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Safety and Efficacy of Propranolol Eye Drops in Treating Retinopathy of Premature (DROP-PROP)

Primary Purpose

Retinopathy of Prematurity

Status
Completed
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Propranolol eye drops
Sponsored by
Azienda Ospedaliero, Universitaria Meyer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Retinopathy of Prematurity focused on measuring Retinopathy of prematurity, Propranolol, Eye drops, Newborns, Retinal angiogenesis, Retinal neovascularization

Eligibility Criteria

1 Month - 4 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Preterm newborns (gestational age 23-32 weeks) with stage 2 ROP, zone II without plus.
  • A signed parental informed consent.

Exclusion Criteria:

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

Sites / Locations

  • Neonatal Intensive Care Unit, A. Meyer University Childrens' Hospital
  • Institute of Pediatrics and Neonatology, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Propranolol eye drops

Arm Description

All the enrolled preterm newborns will receive propranolol as ophthalmic solution (0,1%): 3 microdrops of 6 microliters (μL) propranolol solution (= 6 μg propranolol/microdrop) will be topically applied with a calibrated pipette, in each eye, three times daily (every 8 hours).The treatment will continue until the complete development of retinal vascularization, but no more than 60 days. The propranolol treatment will be always associated to the conventional approach adopted by the Early Treatment for Retinopathy of Prematurity Study (ETROP Cooperative Group.

Outcomes

Primary Outcome Measures

Incidence rate of progression from stage 2 ROP to more severe stage ROP (stage 2 or 3 with plus, stage 4 and stage 5)
Eye drop propranolol is considered to be effective in counteracting the progression of ROP if the treatment decreases the incidence rate of progression from stage 2 ROP to more severe stage ROP (stage 2 or 3 with plus) from actual 38% to 19% or less.
Plasma concentrations of propranolol at the steady state
To evaluate the safety of eye drop propranolol we consider the plasma propranolol concentrations at the steady state. In particular it should be always less than 20 ng/ml, which is the plasma concentration, at the steady state, reported after oral administration of propranolol in the PROP-ROP study

Secondary Outcome Measures

Number of newborns who progress to Stage 3 without plus ROP
Number of newborns who progress to Stage 4 or 5 ROP with total or partial retinal detachment
Number of newborns who need laser treatment
Number of newborns who need rescue treatment with bevacizumab
Number of newborns who need vitrectomy
Collection of adverse events due to eye drop propranolol treatment

Full Information

First Posted
December 10, 2013
Last Updated
July 6, 2015
Sponsor
Azienda Ospedaliero, Universitaria Meyer
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1. Study Identification

Unique Protocol Identification Number
NCT02014454
Brief Title
Safety and Efficacy of Propranolol Eye Drops in Treating Retinopathy of Premature
Acronym
DROP-PROP
Official Title
Safety and Efficacy of Propranolol Eye Drops in Newborns With Retinopathy of Premature (DROP-PROP)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2015
Overall Recruitment Status
Completed
Study Start Date
November 2013 (undefined)
Primary Completion Date
August 2014 (Actual)
Study Completion Date
August 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Azienda Ospedaliero, Universitaria Meyer

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The aim of the present study is to evaluate the safety and efficacy of propranolol eye drops in preterm newborns with a precocious stage of retinopathy of prematurity (ROP). Preterm newborns (gestational age 23-32 weeks) with a stage 2 ROP (zone II without plus) will receive propranolol eye drops treatment until retinal vascularization will be completed. Propranolol concentrations will be measured on dried blood spots during the first 3 days of treatment and at the steady state. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Retinopathy of Prematurity
Keywords
Retinopathy of prematurity, Propranolol, Eye drops, Newborns, Retinal angiogenesis, Retinal neovascularization

