Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study

Lagrèze, Wolf A.; Küchlin, Sebastian; Ihorst, Gabriele; Grotejohann, Birgit; Beisse, Flemming; Volkmann, Martin; Heinrich, Sven; Albrecht, Philipp; Ungewiß, Judith; Wörner, Michael; Hug, Martin; Wolf, Sebastián; Diem, Ricarda; Aktaş, Orhan; Beck, Anna; Beckmann, Arnold; Berthele, Achim; Bönig, Lena; Elflein, Heike M.; Fitzner, Dirk; Fleischer, Vinzenz; Gingele, Stefan; Guthoff, Tanja; Guthoff, Rainer; Hartmann, Kathrin; Hassenstein, Andrea; Heesen, Christoph; Hein, Katharina; Hufendiek, Karsten; Huhn, Konstantin; Hümmert, Martin W.; Klöpfer, Matthias; Kruse, Friedrich E.; Kümpfel, Tania; Linker, Ralf A.; Lorenz, K.; Molnár, Fanni; Mulazzani, Elisabeth; Müller, Marcus; Nickel, Florian T.; Noll, Marion; Pielen, Amelie; Pitz, Susanne; Rauer, Sebastian; Reich, Michael; Rosenkranz, Sina Cathérine; Schwenkenbecher, Philipp; Siller, Nelly; Skripuletz, Thomas; Stangel, Martin; Stellmann, Jan‐Patrick; Stürner, Klarissa Hanja; Uphaus, Timo; Oterendorp, Christian van; Wabbels, Bettina; Wilhelm, Helmut; Ziemann, Ulf; Zipp, Frauke

doi:10.1016/s1474-4422(21)00322-7

Cited by 19 publications

(14 citation statements)

References 31 publications

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“…The TONE study protocol, 13 baseline characteristics, and the 6-month results 11 have previously been described in detail. In brief summary, 108 patients within 10 days of onset of a first episode of acute optic neuritis and high-contrast visual acuity <3/6 in the affected eye were randomized to receive either placebo (saline solution) or 33,000 IU EPO as an adjunct to high-dose methylprednisolone daily for 3 consecutive days.…”

Section: Methodsmentioning

confidence: 99%

“… 7 Following ambiguous results from smaller clinical studies, 8 - 10 we conducted the TONE trial (treatment of optic neuritis with erythropoietin) to assess retinal ganglion cell neuroprotection. 11 The primary end point was set at 6 months as most atrophy occurs in the first 4 months, plateauing thereafter. 12 Because conversions to MS occur within years after optic neuritis, 2 we scheduled an additional long-term open-label assessment 2 years after treatment, the results of which are reported herein.…”

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confidence: 99%

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Treatment With Erythropoietin for Patients With Optic Neuritis

Kuechlin

Ihorst

Grotejohann

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectiveErythropoietin (EPO) is a candidate neuroprotective drug. We assessed its long-term safety and efficacy as an adjunct to methylprednisolone in patients with optic neuritis and focused on conversions to multiple sclerosis (MS).MethodsThe TONE trial randomized 108 patients with acute optic neuritis but without previously known MS to either 33,000 IU EPO or placebo in conjunction with 1,000 mg methylprednisolone daily for 3 days. After reaching the primary end point at 6 months, we conducted an open-label follow-up 2 years after randomization.ResultsThe follow-up was attended by 83 of 103 initially analyzed patients (81%). There were no previously unreported adverse events. The adjusted treatment difference of peripapillary retinal nerve fiber layer atrophy in relation to the fellow eye at baseline was 1.27 µm (95% CI −6.45 to 8.98,p= 0.74). The adjusted treatment difference in low-contrast letter acuity was 2.87 on the 2.5% Sloan chart score (95% CI −7.92 to 13.65). Vision-related quality of life was similar in both treatment arms (National Eye Institute Visual Functioning Questionnaire median score [IQR]: 94.0 [88.0 to 96.9] in the EPO and 93.4 [89.5 to 97.4] in the placebo group). The rate of multiple sclerosis–free survival was 38% in the placebo and 53% in the EPO group (hazard ratio: 1.67, 95% CI 0.96 to 2.88,p= 0.068).DiscussionIn line with the results at 6 months, we found neither structural nor functional benefits in the visual system of patients with optic neuritis as a clinically isolated syndrome, 2 years after EPO administration. Although there were fewer early conversions to MS in the EPO group, the difference across the 2-year window was not statistically significant.Classification of EvidenceThis study provides Class II evidence that for patients with acute optic neuritis, EPO as an adjunct to methylprednisolone is well tolerated and does not improve long-term visual outcomes.Trial Registration InformationThe trial was preregistered before commencement atclinicaltrials.gov(NCT01962571).

