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Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial—study protocol
  1. Ricarda Diem1,
  2. Fanni Molnar2,
  3. Flemming Beisse3,
  4. Nikolai Gross2,
  5. Katharina Drüschler1,
  6. Sven P Heinrich2,
  7. Lutz Joachimsen2,
  8. Sebastian Rauer4,
  9. Amelie Pielen5,
  10. Kurt-Wolfram Sühs6,
  11. Ralf Andreas Linker7,
  12. Cord Huchzermeyer8,
  13. Philipp Albrecht9,
  14. Andrea Hassenstein10,
  15. Orhan Aktas9,
  16. Tanja Guthoff11,
  17. Felix Tonagel12,
  18. Christoph Kernstock12,
  19. Kathrin Hartmann13,
  20. Tania Kümpfel14,
  21. Katharina Hein15,
  22. Christian van Oterendorp16,
  23. Birgit Grotejohann17,
  24. Gabriele Ihorst17,
  25. Julia Maurer17,
  26. Matthias Müller18,
  27. Martin Volkmann19,
  28. Brigitte Wildemann1,
  29. Michael Platten1,
  30. Wolfgang Wick1,
  31. Christoph Heesen20,
  32. Ulrich Schiefer12,18,21,
  33. Sebastian Wolf22,
  34. Wolf A Lagrèze2
  1. 1Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany
  2. 2Eye Center, Medical Center—University of Freiburg, Freiburg im Breisgau, Germany
  3. 3Department of Ophthalmology, Heidelberg University Hospital, Heidelberg, Germany
  4. 4Department of Neurology and Neuroscience, Medical Center—University of Freiburg, Freiburg im Breisgau, Germany
  5. 5Clinic for Ophthalmology, Hannover Medical School, Hannover, Germany
  6. 6Clinic for Neurology, Hannover Medical School, Hannover, Germany
  7. 7Department of Neurology, University Hospital Erlangen, Erlangen, Germany
  8. 8Department of Ophthalmology, University Hospital Erlangen, Erlangen, Germany
  9. 9Department of Neurology, Medical faculty, Heinrich Heine University, Düsseldorf, Germany
  10. 10Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  11. 11Department of Ophthalmology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
  12. 12University Eye Hospital Tübingen, Tübingen, Germany
  13. 13Department of Ophthalmology, University Hospital Munich LMU, Munich, Germany
  14. 14Department of Neurology, University Hospital Munich, Munich, Germany
  15. 15Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
  16. 16Department of Ophthalmology, University Medical Center Göttingen, Göttingen, Germany
  17. 17Clinical Trials Unit, Medical Center—University of Freiburg, Freiburg im Breisgau, Germany
  18. 18Competence Center “Vision Research”, Study Course Ophthalmological Optics, Faculty of Optics and Mechatronics, University of Applied Sciences, Aalen, Germany
  19. 19Medical Service Center PD Dr. Volkmann and Colleges, Karlsruhe, Germany
  20. 20Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  21. 21Center for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
  22. 22Department of Ophthalmology, Bern Photographic Reading Center, University Hospital and University of Bern, Bern, Switzerland
  1. Correspondence to Professor Wolf A Lagrèze; wolf.lagreze{at}uniklinik-freiburg.de

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.

  • Erythropoietin
  • Neuroprotection
  • Optic neuritis
  • Optical coherence tomography
  • Low Contrast Visual Acuity

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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