Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial-study protocol

Ricarda Diem, Fanni Molnar, Flemming Beisse, Nikolai Gross, Katharina Drüschler, Sven P Heinrich, Lutz Joachimsen, Sebastian Rauer, Amelie Pielen, Kurt-Wolfram Sühs, Ralf Andreas Linker, Cord Huchzermeyer, Philipp Albrecht, Andrea Hassenstein, Orhan Aktas, Tanja Guthoff, Felix Tonagel, Christoph Kernstock, Kathrin Hartmann, Tania Kümpfel, Katharina Hein, Christian van Oterendorp, Birgit Grotejohann, Gabriele Ihorst, Julia Maurer, Matthias Müller, Martin Volkmann, Brigitte Wildemann, Michael Platten, Wolfgang Wick, Christoph Heesen, Ulrich Schiefer, Sebastian Wolf, Wolf A Lagrèze, Ricarda Diem, Fanni Molnar, Flemming Beisse, Nikolai Gross, Katharina Drüschler, Sven P Heinrich, Lutz Joachimsen, Sebastian Rauer, Amelie Pielen, Kurt-Wolfram Sühs, Ralf Andreas Linker, Cord Huchzermeyer, Philipp Albrecht, Andrea Hassenstein, Orhan Aktas, Tanja Guthoff, Felix Tonagel, Christoph Kernstock, Kathrin Hartmann, Tania Kümpfel, Katharina Hein, Christian van Oterendorp, Birgit Grotejohann, Gabriele Ihorst, Julia Maurer, Matthias Müller, Martin Volkmann, Brigitte Wildemann, Michael Platten, Wolfgang Wick, Christoph Heesen, Ulrich Schiefer, Sebastian Wolf, Wolf A Lagrèze

Abstract

Introduction: Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function.

Methods and analysis: Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤ 0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33,000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months.

Ethics and dissemination: TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP.

Trial registration number: NCT01962571.

Keywords: Erythropoietin; Low Contrast Visual Acuity; Neuroprotection; Optic neuritis; Optical coherence tomography.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

