title: A prospective, randomised, placebo-controlled, double-masked, three-armed, multicentre phase II/III trial for the Study of a Topical Treatment of Ischaemic Central Retinal Vein Occlusion to Prevent Neovascular Glaucoma - the STRONG study: study protocol for a randomised controlled trial.
abstract: Neovascular glaucoma (NVG) is rare, comprising only 3.9% of all glaucoma cases. The most common cause of NVG is ischaemic central retinal vein occlusion (iCRVO). NVG frequently results in blindness and painful end-stage glaucomatous damage leading to the need for enucleation. Currently, there is no preventive therapy for NVG following iCRVO. Rescue treatments have severe drawbacks. Accordingly, there is a great need for preventing the often visually devastating outcomes of NVG. The STRONG study is designed to test whether the topically active anti-angiogenic agent aganirsen is able to inhibit the formation of neovascularisation leading to the development of secondary NVG in eyes with iCRVO. At the same time, STRONG will provide important information on the natural course of iCRVO and NVG in a large and well-characterised cohort of such patients.
  
  
  
  This protocol describes a phase II/III, prospective, randomised, placebo-controlled, double-masked, three-armed multicentre study for the investigation of aganirsen, a new topical treatment for iCRVO in order to prevent NVG. The study will evaluate the efficacy of two different doses of this newly developed antisense oligonucleotide formulated in an eye emulsion to avoid new vessel formation by blocking insulin receptor substrate-1 (IRS)-1. This leads to subsequent down-regulation of both angiogenic as well as proinflammatory growth factors such as vascular endothelial growth factor (VEGF) and tumour necrosis factor (TNF). Eligible patients (n = 333) will be treated with topical aganirsen or placebo for a period of 24 weeks. They will also be invited to participate in substudies involving analysis of gonioscopic images, detection of biomarkers for NVG and risk factors for iCRVO.
  
  
  
  The STRONG study has the potential to offer a new treatment modality for patients suffering from iCRVO with a high risk of developing NVG. The topical administration can reduce patients' burden and risk related to rescue treatment, such as destructive laser treatment or enucleation, but requires a high level of patient compliance.
  
  
  
  EudraCT: 2014-000239-18; ClinicalTrials.gov, ID: NCT02947867 . (Registered on 15 October 2016); see also http://strong-nvg.com .
authors.affiliation: Department of Ophthalmology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, D-55131, Mainz, Germany. katrin.lorenz@unimedizin-mainz.de.
authors.forename: Katrin
authors.identifier: 0000-0002-1755-7396
authors.initials: K
authors.lastname: Lorenz
authors.affiliation: Department of Ophthalmology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, D-55131, Mainz, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Scheller
authors.affiliation: Department of Ophthalmology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, D-55131, Mainz, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Bell
authors.affiliation: Department of Ophthalmology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, D-55131, Mainz, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Grus
authors.affiliation: Department of Ophthalmology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, D-55131, Mainz, Germany.|Center for Thrombosis and Hemostasis, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
authors.forename: Katharina A
authors.initials: KA
authors.lastname: Ponto
authors.affiliation: Department of Ophthalmology, University of Cologne, Kerpener Str. 62, 50924, Cologne, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Bock
authors.affiliation: Department of Ophthalmology, University of Cologne, Kerpener Str. 62, 50924, Cologne, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Cursiefen
authors.affiliation: Bundesverband Glaukom-Selbsthilfe e.V., Märkische Str. 61, 44141, Dortmund, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Flach
authors.affiliation: Gene Signal International SA, EPFL Innovation Park-A, 1015, Lausanne, Switzerland.
authors.forename: Marta
authors.initials: M
authors.lastname: Gehring
authors.affiliation: NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
authors.forename: Tunde
authors.initials: T
authors.lastname: Peto
authors.affiliation: Faculty of Medicine, University of Coimbra (FMUC), Azinhaga de Santa Comba, Celas, 3000-075, Coimbra, Portugal.|Department of Ophthalmology, Coimbra Hospital and University Center (CHUC), Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal.|Association for Innovation and Biomedical Research on Light and Image (AIBILI), Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.
authors.forename: Rufino
authors.initials: R
authors.lastname: Silva
authors.affiliation: TechnoSTAT Ltd., 34 Jerusalem Rd., Raanana, 4350108, Israel.
authors.forename: Yossi
authors.initials: Y
authors.lastname: Tal
authors.affiliation: Department of Ophthalmology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, D-55131, Mainz, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Pfeiffer
mesh_terms: D060433:Administration, Ophthalmic; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D002985:Clinical Protocols; D004311:Double-Blind Method; D005060:Europe; D015355:Glaucoma, Neovascular / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D006068:Gonioscopy; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects; D009389:Neovascularization, Pathologic; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D009883:Ophthalmic Solutions; D011446:Prospective Studies; D012107:Research Design; D015861:Retinal Neovascularization / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D012170:Retinal Vein Occlusion / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; C540750:GS 101; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D009841:Oligonucleotides; D009883:Ophthalmic Solutions; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Aganirsen; Intraocular pressure; Ischaemic central retinal vein occlusion; Neovascular glaucoma; Neovascularisation; Orphan disease; Placebo; Topical treatment