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 β-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results. Clinical Trial Registration The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

Current evidence and outcomes for retinopathy of prematurity prevention: insight into novel maternal and placental contributions

“…However, studies in preterm infants have raised concern for both efficacy and safety. Although oral propranolol showed promise in halting ROP progression, there was an increase in adverse life-threatening side-effects in pilot clinical trials [100], and a recent multi-center phase IIB study using 0.2% propranolol in newborns with stage 1 ROP reported that despite overall favorable treatment results, early treatment resulted in worse ROP disease, suggesting that a β-adrenoreceptor blockade is only useful during the proliferative phase [101]. These findings may harmonize the disparate data with regard to efficacy of propranolol for ROP treatment, but nevertheless raise concern for preventive β-adrenoreceptor inhibition in ROP.…”

Update in the Treatment of Retinopathy of Prematurity

“…During the last 6-year, five studies 48, [57][58][59][60] have been published with the use of oral propranolol as a treatment or prophylaxis and two studies using propranolol drops of ROP. 61,62 One of the first publications by Filippi et al 57 in 2013 evaluated the safety and effectiveness of oral propranolol in 52 preterm infants with ROP. This study showed a tendency to a decrease of the progression to stage 4 ROP and a decrease in the need for laser treatment and or bevacizumab.…”

“…61 The same group of researchers conducted a second study, increasing the concentration of propranolol eye microdrops to 0.2%. 62 They studied 98 VLBW infants with ROP stage 1 and compared it with a historical control group. They demonstrated that progression of ROP to stage 2 or 3 plus was significantly lower in the group treated with eye microdrops of propranolol versus the historical control group.…”

“…They also monitored plasma propranolol values, which were consistently below the cutoff level of 20 ug/mL. 62 They argue that the effectiveness of propranolol occurs in the proliferative phase of the disease, when VEGF levels are high, but it would be detrimental to administer it during the ischemic phase (phase 1) when VEGF levels are low. 62 A pilot study 48 was started in our center in 2012 using oral propranolol in 20 preterm infants with prethreshold retinopathy (stage 2 or 3, in zone II or III, with no plus disease).…”

Refractive Outcome in Preterm Newborns With ROP After Propranolol Treatment. A Retrospective Observational Cohort Study

“…A first clinical trial performed in newborns with stage 2 ROP demonstrated that propranolol 0.1% eye micro-drops were well-tolerated, but not sufficiently effective (28). On the contrary, a second clinical trial demonstrated that propranolol eye micro-drops administered a higher concentration (0.2%) and started at an earlier stage of the disease (stage 1 ROP) reduced ROP progression and showed an excellent safety profile (29).…”