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

Study Overview
=================
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.

Official Title
-----------------
Safety and Efficacy of Propranolol Eye Drops in Newborns With Retinopathy of Premature (DROP-PROP)

Conditions
-----------------
Retinopathy of Prematurity

Intervention / Treatment
-----------------
* Drug: Propranolol eye drops


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 4 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Propranolol eye drops<br>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. | Drug: Propranolol eye drops<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | participants will be followed for the duration of hospital stay, an expected average of 2 months | 
| 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 | 10th day of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 or 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 laser treatment |  | participants will be followed for the duration of hospital stay, an expected average of 2 months | 
| Number of newborns who need rescue treatment with bevacizumab |  | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Retinopathy of prematurity, Propranolol, Eye drops, Newborns, Retinal angiogenesis, Retinal neovascularization