Premature, Diseases; Retinal Diseases; Premature Birth; Retinopathy of Prematurity; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Pharmaceutical Solutions; Propranolol; Ophthalmic Solutions
• Other Study ID Numbers: DROP-ROP-0.2%