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Propranolol eye drops
Arm Type
Experimental
Arm Description
All the enrolled preterm newborns will receive propranolol as ophthalmic solution (0,1%): 3 microdrops of 6 microliters (μL) propranolol solution (= 6 μg propranolol/microdrop) will be topically applied with a calibrated pipette, in each eye, three times daily (every 8 hours).The treatment will continue until the complete development of retinal vascularization, but no more than 60 days. The propranolol treatment will be always associated to the conventional approach adopted by the Early Treatment for Retinopathy of Prematurity Study (ETROP Cooperative Group.
Intervention Type
Drug
Intervention Name(s)
Propranolol eye drops
Intervention Description
All the enrolled preterm newborns will receive propranolol as ophthalmic solution (0,1%): 3 microdrops of 6 microliters (μL) propranolol solution (= 6 μg propranolol/microdrop) will be topically applied with a calibrated pipette, in each eye, three times daily (every 8 hours).The treatment will continue until the complete development of retinal vascularisation, but no more than 60 days. The propranolol treatment will be always associated to the conventional approach adopted by the ETROP Cooperative Group.
Primary Outcome Measure Information:
Title
Incidence rate of progression from stage 2 ROP to more severe stage ROP (stage 2 or 3 with plus, stage 4 and stage 5)
Description
Eye drop propranolol is considered to be effective in counteracting the progression of ROP if the treatment decreases the incidence rate of progression from stage 2 ROP to more severe stage ROP (stage 2 or 3 with plus) from actual 38% to 19% or less.
Time Frame
participants will be followed for the duration of hospital stay, an expected average of 2 months
Title
Plasma concentrations of propranolol at the steady state
Description
To evaluate the safety of eye drop propranolol we consider the plasma propranolol concentrations at the steady state. In particular it should be always less than 20 ng/ml, which is the plasma concentration, at the steady state, reported after oral administration of propranolol in the PROP-ROP study
Time Frame
10th day of treatment
Secondary Outcome Measure Information:
Title
Number of newborns who progress to Stage 3 without plus ROP
Time Frame
participants will be followed for the duration of hospital stay, an expected average of 2 months
Title
Number of newborns who progress to Stage 4 or 5 ROP with total or partial retinal detachment
Time Frame
participants will be followed for the duration of hospital stay, an expected average of 2 months
Title
Number of newborns who need laser treatment
Time Frame
participants will be followed for the duration of hospital stay, an expected average of 2 months
Title
Number of newborns who need rescue treatment with bevacizumab
Time Frame
participants will be followed for the duration of hospital stay, an expected average of 2 months
Title
Number of newborns who need vitrectomy
Time Frame
participants will be followed for the duration of hospital stay, an expected average of 2 months
Title
Collection of adverse events due to eye drop propranolol treatment
Time Frame
participants will be followed for the duration of hospital stay, an expected average of 2 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Month
Maximum Age & Unit of Time
4 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Preterm newborns (gestational age 23-32 weeks) with stage 2 ROP, zone II without plus. A signed parental informed consent. Exclusion Criteria: Newborns with heart failure; Newborns with congenital cardiovascular anomalies, except for persistent ductus arteriosus, patent foramen ovale and small ventricular septal defects; Newborns with recurrent bradycardia (heart rate < 90 beat per minute); Newborns with second or third degree atrioventricular block; Newborns with hypotension; Newborns with renal failure; Newborns with actual cerebral haemorrhage; Newborns with other diseases which contraindicate the use of beta-adrenoreceptor blockers.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Luca Filippi, MD
Organizational Affiliation
Azienda Ospedaliero, Universitaria Meyer
Official's Role
Principal Investigator
Facility Information:
Facility Name
Neonatal Intensive Care Unit, A. Meyer University Childrens' Hospital
City
Florence
ZIP/Postal Code
50139
Country
Italy
Facility Name
Institute of Pediatrics and Neonatology, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan
City
Milan
ZIP/Postal Code
20122
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
24054431
Citation
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.
Results Reference
background
PubMed Identifier
23528535
Citation
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.
Results Reference
background
PubMed Identifier
23205867
Citation
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.
Results Reference
background
PubMed Identifier
23434527
Citation
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.
Results Reference
background
PubMed Identifier
27814346
Citation
Filippi L, Cavallaro G, Bagnoli P, Dal Monte M, Fiorini P, Berti E, Padrini L, Donzelli G, Araimo G, Cristofori G, Fumagalli M, la Marca G, Della Bona ML, Pasqualetti R, Fortunato P, Osnaghi S, Tomasini B, Vanni M, Calvani AM, Milani S, Cortinovis I, Pugi A, Agosti M, Mosca F. Propranolol 0.1% eye micro-drops in newborns with retinopathy of prematurity: a pilot clinical trial. Pediatr Res. 2017 Feb;81(2):307-314. doi: 10.1038/pr.2016.230. Epub 2016 Nov 4.
Results Reference
derived

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Safety and Efficacy of Propranolol Eye Drops in Treating Retinopathy of Premature

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