Clinical Trial

. 2016 Mar 1;6(3):e010956.

doi: 10.1136/bmjopen-2015-010956.

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

Ricarda Diem¹, Fanni Molnar², Flemming Beisse³, Nikolai Gross², Katharina Drüschler¹, Sven P Heinrich², Lutz Joachimsen², Sebastian Rauer⁴, Amelie Pielen⁵, Kurt-Wolfram Sühs⁶, Ralf Andreas Linker⁷, Cord Huchzermeyer⁸, Philipp Albrecht⁹, Andrea Hassenstein¹⁰, Orhan Aktas⁹, Tanja Guthoff¹¹, Felix Tonagel¹², Christoph Kernstock¹², Kathrin Hartmann¹³, Tania Kümpfel¹⁴, Katharina Hein¹⁵, Christian van Oterendorp¹⁶, Birgit Grotejohann¹⁷, Gabriele Ihorst¹⁷, Julia Maurer¹⁷, Matthias Müller¹⁸, Martin Volkmann¹⁹, Brigitte Wildemann¹, Michael Platten¹, Wolfgang Wick¹, Christoph Heesen²⁰, Ulrich Schiefer²¹, Sebastian Wolf²², Wolf A Lagrèze²

Affiliations

¹ Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
² Eye Center, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
³ Department of Ophthalmology, Heidelberg University Hospital, Heidelberg, Germany.
⁴ Department of Neurology and Neuroscience, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
⁵ Clinic for Ophthalmology, Hannover Medical School, Hannover, Germany.
⁶ Clinic for Neurology, Hannover Medical School, Hannover, Germany.
⁷ Department of Neurology, University Hospital Erlangen, Erlangen, Germany.
⁸ Department of Ophthalmology, University Hospital Erlangen, Erlangen, Germany.
⁹ Department of Neurology, Medical faculty, Heinrich Heine University, Düsseldorf, Germany.
¹⁰ Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹¹ Department of Ophthalmology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
¹² University Eye Hospital Tübingen, Tübingen, Germany.
¹³ Department of Ophthalmology, University Hospital Munich LMU, Munich, Germany.
¹⁴ Department of Neurology, University Hospital Munich, Munich, Germany.
¹⁵ Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
¹⁶ Department of Ophthalmology, University Medical Center Göttingen, Göttingen, Germany.
¹⁷ Clinical Trials Unit, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
¹⁸ Competence Center "Vision Research", Study Course Ophthalmological Optics, Faculty of Optics and Mechatronics, University of Applied Sciences, Aalen, Germany.
¹⁹ Medical Service Center PD Dr. Volkmann and Colleges, Karlsruhe, Germany.
²⁰ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²¹ University Eye Hospital Tübingen, Tübingen, Germany Competence Center "Vision Research", Study Course Ophthalmological Optics, Faculty of Optics and Mechatronics, University of Applied Sciences, Aalen, Germany Center for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
²² Department of Ophthalmology, Bern Photographic Reading Center, University Hospital and University of Bern, Bern, Switzerland.

PMID: 26932144
PMCID: PMC4785322
DOI: 10.1136/bmjopen-2015-010956

Clinical Trial

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

Ricarda Diem et al. BMJ Open. 2016.

. 2016 Mar 1;6(3):e010956.

doi: 10.1136/bmjopen-2015-010956.

Authors

Affiliations

¹ Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
² Eye Center, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
³ Department of Ophthalmology, Heidelberg University Hospital, Heidelberg, Germany.
⁴ Department of Neurology and Neuroscience, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
⁵ Clinic for Ophthalmology, Hannover Medical School, Hannover, Germany.
⁶ Clinic for Neurology, Hannover Medical School, Hannover, Germany.
⁷ Department of Neurology, University Hospital Erlangen, Erlangen, Germany.
⁸ Department of Ophthalmology, University Hospital Erlangen, Erlangen, Germany.
⁹ Department of Neurology, Medical faculty, Heinrich Heine University, Düsseldorf, Germany.
¹⁰ Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹¹ Department of Ophthalmology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
¹² University Eye Hospital Tübingen, Tübingen, Germany.
¹³ Department of Ophthalmology, University Hospital Munich LMU, Munich, Germany.
¹⁴ Department of Neurology, University Hospital Munich, Munich, Germany.
¹⁵ Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
¹⁶ Department of Ophthalmology, University Medical Center Göttingen, Göttingen, Germany.
¹⁷ Clinical Trials Unit, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
¹⁸ Competence Center "Vision Research", Study Course Ophthalmological Optics, Faculty of Optics and Mechatronics, University of Applied Sciences, Aalen, Germany.
¹⁹ Medical Service Center PD Dr. Volkmann and Colleges, Karlsruhe, Germany.
²⁰ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²¹ University Eye Hospital Tübingen, Tübingen, Germany Competence Center "Vision Research", Study Course Ophthalmological Optics, Faculty of Optics and Mechatronics, University of Applied Sciences, Aalen, Germany Center for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
²² Department of Ophthalmology, Bern Photographic Reading Center, University Hospital and University of Bern, Bern, Switzerland.

PMID: 26932144
PMCID: PMC4785322
DOI: 10.1136/bmjopen-2015-010956

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/

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

Affiliations

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

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

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Medical