Background and Purpose:Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients.Methods:The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging–verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up.Results:Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802).Conclusions:This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial.Registration:URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

中文翻译：

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茶碱作为急性缺血性卒中溶栓治疗的附加药物：一项随机安慰剂对照试验。

背景与目的：延迟再通会增加急性缺血性中风的梗塞生长风险和临床预后不良。血管活性剂茶碱已在动物卒中模型中显示出神经保护作用，但在病例系列和随机临床试验中尚无定论。这项研究的主要目的是评估茶碱作为溶栓治疗的附加药物在急性缺血性中风患者中是否安全有效。方法：TEA-Stroke试验（急性缺血性中风中的茶碱）是一名研究者，通过一项随机，双盲，安慰剂对照设计，启动了2中心概念验证的II期临床研究。主要纳入标准为磁共振成像验证的急性缺血性卒中，中度至重度神经功能缺损（美国国立卫生研究院卒中量表评分≥4），并在发病后4.5小时内进行溶栓治疗。参与者以1：1的比例随机分配至220 mg静脉茶碱或安慰剂。共同的主要结果是美国国立卫生研究院卒中量表评分的早期临床改善和在24小时随访时磁共振成像的梗塞增长。结果：茶碱作为溶栓治疗的辅助手段改善了美国国立卫生研究院24小时内的卒中量表评分平均为4.7点（SD，5.6），而对照组为1.3点（SD，7.5）（1至220毫克静脉茶碱或安慰剂。共同的主要结果是美国国立卫生研究院卒中量表评分的早期临床改善和在24小时随访时磁共振成像的梗塞增长。结果：茶碱作为溶栓治疗的辅助手段改善了美国国立卫生研究院24小时内的卒中量表评分平均为4.7点（SD，5.6），而对照组为1.3点（SD，7.5）（1至220毫克静脉茶碱或安慰剂。共同的主要结果是美国国立卫生研究院卒中量表评分的早期临床改善和在24小时随访时磁共振成像的梗塞增长。结果：茶碱作为溶栓治疗的辅助手段改善了美国国立卫生研究院24小时内的卒中量表评分平均为4.7点（SD，5.6），而对照组为1.3点（SD，7.5）（P = 0.044）。茶碱组和对照组的平均梗塞增长分别为141.6％（SD，126.5）和104.1％（SD，62.5）（P = 0.146）。茶碱组在90天时的功能独立性为61％，对照组为58％（P= 0.802）。结论：这项概念验证试验研究了茶碱作为急性缺血性卒中溶栓治疗的附加药物。事后校正多重性（邦费罗尼技术）后，共同主要终点的早期临床改善和24小时随访时梗塞的增长无显着差异。较小的研究规模无法得出关于茶碱是否具有神经保护作用的结论，但可以提供有希望的临床信号，可能支持未来的临床试验。注册：URL：https://www.clinicaltrials.gov。唯一标识符：EudraCT号2013-001989-42。