Background

Spinal cord injury results in permanent neurological impairment and disability due to the absence of spontaneous regeneration. NG101, a recombinant human antibody, neutralises the neurite growth-inhibiting protein Nogo-A, promoting neural repair and motor recovery in animal models of spinal cord injury. We aimed to evaluate the efficacy of intrathecal NG101 on recovery in patients with acute cervical traumatic spinal cord injury.

Methods

This randomised, double-blind, placebo-controlled phase 2b clinical trial was done at 13 hospitals in the Czech Republic, Germany, Spain, and Switzerland. Patients aged 18–70 years with acute, complete or incomplete cervical spinal cord injury (neurological level of injury C1–C8) within 4–28 days of injury were eligible for inclusion. Participants were initially randomly assigned 1:1 to intrathecal treatment with 45 mg NG101 or placebo (phosphate-buffered saline); 18 months into the study, the ratio was adjusted to 3:1 to achieve a final distribution of 2:1 to improve enrolment and drug exposure. Randomisation was done using a centralised, computer-based randomisation system and was stratified according to nine distinct outcome categories with a validated upper extremity motor score (UEMS) prediction model based on clinical parameters at screening. Six intrathecal injections were administered every 5 days over 4 weeks, starting within 28 days of injury. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was change in UEMS at 6 months, analysed alongside safety in the full analysis set. The completed trial was registered at ClinicalTrials.gov, NCT03935321.

Findings

From May 20, 2019, to July 20, 2022, 463 patients with acute traumatic cervical spinal cord injury were screened, 334 were deemed ineligible and excluded, and 129 were randomly assigned to an intervention (80 patients in the NG101 group and 49 in the placebo group). The full analysis set comprised 78 patients from the NG101 group and 48 patients from the placebo group. 107 (85%) patients were male and 19 (15%) patients were female, with a median age of 51·5 years (IQR 30·0–60·0). Across all patients, the primary endpoint showed no significant difference between groups (with UEMS change at 6 months 1·37 [95% CI –1·44 to 4·18]; placebo group mean 19·20 [SD 11·78] at baseline and 30·91 [SD 15·49] at day 168; NG101 group mean 18·23 [SD 15·14] at baseline and 31·31 [19·54] at day 168). Treatment-related adverse events were similar between groups (nine in the NG101 group and six in the placebo group). 25 severe adverse events were reported: 18 in 11 (14%) patients in the NG101 group and seven in six (13%) patients in the placebo group. Although no treatment-related fatalities were reported in the NG101 group, one fatality not related to treatment occurred in the placebo group. Infections were the most common adverse event affecting 44 (92%) patients in the placebo group and 65 (83%) patients in the NG101 group.

Interpretation

NG101 did not improve UEMS in patients with acute spinal cord injury. Post-hoc subgroup analyses assessing UEMS and Spinal Cord Independence Measure of self-care in patients with motor-incomplete injury indicated potential beneficial effects that require investigation in future studies.

Funding

EU program Horizon2020; Swiss State Secretariat for Education, Research and Innovation; Wings for Life; the Swiss Paraplegic Foundation; and the CeNeReg project of Wyss Zurich (University of Zurich and Eidgenössische Technische Hochschule Zurich).

中文翻译：

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Nogo-A 鞘内抗体在急性颈脊髓损伤患者中的安全性和有效性：一项随机、双盲、多中心、安慰剂对照、2b 期试验

 背景

脊髓损伤由于缺乏自发再生而导致永久性神经损伤和残疾。NG101 是一种重组人抗体，可中和神经突生长抑制蛋白 Nogo-A，促进脊髓损伤动物模型的神经修复和运动恢复。我们旨在评估鞘内注射 NG101 对急性颈椎创伤性脊髓损伤患者恢复的疗效。

 方法

这项随机、双盲、安慰剂对照的 2b 期临床试验在捷克共和国、德国、西班牙和瑞士的 13 家医院进行。受伤后 4-28 天内患有急性、完全或不完全性颈脊髓损伤（损伤神经水平 C1-C8）的 18-70 岁患者符合纳入条件。参与者最初被 1：1 随机分配到 45 mg NG101 或安慰剂（磷酸盐缓冲盐水）鞘内治疗组;研究开始 18 个月后，该比例调整为 3：1，以实现 2：1 的最终分布，以提高入学率和药物暴露率。随机化是使用基于计算机的集中式随机化系统完成的，并根据 9 个不同的结果类别进行分层，并使用基于筛选时临床参数的经过验证的上肢运动评分 （UEMS） 预测模型。在受伤后 28 天内开始，在 4 周内每 5 天进行 6 次鞘内注射。研究人员、研究人员和研究参与者对治疗分配不知情。主要结局是 6 个月时 UEMS 的变化，与完整分析集中的安全性一起分析。完成的试验在 NCT03935321 ClinicalTrials.gov 注册。

 发现

从 2019 年 5 月 20 日到 2022 年 7 月 20 日，筛查了 463 名急性创伤性颈脊髓损伤患者，334 名被认为不符合资格并被排除在外，129 名被随机分配到干预组（NG101 组 80 名患者，安慰剂组 49 名患者）。完整的分析集包括 NG101 组的 78 名患者和安慰剂组的 48 名患者。107 例 （85%） 患者为男性，19 例 （15%） 患者为女性，中位年龄为 51·5 岁 （IQR 30·0–60·0）。在所有患者中，主要终点显示组间无显著差异（6 个月时 UEMS 变化为 1·37 [95% CI –1·44 至 4·18];安慰剂组基线时平均值为 19·20 [SD 11·78]，第 168 天时为 30·91 [SD 15·49];NG101 组基线时平均值为 18·23 [SD 15·14]，第 168 天时为 31·31 [19·54]）。两组之间与治疗相关的不良事件相似 （NG101 组为 9 例，安慰剂组为 6 例）。报告了 25 例严重不良事件：NG101 组每 11 名患者中有 18 名 （14%） 发生，安慰剂组每 6 名患者中有 7 名 （13%） 发生。尽管 NG101 组没有报告与治疗相关的死亡病例，但安慰剂组发生了 1 例与治疗无关的死亡病例。感染是最常见的不良事件，影响安慰剂组 44 例 （92%） 患者和 NG101 组 65 例 （83%） 患者。

 解释

NG101 没有改善急性脊髓损伤患者的 UEMS。评估 UEMS 和运动不完全损伤患者自我护理的脊髓独立性测量的事后亚组分析表明潜在的有益影响，需要在未来的研究中进行调查。

 资金

欧盟计划 Horizon2020;瑞士教育、研究和创新国务秘书处;生命之翼;瑞士截瘫基金会;以及 Wyss Zurich（苏黎世大学和苏黎世 Eidgenössische Technische Hochschule）的 CeNeReg 项目。