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      Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial

      research-article
      Author(s): 1 , , 2 , 1 , 1 , 2 , 2 , 3 , 3 , 3 , 4 , 5 , 6 , 6 , 7 , 7 , 8 , 8 , 9 , 10 , 11 , 11 , 12 , 13 , 14 , 14 , 15 , 15 , 16 , 16 , 17 , 18 , 19 , 1 , 2
      Publication date (Electronic):
      Journal: BMC Pediatrics
      Publisher: BioMed Central
      Keywords: Propranolol, Beta blocker, Proliferative retinopathy, Angiogenesis

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          Abstract

          Background

          Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1).

          Methods

          A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23–32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations.

          Discussion

          Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue.

          Trial registration

          ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014–005472-29.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12887-017-0923-8) contains supplementary material, which is available to authorized users.

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          Most cited references59

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          Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial.

          Early Treatment For Retinopathy Of Prematurity Cooperative Group (2003)
          To determine whether earlier treatment using ablation of the avascular retina in high-risk prethreshold retinopathy of prematurity (ROP) results in improved grating visual acuity and retinal structural outcomes compared with conventional treatment. Infants with bilateral high-risk prethreshold ROP (n = 317) had one eye randomized to early treatment with the fellow eye managed conventionally (control eye). In asymmetric cases (n = 84), the eye with high-risk prethreshold ROP was randomized to early treatment or conventional management. High risk was determined using a model based on the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity natural history cohort. At a corrected age of 9 months, visual acuity was assessed by masked testers using the Teller acuity card procedure. At corrected ages of 6 and 9 months, eyes were examined for structural outcome. Outcomes for the 2 treatment groups of eyes were compared using chi2 analysis, combining data for bilateral and asymmetric cases. Grating acuity results showed a reduction in unfavorable visual acuity outcomes with earlier treatment, from 19.5% to 14.5% (P =.01). Unfavorable structural outcomes were reduced from 15.6% to 9.1% (P<.001) at 9 months. Further analysis supported retinal ablative therapy for eyes with type 1 ROP, defined as zone I, any stage ROP with plus disease (a degree of dilation and tortuosity of the posterior retinal blood vessels meeting or exceeding that of a standard photograph); zone I, stage 3 ROP without plus disease; or zone II, stage 2 or 3 ROP with plus disease. The analysis supported a wait-and-watch approach to type 2 ROP, defined as zone I, stage 1 or 2 ROP without plus disease or zone II, stage 3 ROP without plus disease. These eyes should be considered for treatment only if they progress to type 1 or threshold ROP. Early treatment of high-risk prethreshold ROP significantly reduced unfavorable outcomes to a clinically important degree. Additional analyses led to modified recommendations for the use of peripheral retinal ablation in eyes with ROP. Long-term follow-up is being conducted to learn whether the benefits noted in the first year after birth will persist into childhood.
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            Oxygen-induced retinopathy in the mouse.

            L. Smith, E Wesolowski, A. McLellan … (1994)
            To develop oxygen-induced retinopathy in the mouse with reproducible and quantifiable proliferative retinal neovascularization suitable for examining pathogenesis and therapeutic intervention for retinal neovascularization in retinopathy of prematurity (ROP) and other vasculopathologies. One-week-old C57BL/6J mice were exposed to 75% oxygen for 5 days and then to room air. A novel fluorescein-dextran perfusion method has been developed to assess the vascular pattern. The proliferative neovascular response was quantified by counting the nuclei of new vessels extending from the retina into the vitreous in 6 microns sagittal cross-sections. Cross-sections were also stained for glial fibrillary acidic protein (GFAP). Fluorescein-dextran angiography delineated the entire vascular pattern, including neovascular tufts in flat-mounted retinas. Hyperoxia-induced neovascularization occurred at the junction between the vascularized and avascular retina in the mid-periphery. Retinal neovascularization occurred in all the pups between postnatal day 17 and postnatal day 21. There was a mean of 89 neovascular nuclei per cross-section of 9 eyes in hyperoxia compared to less than 1 nucleus per cross-section of 8 eyes in the normoxia control (P < 0.0001). Proliferative vessels were not associated with GFAP-positive astrocyte processes. The authors have described a reproducible and quantifiable mouse model of oxygen-induced retinal neovascularization that should prove useful for the study of pathogenesis of retinal neovascularization as well as for the study of medical intervention for ROP and other retinal angiopathies.
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              Retinopathy of prematurity: a global perspective of the epidemics, population of babies at risk and implications for control.

              Clare Gilbert (2008)
              Globally at least 50,000 children are blind from retinopathy of prematurity (ROP) which is now a significant cause of blindness in many middle income countries in Latin American and Eastern Europe. Retinopathy of prematurity is also being reported from the emerging economies of India and China. The characteristics of babies developing severe disease varies, with babies in middle and low income countries having a much wider range of birth weights and gestational ages than is currently the case in industrialized countries. Rates of disease requiring treatment also tend to be higher in middle and low income countries suggesting that babies are being exposed to risk factors which are, to a large extent, being controlled in industrialised countries. The reasons for this "third epidemic" of ROP are discussed as well as strategies for control, including the need for locally relevant, evidence based criteria which ensure that all babies at risk are examined.
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                Author and article information

                Contributors
                Luca Filippi: 39-(0)55-5662434 , l.filippi@meyer.it
                Journal
                Journal ID (nlm-ta): BMC Pediatr
                Journal ID (iso-abbrev): BMC Pediatr
                Title: BMC Pediatrics
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1471-2431
                Publication date (Electronic): 14 July 2017
                Publication date PMC-release: 14 July 2017
                Publication date Collection: 2017
                Volume: 17
                Electronic Location Identifier: 165
                Affiliations
                [1 ]Neonatal Intensive Care Unit - Medical Surgical Fetal-Neonatal Department, Meyer University Children’s’ Hospital, viale Pieraccini 24, 50134 Florence, Italy
                [2 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Neonatal Intensive Care Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, , Università degli Studi di Milano, ; Milan, Italy
                [3 ]ISNI 0000 0004 1756 8604, GRID grid.415025.7, , Neonatal Intensive Care Unit, MBBM Foundation, San Gerardo Hospital, ; Monza, Italy
                [4 ]ISNI 0000 0004 1759 0844, GRID grid.411477.0, Department of Pediatrics, Obstetrics and Reproductive Medicine, Neonatal Intensive Care Unit, , University Hospital of Siena, ; Policlinico Santa Maria alle Scotte, Siena, Italy
                [5 ]ISNI 0000 0004 1757 4641, GRID grid.9024.f, Department of Molecular and Developmental Medicine, , University of Siena, ; Via Banchi di Sotto, 55, 53100 Siena, Italy
                [6 ]Neonatal Intensive Care Unit, Del Ponte Hospital, Varese, Italy
                [7 ]GRID grid.412725.7, Neonatal Intensive Care Unit, Children’s Hospital, , University Hospital “Spedali Civili” of Brescia, ; Brescia, Italy
                [8 ]Pediatric Ophthalmology, A. Meyer” University Children’s Hospital, Florence, Italy
                [9 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Department of Ophthalmology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, , Università degli Studi di Milano, ; Milan, Italy
                [10 ]ISNI 0000 0004 1756 8604, GRID grid.415025.7, , Department of Ophthalomolgy, ASST Monza, San Gerardo Hospital, ; Monza, Italy
                [11 ]ISNI 0000 0004 1759 0844, GRID grid.411477.0, Pediatric Ophthalmology, , University Hospital of Siena, ; Policlinico Santa Maria alle Scotte, Siena, Italy
                [12 ]ISNI 0000000121724807, GRID grid.18147.3b, Department of Surgical and Morphological Sciences, Section of Ophthalmology, , University of Insubria, ; Varese, Italy
                [13 ]GRID grid.412725.7, Department of Ophthalmology, , University Hospital “Spedali Civili” of Brescia, ; Brescia, Italy
                [14 ]ISNI 0000 0004 1757 2304, GRID grid.8404.8, Department of Neurosciences, Psychology, Pharmacology and Child Health, , University of Florence, Newborn Screening, Biochemistry and Pharmacology Laboratory, Meyer Children’s University Hospital, ; Florence, Italy
                [15 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Laboratory “G.A. Maccacro”, Department of Clinical Sciences and Community Health, , University of Milan, ; Milan, Italy
                [16 ]ISNI 0000 0004 1757 3729, GRID grid.5395.a, Department of Biology, Unit of General Physiology, , University of Pisa, ; Pisa, Italy
                [17 ]Department of Pharmacy, “A. Meyer” University Children’s Hospital, Florence, Italy
                [18 ]Clinical Trial Office, “A. Meyer” University Children’s Hospital, viale Pieraccini 24, 50134 Florence, Italy
                [19 ]GRID grid.412966.e, Department of Pediatrics, , Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), ; Maastricht, The Netherlands
                Article
                Publisher ID: 923
                DOI: 10.1186/s12887-017-0923-8
                PMC ID: 5513165
                PubMed ID: 28709412
                SO-VID: bb80f05d-29bf-4d17-bd76-d88ef40dec3b
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 22 November 2016
                Date accepted : 5 July 2017
                Categories
                Subject: Study Protocol
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Pediatrics
                Keywords: propranolol,beta blocker,proliferative retinopathy,angiogenesis
                Data availability:
                ScienceOpen disciplines: Pediatrics
                Keywords: propranolol, beta blocker, proliferative retinopathy, angiogenesis

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