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Oral Propranolol Improve Retinopathy of Prematurity Outcomes in Very Preterm Infants

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ClinicalTrials.gov Identifier: NCT02977000
Recruitment Status : Unknown
Verified November 2016 by Huiqing Sun, Zhengzhou Children's Hospital, China.
Recruitment status was:  Recruiting
First Posted : November 30, 2016
Last Update Posted : December 1, 2016
Sponsor:
Information provided by (Responsible Party):
Huiqing Sun, Zhengzhou Children's Hospital, China

Tracking Information
First Submitted Date  ICMJE November 22, 2016
First Posted Date  ICMJE November 30, 2016
Last Update Posted Date December 1, 2016
Study Start Date  ICMJE May 2016
Estimated Primary Completion Date March 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 26, 2016)
The rates of regression of Retinopathy of Prematurity [ Time Frame: 2 years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02977000 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Oral Propranolol Improve Retinopathy of Prematurity Outcomes in Very Preterm Infants
Official Title  ICMJE Department of Neonatology, Children's Hospital of Zhengzhou
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Retinopathy of Prematurity
Intervention  ICMJE Drug: Propranolol
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.
Study Arms  ICMJE Experimental: Propranolol
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.
Intervention: Drug: Propranolol
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: November 26, 2016)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2018
Estimated Primary Completion Date March 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • preterm newborns with GA <32 weeks of age and Stage 2 ROP without plus in zone II

Exclusion Criteria:

  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 24 Weeks to 45 Weeks   (Child)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02977000
Other Study ID Numbers  ICMJE ROP-PROP
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Huiqing Sun, Zhengzhou Children's Hospital, China
Study Sponsor  ICMJE Huiqing Sun
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Ligong Hou, MD Chidren's Hospital of Zhengzhou
PRS Account Zhengzhou Children's Hospital, China
Verification Date November 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP