Minnema Amy Janelle, Mehta A, Boling Warren W, Schwab Jan, Simard J Marc, Farhadi H Francis
Department of Neurological Surgery, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Department of Neurosurgery, University of Illinois at Chicago, Chicago, Illinois, USA.
BMJ Open. 2019 Oct 10;9(10):e031329. doi: 10.1136/bmjopen-2019-031329.
Acute traumatic spinal cord injury (tSCI) is a devastating neurological disorder with no pharmacological neuroprotective strategy proven effective to date. Progressive haemorrhagic necrosis (PHN) represents an increasingly well-characterised mechanism of secondary injury after tSCI that negatively impacts neurological outcomes following acute tSCI. Preclinical studies evaluating the use of the Food and Drug Administration-approved sulfonylurea receptor 1-transient receptor potential melastatin 4 channel blocker glyburide in rodent models have shown reduced secondary microhaemorrhage formation and the absence of capillary fragmentation, the pathological hallmark of PHN.
In this initial phase multicentre open-label pilot study, we propose to enrol 10 patients with acute cervical tSCI to primarily assess the feasibility, and safety of receiving oral glyburide within 8 hours of injury. Secondary objectives include pharmacokinetics and preliminary evaluations on neurological recovery as well as blood and MRI-based injury biomarkers. Analysis will be performed using the descriptive and non-parametric statistics.
Glyburide has been shown as an effective neuroprotective agent in preclinical tSCI models and in the treatment of ischaemic stroke with the additional risk of a hypoglycaemic response. Given the ongoing secondary injury and the traumatic hyperglycaemic stress response seen in patients with tSCI, glyburide; thus, offers an appealing neuroprotective strategy to supplement standard of care treatment. The study protocol was approved by the Ohio State University Biomedical Institutional Review Board. The protocol was amended in February 2017 with changes related to study feasibility and patient recruitment. Specifically, the route of administration was changed to the oral form to allow for streamlined and rapid drug administration, and the injury-to-drug time window was extended to 8 hours in an effort to further enhance enrolment. Participants or legally authorised representatives are informed about the trial and its anticipated risks orally and in written form using an approved informed consent form prior to inclusion. The findings of this study will be disseminated to the participants and to academic peers through scientific conferences and peer-reviewed journal publications.
NCT02524379 and 2014H0335.
急性创伤性脊髓损伤（tSCI）是一种毁灭性的神经疾病，迄今为止尚无经证实有效的药理学神经保护策略。进行性出血性坏死（PHN）是tSCI后继发性损伤中一种特征日益明确的机制，对急性tSCI后的神经功能预后产生负面影响。在啮齿动物模型中评估使用美国食品药品监督管理局批准的磺酰脲受体1-瞬时受体电位香草酸亚型4通道阻滞剂格列本脲的临床前研究显示，继发性微出血形成减少，且不存在PHN的病理标志——毛细血管破裂。
在这项初始阶段的多中心开放标签试点研究中，我们计划招募10例急性颈髓tSCI患者，主要评估在受伤后8小时内口服格列本脲的可行性和安全性。次要目标包括药代动力学以及对神经恢复、血液和基于磁共振成像的损伤生物标志物的初步评估。将使用描述性和非参数统计进行分析。
格列本脲在临床前tSCI模型和缺血性中风治疗中已显示为一种有效的神经保护剂，但存在低血糖反应的额外风险。鉴于tSCI患者中存在持续的继发性损伤和创伤性高血糖应激反应，格列本脲因此提供了一种有吸引力的神经保护策略来补充标准治疗。该研究方案已获俄亥俄州立大学生物医学机构审查委员会批准。该方案于2017年2月进行了修订，涉及研究可行性和患者招募的变更。具体而言，给药途径改为口服形式，以实现简化和快速给药，并且将受伤至用药的时间窗口延长至8小时，以进一步提高入组率。在纳入之前，使用经批准的知情同意书以口头和书面形式告知参与者或其法定授权代表有关试验及其预期风险。本研究的结果将通过科学会议和同行评审期刊出版物传播给参与者和学术同行。
NCT02524379和2014H0335。
