胞磷胆碱不能改善脑创伤患者功能或认知

《美国医学会杂志》11月21日发表的大规模随机临床试验证实，胞磷胆碱在改善创伤性脑损伤(TBI)患者功能或认知方面并不优于安慰剂(JAMA 2012;308:1993-2000)。

哈佛大学医学院物理治疗与康复系的Ross D. Zafonte博士及其同事报告称，内源性化合物胞磷胆碱是体内胆碱转变为磷脂酰胆碱的中间体，被认为具有广泛的神经保护作用，在美国之外的59个国家已被批准用于治疗TBI。作为功能食品，在美国也被广泛用于多种神经障碍疾病。而基于上述新发现，世界各地应用胞磷胆碱治疗TBI的做法将受到质疑。

胞磷胆碱脑损伤治疗试验(COBRIT)是首个大规模比较胞磷胆碱与安慰剂用于TBI急性期和急性后期的Ⅲ期双盲研究，纳入美国8家Ⅰ级创伤中心收治的不同严重程度的1,213例创伤患者。受试者年龄18~70岁，种族和人口学特征呈多样性。同典型TBI患者一样，受试者中3/4为男性，半数以上年龄小于45岁。

受试者被随机分组，分别通过肠道途径接受90天的胞磷胆碱(607例)或外观完全一样的安慰剂(606例)。对于不能吞服常规口服片剂的患者，将片剂研碎，与水或盐水混合后通过鼻饲管或经皮内镜胃造瘘管灌服，剂量为每日2,000 mg，均在损伤后24 h内开始治疗。主要结局为90天功能状态和认知表现，通过对TBI临床试验网络核心测试组合的全部9个部分进行评估，涵盖了格拉斯哥预后扩展量表(GOS-E)的内容。

中期分析结果显示，胞磷胆碱组与安慰剂组总体评分[比值比(OR)，0.98；95%置信区间(CI)，0.83~1.15]或单项评分均无差异。尤其是GOS-E评分改善率，两组几乎完全一样，分别为35.4%和35.6%。预计进一步治疗将不会改变主要结局，因而该研究被提前终止。

校正患者基线简化损伤评分或按照患者TBI严重程度分层的分析结果仍然如此。对已服用计划用药75%以上患者的分析结果也未见改变。180天各项检测结果也未见组间差异。研究期间共有73例患者死亡，两组生存率未见显著差异。同样，总不良事件率或严重不良事件率均无组间差异。

克利夫兰退伍军人医学中心神经病与多发伤中心和神经科的Robert L. Ruff博士和Ronald G. RiechersⅡ博士在随刊述评中指出，很可能没有任何单一治疗药物能够有效改善TBI患者功能结局，因为TBI涉及多种不同的病理机制，包括血肿、水肿、栓塞、挫伤和炎症等。如此多样且复杂的病理机制，意味着改善这些患者的康复需要多模式治疗干预(JAMA 2012;308:2032-3)。

该研究由美国国立儿童健康与人类发育研究所资助。试验用药和安慰剂由Ferrer Grupo提供。研究者无利益冲突披露。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Citicoline proved to be no better than placebo at improving function or cognition after traumatic brain injury in the first large randomized clinical trial to test it in this patient population.

Citicoline, an endogenous compound that is an intermediate in the biosynthesis of phosphatidylcholine from choline, is thought to have a range of neuroprotective properties and has been approved as a treatment for traumatic brain injury (TBI) in 59 countries other than the United States. But it is widely available in the United States as a nutraceutical used for a range of neurological disorders, Dr. Ross D. Zafonte of the department of physical medicine and rehabilitation at Harvard Medical School, Boston, and his associates said in the November 21 issue of JAMA.

Given these new findings, "the worldwide use of citicoline for TBI should now be questioned," the investigators wrote.

It’s likely that no single therapeutic agent will ever be sufficient to improve functional outcomes in TBI because there is such a variety of pathological mechanisms at work, including hematoma, edema, infarction, contusions, and inflammation, Dr. Robert L. Ruff and Dr. Ronald G. Riechers II of the neurology and polytrauma services and the department of neurology at the Cleveland (Ohio) Veterans Affairs Medical Center said in an editorial (JAMA 2012;308:2032-3). "The diverse and complex nature of the pathological mechanisms activated by TBI suggests that multimodal treatment interventions may be needed to improve recovery."

Dr. Zafonte and his colleagues conducted the Citicoline Brain Injury Treatment Trial (COBRIT), the first large, phase III, double-blind study to compare citicoline with placebo in the acute and postacute phases after TBI. They enrolled patients with a broad range of severity of injury who had presented to eight level I trauma centers across the country (JAMA 2012;308:1993-2000).

The 1,213 study subjects were aged 18-70 years, and the study population was ethnically and demographically diverse. As is typical for TBI patients, three-quarters of the study subjects were male, and more than half were younger than age 45 years.

These patients were randomly assigned to receive 90 days of either citicoline (607 patients) or identical-looking placebo (606) through an enteral route; those who could not swallow the regular oral tablets received the compound as crushed tablets mixed with water or saline and administered via a nasogastric or percutaneous endoscopic gastrostomy tube. The dosage was 2,000 mg per day.

Treatment commenced within 24 hours of sustaining the injury.

The primary outcome of the study was functional status and cognitive performance at 90 days, as measured by all nine components of the TBI Clinical Trials Network Core Battery. This included the Glasgow Outcome Scale-Extended (GOS-E) instrument.

COBRIT was halted early when an interim analysis indicated that further accrual would not change the main outcome: Patients given citicoline did not differ from those given placebo when tested using the combined Battery (odds ratio, 0.98 [95% confidence interval, 0.83-1.15]) or when tested on any of the individual elements of the Battery.

In particular, rates of improvement on the GOS-E were almost exactly the same: 35.4% among subjects given citicoline and 35.6% among those given placebo, the researchers reported.

These findings didn’t change when the data were adjusted to account for patients’ results on the Abbreviated Injury Score at baseline or when the subjects were categorized by the severity of their TBI. The results also did not change when the analysis was restricted to only subjects who took at least 75% of their assigned study medication.

There also were no significant differences between the groups in any measure at 180 days post injury.

A total of 73 subjects died during the study, with no significant difference in survival between the groups.

Similarly, there were no differences between the groups in the overall rates of adverse events or in the rates of serious adverse events.

This study was supported by the National Institute of Child Health and Human Development. Ferrer Grupo provided the citicoline and identical placebo used in the study. No financial conflicts of interest were reported.