Treatment of Optic Neuritis With Erythropoietin (TONE): A Randomized, Double-Blind, Placebo-Controlled Study

Abstract

Background: The human cytokine erythropoietin (EPO) conveys neuroprotection in preclinical models and has shown ambiguous results in phase 2 clinical trials in optic neuritis. We assessed the efficacy and safety of EPO in optic neuritis as a clinically isolated syndrome in a sufficiently powered RCT. Methods: This randomized, placebo-controlled, double-blind phase 3 trial conducted at 12 German tertiary care centres included participants aged 18-50 years with an acute presentation of unilateral optic neuritis within 10 days, visual acuity ≤ 0·5 and without previously known multiple sclerosis. Participants were randomly assigned (1:1) to receive either 33.000 IU erythropoietin or placebo intravenously for three days as an adjunct to high-dose methylprednisolone (1000 mg/day). Block Randomisation was performed with randomly varying block sizes, stratified by study site and distributed using sealed envelopes. All trial participants and all study staff were masked from treatment assignment with the exception of the trial pharmacist. The first primary outcome was the amount of retinal nerve fibre layer (RNFL) atrophy, measured by optic coherence tomography (OCT) as the difference in RNFL thickness between the affected eye at week 26 and the unaffected eye at baseline. The second primary outcome was low contrast visual acuity at week 26, measured as the 2·5% Sloan chart score of the affected eye. Analysis was performed in a set of all randomised participants for whom treatment was started and at least one follow-up OCT measurement was available. Safety was analysed in all patients who received at least one dose of the trial medication. Findings: The study enrolled 108 participants between November 25 th , 2014 and October 9 th , 2017, 55 of which were assigned to EPO and 53 to placebo. Five patients were excluded from the primary analysis due to screening failure, revised diagnosis or loss to follow-up, yielding a full analysis set of 52 EPO and 51 placebo recipients. The adjusted mean treatment difference of EPO versus placebo was 1·02 µm of RNFL atrophy (95% CI -5·51 to 7·55; p=0·76; unadjusted 15·9 vs 14·7 µm) and -4·03 (-13·6 to 5·01; p=0·38) on the letter score for low contrast visual acuity (unadjusted 49·06 vs 49·60). One patient in the EPO group developed a sinus venous thrombosis which was treated with anticoagulants and resolved without sequelae. Interpretation: EPO conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis. Trial Registration: This trial is registered with ClinicalTrials.gov (NCT01962571). Funding Statement: German Ministry of Health and Science (BMBF), Clinical trials programme. Declaration of Interests: WL reports grants from the German Federal Ministry for Education and Research (BMBF) and the German Research Foundation (DFG). He received speakers’ honoraria from and worked on advisory boards for Alcon, Allergan, Santhera, Boehringer Ingelheim, and Merz Pharma. SK has received a doctoral fellowship with funding from the University of Freiburg, Faculty of Medicine and the Else Kroner-Fresenius foundation. GI has received funding from Novartis and Janssen Pharmaceutica. BG and FB have nothing to report. MV has worked on an advisory board for Roche Pharma. SH has received funding from the DFG, the German Federal Institute for Sport Science and the German Ophthalmological Society. PA reports reports grants, personal fees, and non-financial support from Allergan, Biogen, Celgene, Ipsen, Merck, Merz Pharmaceuticals, Novartis, Roche, and Teva outside the submitted work. JU has received a doctoral fellowship with funding from the Ministry of Science, Research and Arts Baden-Wuerttemberg as part of the HAW-Prom program. She received a speakers’ honorary from AMO Ireland (affiliated to Johnson & Johnson Vision) and is co-inventor of patents/patent applications with the numbers 10 2017 126 741, WO 2020/089284 A1 and 20 174 551.0. MW is a managing partner of Blickshift GmbH and coinventor of patent applications WO 2020/089284 A1 and 20 174 551.0. MH reports grants from Bristol-Myers Squibb and speaker’s honoraria from Amgen, Baxter Deutschland, CSL Behring, Biotest Pharma, Fresenius Kabi, Leo Pharma, Merck Serono, Novartis Pharma, Pfizer, Roche Pharma, and Sun Pharmaceuticals Industries. SW has served as a consultant for Bayer, Novartis, Chengdu Kanghong Biotech, Zeiss, and Roche and has received grant support from Zeiss and Heidelberg Engineering. RD was funded by the BMBF, the DFG, and the Hertie Foundation. Ethics Approval Statement: The study protocol was approved by the institutional review boards and ethics committees of each participating site under the conduct of the ethics committee of the University of Freiburg, Germany.