Background

The human cytokine erythropoietin conveys neuroprotection in animal models but has shown ambiguous results in phase 2 clinical trials in patients with optic neuritis. We assessed the safety and efficacy of erythropoietin in patients with optic neuritis as a clinically isolated syndrome in a multicentre, prospective, randomised clinical trial.

Methods

This randomised, placebo-controlled, double-blind phase 3 trial, conducted at 12 tertiary referral centres in Germany, included participants aged 18–50 years, within 10 days of onset of unilateral optic neuritis, with visual acuity of 0·5 or less, and without a previous diagnosis of multiple sclerosis. Participants were randomly assigned (1:1) to receive either 33 000 IU erythropoietin or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1000 mg per day). Block randomisation was performed by the trial statistician using an SAS code that generated randomly varying block sizes, stratified by study site and distributed using sealed envelopes. All trial participants and all study staff were masked to treatment assignment, except the trial pharmacist. The first primary outcome was atrophy of the peripapillary retinal nerve fibre layer (pRNFL), measured by optic coherence tomography (OCT) as the difference in pRNFL thickness between the affected eye at week 26 and the unaffected eye at baseline. The second primary outcome was low contrast letter acuity at week 26, measured as the 2·5% Sloan chart score of the affected eye. Analysis was performed in the full analysis 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. This trial is registered at ClinicalTrials.gov, NCT01962571.

Findings

108 participants were enrolled between Nov 25, 2014, and Oct 9, 2017, of whom 55 were assigned to erythropoietin and 53 to placebo. Five patients were excluded from the primary analysis due to not receiving the allocated medication, withdrawn consent, revised diagnosis, or loss to follow-up, yielding a full analysis set of 52 patients in the erythropoietin group and 51 in the placebo group. Mean pRNFL atrophy was 15·93 μm (SD 14·91) in the erythropoietin group and 14·65 μm (15·60) in the placebo group (adjusted mean treatment difference 1·02 μm; 95% CI −5·51 to 7·55; p=0·76). Mean low contrast letter acuity scores were 49·60 (21·31) in the erythropoietin group and 49·06 (21·93) in the placebo group (adjusted mean treatment difference −4·03; −13·06 to 5·01). Adverse events occurred in 43 (81%) participants in the erythropoietin group and in 42 (81%) in the placebo group. The most common adverse event was headache, occuring in 15 (28%) patients in the erythropoietin group and 13 (25%) patients in the placebo group. Serious adverse events occurred in eight (15%) participants in the erythropoietin and in four (8%) in the placebo group. One patient (2%) in the erythropoietin group developed a venous sinus thrombosis, which was treated with anticoagulants and resolved without sequelae.

Interpretation

Erythropoietin as an adjunct to corticosteroids conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis. Future research could focus on modified erythropoietin administration, assess its efficacy independent of corticosteroids, and investigate whether it affects the conversion of optic neuritis to multiple sclerosis.

Funding

German Federal Ministry of Education and Research (BMBF).

中文翻译：

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促红细胞生成素治疗视神经炎 (TONE) 患者的安全性和有效性：一项随机、双盲、多中心、安慰剂对照研究

背景

人类细胞因子促红细胞生成素在动物模型中具有神经保护作用，但在视神经炎患者的 2 期临床试验中显示出模棱两可的结果。我们在一项多中心、前瞻性、随机临床试验中评估了促红细胞生成素在视神经炎患者中作为临床孤立综合征的安全性和有效性。

方法

这项随机、安慰剂对照、双盲 3 期试验在德国的 12 个三级转诊中心进行，参与者年龄在 18-50 岁之间，在单侧视神经炎发作后 10 天内，视力为 0·5 或更低，并且之前没有多发性硬化症的诊断。参与者被随机分配 (1:1) 接受 33000 IU 促红细胞生成素或安慰剂静脉注射 3 天，作为大剂量静脉注射甲基强的松龙（每天 1000 毫克）的辅助治疗。试验统计学家使用 SAS 代码进行区组随机化，该代码生成随机变化的区组大小，按研究地点分层并使用密封信封分发。除试验药剂师外，所有试验参与者和所有研究人员都对治疗分配不知情。第一个主要结果是视盘周围视网膜神经纤维层 (pRNFL) 的萎缩，通过光学相干断层扫描 (OCT) 测量为第 26 周受影响的眼睛和基线时未受影响的眼睛之间 pRNFL 厚度的差异。第二个主要结果是第 26 周时的低对比度字母敏锐度，测量为受影响眼睛的 2·5% Sloan 图评分。在开始治疗的所有随机参与者的完整分析集中进行分析，并且至少有一个后续 OCT 测量可用。在接受至少一剂试验药物的所有患者中分析了安全性。该试验已在 ClinicalTrials.gov 注册，NCT01962571。通过光学相干断层扫描 (OCT) 测量第 26 周受影响的眼睛和基线时未受影响的眼睛之间 pRNFL 厚度的差异。第二个主要结果是第 26 周时的低对比度字母敏锐度，测量为受影响眼睛的 2·5% Sloan 图评分。在开始治疗的所有随机参与者的完整分析集中进行分析，并且至少有一个后续 OCT 测量可用。在接受至少一剂试验药物的所有患者中分析了安全性。该试验已在 ClinicalTrials.gov 注册，NCT01962571。通过光学相干断层扫描 (OCT) 测量第 26 周受影响的眼睛和基线时未受影响的眼睛之间 pRNFL 厚度的差异。第二个主要结果是第 26 周时的低对比度字母敏锐度，测量为受影响眼睛的 2·5% Sloan 图评分。在开始治疗的所有随机参与者的完整分析集中进行分析，并且至少有一个后续 OCT 测量可用。在接受至少一剂试验药物的所有患者中分析了安全性。该试验已在 ClinicalTrials.gov 注册，NCT01962571。在开始治疗的所有随机参与者的完整分析集中进行分析，并且至少有一个后续 OCT 测量可用。在接受至少一剂试验药物的所有患者中分析了安全性。该试验已在 ClinicalTrials.gov 注册，NCT01962571。在开始治疗的所有随机参与者的完整分析集中进行分析，并且至少有一个后续 OCT 测量可用。在接受至少一剂试验药物的所有患者中分析了安全性。该试验已在 ClinicalTrials.gov 注册，NCT01962571。

发现

108 名参与者在 2014 年 11 月 25 日至 2017 年 10 月 9 日期间入组，其中 55 人被分配到促红细胞生成素组，53 人被分配到安慰剂组。由于未接受分配的药物、撤回同意、修订诊断或失访，五名患者被排除在主要分析之外，产生了一组完整的分析集，其中包括促红细胞生成素组的 52 名患者和安慰剂组的 51 名患者。促红细胞生成素组的平均 pRNFL 萎缩为 15·93 μm (SD 14·91)，安慰剂组为 14·65 μm (15·60)（调整后的平均治疗差异为 1·02 μm；95% CI -5·51 至7·55；p=0·76)。促红细胞生成素组的平均低对比度字母敏锐度评分为 49·60 (21·31)，安慰剂组为 49·06 (21·93)（调整后的平均治疗差异 -4·03；-13·06 至 5·01 ）。促红细胞生成素组 43 名 (81%) 参与者和安慰剂组 42 名 (81%) 参与者发生了不良事件。最常见的不良事件是头痛，发生在促红细胞生成素组 15 名 (28%) 患者和安慰剂组 13 名 (25%) 患者中。8 名 (15%) 的红细胞生成素参与者和 4 名 (8%) 的安慰剂组参与者发生了严重的不良事件。促红细胞生成素组 1 名患者 (2%) 出现静脉窦血栓形成，经抗凝治疗后无后遗症得到缓解。

解释

促红细胞生成素作为皮质类固醇的辅助剂，在视神经炎后的视觉通路中既没有功能性也没有结构性神经保护作用。未来的研究可以集中在改良的促红细胞生成素给药上，评估其独立于皮质类固醇的疗效，并调查它是否会影响视神经炎向多发性硬化的转化。

资金

德国联邦教育与研究部 (BMBF)。