Retinopathy of Prematurity Clinical Trial
Official title:
Department of Neonatology, Children's Hospital of Zhengzhou
Retinopathy of prematurity (ROP) is a major cause of blindness and visual impairment in
children in both developing and developed countries around the world. ROP is a
multifactorial disease characterized by perturbation of normal vascular development in the
retina. The pathogenesis of ROP is hypothesized to consist of two distinct phases of which
the second phase is characterized by hypoxia-induced up-regulation of vascular endothelial
growth factor (VEGF) and retinal neovascularization.
Recent studies have shown a relationship between the β-adrenergic system and angiogenesis.
This relationship has been observed in several diseases, like infantile hemangiomas, ROP,
and neoplasias. Studies in animal models have shown that norepinephrine stimulates VEGF
expression and secretion in retinal cells. In oxygen induced retinopathy, blockage of
β-adrenergic receptors (β-AR) can inhibit the angiogenic cascade and interfere with further
proliferation of retinal vasculature. Also, angiogenesis seems to be impaired in β-Argene
deficient mice, when exposed to hypoxia and other stimuli, but this function is restored
after gene therapy.
Assuming in human preterm newborns with ROP that VEGF overexpression and retinal
neovascularization in response to hypoxia might involve b-AR activation, we design
prospective randomized study to assess the effect of oral propranolol on the progression of
early stages of ROP in very low birth weight infants.
Retinopathy of prematurity (ROP) is a major cause of blindness and visual impairment in
children in both developing and developed countries around the world. ROP is a
multifactorial disease characterized by perturbation of normal vascular development in the
retina. The pathogenesis of ROP is hypothesized to consist of two distinct phases of which
the second phase is characterized by hypoxia-induced up-regulation of vascular endothelial
growth factor (VEGF) and retinal neovascularization.
Recent studies have shown a relationship between the β-adrenergic system and angiogenesis.
This relationship has been observed in several diseases, like infantile hemangiomas, ROP,
and neoplasias. Studies in animal models have shown that norepinephrine stimulates VEGF
expression and secretion in retinal cells. In oxygen induced retinopathy, blockage of
β-adrenergic receptors (β-AR) can inhibit the angiogenic cascade and interfere with further
proliferation of retinal vasculature. Also, angiogenesis seems to be impaired in β-Argene
deficient mice, when exposed to hypoxia and other stimuli, but this function is restored
after gene therapy.
An association between ROP and infantile hemangiomas was observed over 50 years ago with a
higher prevalence of ROP in children with hemangiomas. Studies have also shown that β-AR
blockage reduces VEGF levels and favors the regression of infantile hemangiomas. The
treatment of choice in threshold stages of ROP is laser photocoagulation and/or intravitreal
bevacizumab injections, but management of early stages of ROP, until now has been expectant,
with ophthalmologic follow-up but no therapeutic interventions to prevent its progression.
Propranolol is a non-selective β-AR blocker, with equal affinity for β1 and β2 receptors. It
has a systemic effect, and acts in different tissues. In vivo models of proliferative
retinopathies have shown a strong inhibitory role of β-AR on vascular changes. In
particular, β2-AR seems to be the most involved in these responses
. Propranolol has shown to be highly effective in inhibiting both the increase of VEGF
expression caused by a hypoxic insult, and the consequent neovascular Response. Studies have
shown that propranolol reduces the overproduction of VEGF in oxygen induced retinopathy, but
VEGF levels remain unchanged in the normal retina. Assuming in human preterm newborns with
ROP that VEGF overexpression and retinal neovascularization in response to hypoxia might
involve b-AR activation, we design prospective randomized study to assess the effect of oral
propranolol on the progression of early stages of ROP in very low birth weight infants.
Methods:
A randomized controlled trial was performed with preterm newborns with GA <32 weeks of age
and Stage 2 ROP without plus in zone II, Although infants were receiving supplemental
oxygen, the target range of oxygen saturation was maintained between 91% and 95%. The
treated and control newborns are randomized with a 1:1 allocation in blocks of 8 by using a
computer random number generator and stratified by center in 2 groups of GA 24-28 and 28-32
weeks; Exclusion criteria included newborns with congenital or acquired cardiovascular
anomalies, renal failure or cerebral hemorrhage at enrollment, and newborns with ROP in zone
I or at a more advanced stage than Stage 2 without plus in zone II.
With severe adverse effects related to propranolol (severe bradycardia, hypotension, or
wheezing), the administration of propranolol was permanently discontinued. If these episodes
had been observed within the first 2 days of treatment, these newborns were included into
the control group.
All newborns withGA <32 weeks had ophthalmologic evaluations through indirect
ophthalmoscopy. When ROP in zone II reached Stage 2 without plus, newborns were enrolled,
and ophthalmologic examinations were scheduled weekly or more frequently, according to the
severity of ROP. Propranolol was administered orally as a dose of 1.5 mg/kg.d divided q8h.
investigators used powdered drug, dissolved in 5% dextrose. The treatment was continued
until complete development of retinal vascularization, although administration was not
permitted for more than 90 days.
Statistical analyses were performed with the Statistical Software SPSS 17.0. investigators
used t tests to assess possible differences in demographic, biochemical, hemodynamic, and
respiratory variables between the treated and control newborns. The null hypothesis was
accepted with a P > .05. The efficacy of the treatment was evaluated by means of the risk
ratio, which is the ratio between the proportion of subjects progressing to more
advanced-stage ROP in the propranolol group vs the control group. The relative reduction of
risk, which is the reduction percent of events in the treated group vs the control group
event rate, was calculated when it was not possible to calculate the risk ratio.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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