References

    1. Gal RL, Vedula SS, Beck R. Corticosteroids for treating optic neuritis. Cochrane Database Syst Rev 2015;8:CD001430 10.1002/14651858.CD001430.pub4
    1. Diem R, Hobom M, Maier K et al. . Methylprednisolone increases neuronal apoptosis during autoimmune CNS inflammation by inhibition of an endogenous neuroprotective pathway. J Neurosci 2003;23:6993–7000.
    1. Sättler MB, Merkler D, Maier K et al. . Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis. Cell Death Differ 2004;11:S181–92. 10.1038/sj.cdd.4401504
    1. Brines ML, Ghezzi P, Keenan S et al. . Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 2000;97:10526–31. 10.1073/pnas.97.19.10526
    1. Diem R, Sättler MB, Merkler D et al. . Combined therapy with methylprednisolone and erythropoietin in a model of multiple sclerosis. Brain 2005;128:375–85. 10.1093/brain/awh365
    1. Sühs KW, Hein K, Sättler MB et al. . A randomized, double-blind, phase 2 study of erythropoietin in optic neuritis. Ann Neurol 2012;72:199–210. 10.1002/ana.23573
    1. Ehrenreich H, Hinze-Selch D, Stawicki S et al. . Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 2007;12:206–20. 10.1038/sj.mp.4001907
    1. Sirén AL, Fasshauer T, Bartels C et al. . Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system. Neurotherapeutics 2009;6:108–27. 10.1016/j.nurt.2008.10.041
    1. Heuberger JA, Cohen Tervaert JM, Schepers FM et al. . Erythropoietin doping in cycling: lack of evidence for efficacy and a negative risk-benefit. Br J Clin Pharmacol 2013;75:1406–21. 10.1111/bcp.12034
    1. Pollock C, Johnson DW, Hörl WH et al. . Pure red cell aplasia induced by erythropoiesis-stimulating agents. Clin J Am Soc Nephrol 2008;3:193–9. 10.2215/CJN.02440607
    1. Beck RW, Cleary PA, Anderson MM Jr et al. . A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med 1992;326:581–8. 10.1056/NEJM199202273260901
    1. Petzold A, Wattjes MP, Costello F et al. . The investigation of acute optic neuritis: a review and proposed protocol. Nat Rev Neurol 2014;10:447–58. 10.1038/nrneurol.2014.108
    1. Henderson AP, Altmann DR, Trip AS et al. . A serial study of retinal changes following optic neuritis with sample size estimates for acute neuroprotection trials. Brain 2010;133:2592–602. 10.1093/brain/awq146
    1. Petzold A, de Boer JF, Schippling S et al. . Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol 2010;9:921–32. 10.1016/S1474-4422(10)70168-X
    1. Costello F, Coupland S, Hodge W et al. . Quantifying axonal loss after optic neuritis with optical coherence tomography. Ann Neurol 2006;59:963–9. 10.1002/ana.20851
    1. Fisher JB, Jacobs DA, Markowitz CE et al. . Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 2006;113:324–32. 10.1016/j.ophtha.2005.10.040
    1. Frohman E, Costello F, Zivadinov R et al. . Optical coherence tomography in multiple sclerosis. Lancet Neurol 2006;5:853–63. 10.1016/S1474-4422(06)70573-7
    1. Trip SA, Schlottmann PG, Jones SJ et al. . Quantification of optic nerve head topography in optic neuritis: a pilot study. Br J Ophthalmol 2006;90:1128–31. 10.1136/bjo.2006.092031
    1. Trip SA, Schlottmann PG, Jones SJ et al. . Optic nerve atrophy and retinal nerve fibre layer thinning following optic neuritis: evidence that axonal loss is a substrate of MRI-detected atrophy. Neuroimage 2006;31:286–93. 10.1016/j.neuroimage.2005.11.051
    1. Menke MN, Dabov S, Knecht P et al. . Reproducibility of retinal thickness measurements in healthy subjects using Spectralis optical coherence tomography. Am J Ophthalmol 2009;147:467–72. 10.1016/j.ajo.2008.09.005
    1. Budenz DL, Fredette MJ, Feuer WJ et al. . Reproducibility of peripapillary retinal nerve fiber thickness measurements with stratus OCT in glaucomatous eyes. Ophthalmology 2008;115:661–6. 10.1016/j.ophtha.2007.05.035
    1. Steel DH, Waldock A. Measurement of the retinal nerve fibre layer with scanning laser polarimetry in patients with previous demyelinating optic neuritis. J Neurol Neurosurg Psychiatry 1998;64:505–9. 10.1136/jnnp.64.4.505
    1. Mowry EM, Loguidice MJ, Daniels AB et al. . Vision related quality of life in multiple sclerosis: correlation with new measures of low and high contrast letter acuity. J Neurol Neurosurg Psychiatry 2009;80:767–72. 10.1136/jnnp.2008.165449
    1. Walter SD, Ishikawa H, Galetta KM et al. . Ganglion cell loss in relation to visual disability in multiple sclerosis. Ophthalmology 2012;119:1250–7. 10.1016/j.ophtha.2011.11.032
    1. Arditi A. Improving the design of the letter contrast sensitivity test. Invest Ophthalmol Vis Sci 2005;46:2225–9. 10.1167/iovs.04-1198
    1. Schiefer U, Pätzold J, Dannheim F. Konventionelle Perimetrie. Ophthalmologe 2005;102:627–46. 10.1007/s00347-005-1189-3
    1. Mangione CM, Lee PP, Gutierrez PR et al. . Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol 2001;119:1050–8. 10.1001/archopht.119.7.1050
    1. Bowd C, Zangwill LM, Medeiros FA et al. . Structure-function relationships using confocal scanning laser ophthalmoscopy, optical coherence tomography, and scanning laser polarimetry. Invest Ophthalmol Vis Sci 2006;47:2889–95. 10.1167/iovs.05-1489
    1. Trip SA, Schlottmann PG, Jones SJ et al. . Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol 2005;58:383–91. 10.1002/ana.20575
    1. Wang XL, Yu T, Xia DZ et al. . Measurement of retinal nerve fiber layer thickness in optic atrophy eyes of patients with optic neuritis using optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 2010;248:1013–18. 10.1007/s00417-010-1326-9
    1. Klistorner A, Arvind H, Garrick R et al. . Interrelationship of optical coherence tomography and multifocal visual-evoked potentials after optic neuritis. Invest Ophthalmol Vis Sci 2010;51:2770–7. 10.1167/iovs.09-4577
    1. Kupersmith MJ, Gal RL, Beck RW et al. . Visual function at baseline and 1 month in acute optic neuritis: predictors of visual outcome. Neurology 2007;69:508–14. 10.1212/01.wnl.0000267272.60714.42
    1. Friede T, Kieser M. Sample size recalculation in internal pilot study designs: a review. Biom J 2006;48:537–55. 10.1002/bimj.200510238
    1. Gordon-Lipkin E, Chodkowski B, Reich DS et al. . Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology 2007;69:1603–9. 10.1212/
    1. Polman CH, Reingold SC, Edan G et al. . Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;58:840–6. 10.1002/ana.20703
    1. Polman CH, Reingold SC, Banwell B et al. . Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292–302. 10.1002/ana.22366

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