title: Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial-study protocol.
abstract: BACKGROUND
  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
  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.
  
  
  BACKGROUND
  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.
  
  
  BACKGROUND
  NCT01962571.
authors.affiliation: Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Diem
authors.affiliation: Eye Center, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Fanni
authors.initials: F
authors.lastname: Molnar
authors.affiliation: Department of Ophthalmology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Flemming
authors.initials: F
authors.lastname: Beisse
authors.affiliation: Eye Center, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Gross
authors.affiliation: Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Drüschler
authors.affiliation: Eye Center, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Sven P
authors.initials: SP
authors.lastname: Heinrich
authors.affiliation: Eye Center, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Joachimsen
authors.affiliation: Department of Neurology and Neuroscience, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rauer
authors.affiliation: Clinic for Ophthalmology, Hannover Medical School, Hannover, Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Pielen
authors.affiliation: Clinic for Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Kurt-Wolfram
authors.initials: KW
authors.lastname: Sühs
authors.affiliation: Department of Neurology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Ralf Andreas
authors.initials: RA
authors.lastname: Linker
authors.affiliation: Department of Ophthalmology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Cord
authors.initials: C
authors.lastname: Huchzermeyer
authors.affiliation: Department of Neurology, Medical faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Albrecht
authors.affiliation: Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hassenstein
authors.affiliation: Department of Neurology, Medical faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Orhan
authors.initials: O
authors.lastname: Aktas
authors.affiliation: Department of Ophthalmology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Guthoff
authors.affiliation: University Eye Hospital Tübingen, Tübingen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Tonagel
authors.affiliation: University Eye Hospital Tübingen, Tübingen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kernstock
authors.affiliation: Department of Ophthalmology, University Hospital Munich LMU, Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hartmann
authors.affiliation: Department of Neurology, University Hospital Munich, Munich, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Kümpfel
authors.affiliation: Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hein
authors.affiliation: Department of Ophthalmology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: van Oterendorp
authors.affiliation: Clinical Trials Unit, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Grotejohann
authors.affiliation: Clinical Trials Unit, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Ihorst
authors.affiliation: Clinical Trials Unit, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Maurer
authors.affiliation: Competence Center "Vision Research", Study Course Ophthalmological Optics, Faculty of Optics and Mechatronics, University of Applied Sciences, Aalen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Medical Service Center PD Dr. Volkmann and Colleges, Karlsruhe, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Volkmann
authors.affiliation: Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wildemann
authors.affiliation: Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.affiliation: Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Heesen
authors.affiliation: 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.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schiefer
authors.affiliation: Department of Ophthalmology, Bern Photographic Reading Center, University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wolf
authors.affiliation: Eye Center, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Wolf A
authors.initials: WA
authors.lastname: Lagrèze
mesh_terms: D000293:Adolescent; D000328:Adult; D002985:Clinical Protocols; D004311:Double-Blind Method; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005858:Germany; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009902:Optic Neuritis / Q000188:drug therapy*; D016016:Proportional Hazards Models; D012160:Retina / Q000503:physiopathology*; D016896:Treatment Outcome; D014792:Visual Acuity; D055815:Young Adult
chemical_list: D004921:Erythropoietin
keywords: Erythropoietin; Low Contrast Visual Acuity; Neuroprotection; Optic neuritis; Optical coherence tomography