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Treatment With Erythropoietin for Patients With Optic Neuritis

Kuechlin

Ihorst

Grotejohann

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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“…Retinal nerve fiber thinning was less apparent, and visual evoked potential latencies were shorter in the EPO add-on group than in the control group. One randomized, placebo-controlled, double blind, phase 3 study compared patients receiving intravenous EPO (33,000 IU/day) plus methylprednisolone to patients receiving placebo plus methylprednisolone [88]. Mean RNFL thickness atrophy and mean low contrast letter acuity scores showed no difference between these two groups [88].…”

Section: Current Strategy Of Epo For Optic Nerve Protection and Repairmentioning

confidence: 99%

“…One randomized, placebo-controlled, double blind, phase 3 study compared patients receiving intravenous EPO (33,000 IU/day) plus methylprednisolone to patients receiving placebo plus methylprednisolone [88]. Mean RNFL thickness atrophy and mean low contrast letter acuity scores showed no difference between these two groups [88]. Most of the studies failed to demonstrate EPO to be a structurally and functionally neuroprotective agent as an add-on therapy in optic neuritis.…”

Section: Current Strategy Of Epo For Optic Nerve Protection and Repairmentioning

confidence: 99%

Erythropoietin in Optic Neuropathies: Current Future Strategies for Optic Nerve Protection and Repair

Lai

Lin

et al. 2022

IJMS

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Erythropoietin (EPO) is known as a hormone for erythropoiesis in response to anemia and hypoxia. However, the effect of EPO is not only limited to hematopoietic tissue. Several studies have highlighted the neuroprotective function of EPO in extra-hematopoietic tissues, especially the retina. EPO could interact with its heterodimer receptor (EPOR/βcR) to exert its anti-apoptosis, anti-inflammation and anti-oxidation effects in preventing retinal ganglion cells death through different intracellular signaling pathways. In this review, we summarized the available pre-clinical studies of EPO in treating glaucomatous optic neuropathy, optic neuritis, non-arteritic anterior ischemic optic neuropathy and traumatic optic neuropathy. In addition, we explore the future strategies of EPO for optic nerve protection and repair, including advances in EPO derivates, and EPO deliveries. These strategies will lead to a new chapter in the treatment of optic neuropathy.

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“…After 16 weeks of EPO treatment, retinal nerve fiber layer thinning was less apparent and visual evoked potentials were significantly shorter [ 335 ] (Table 8 ). A phase III study was then conducted and results have just been published [ 336 ]. However, the study did not confirm previous results and displayed neither functional nor structural neuroprotection in the visual pathways after optic neuritis.…”

Section: Neuroprotective Effect Of Drugs Under Developmentmentioning

confidence: 99%

A Narrative Review on Axonal Neuroprotection in Multiple Sclerosis

et al. 2022

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) resulting in demyelination and neurodegeneration. The therapeutic strategy is now largely based on reducing inflammation with immunosuppressive drugs. Unfortunately, when disease progression is observed, no drug offers neuroprotection apart from its anti-inflammatory effect. In this review, we explore current knowledge on the assessment of neurodegeneration in MS and look at putative targets that might prove useful in protecting the axon from degeneration. Among them, Bruton’s tyrosine kinase inhibitors, anti-apoptotic and antioxidant agents, sex hormones, statins, channel blockers, growth factors, and molecules preventing glutamate excitotoxicity have already been studied. Some of them have reached phase III clinical trials and carry a great message of hope for our patients with MS.

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Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study

Cited by 19 publications

References 31 publications

Treatment With Erythropoietin for Patients With Optic Neuritis

Treatment With Erythropoietin for Patients With Optic Neuritis

Erythropoietin in Optic Neuropathies: Current Future Strategies for Optic Nerve Protection and Repair

A Narrative Review on Axonal Neuroprotection in Multiple Sclerosis

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