Efficacy and safety of minocycline in patients with acute ischaemic stroke (EMPHASIS): a multicentre, double-blind, randomised controlled trial.

The EMPHASIS trial was designed to provide robust evidence regarding its efficacy and safety in patients with acute ischaemic stroke.

EMPHASIS试验旨在提供关于米诺环素在急性缺血性中风患者中疗效和安全性的有力证据。

Methods

A multicentre, double-blind, randomised, placebo-controlledtrial was conducted at 58 hospitals across China.

在中国的58家医院进行了一项多中心、双盲、随机、安慰剂对照试验。

Patients who had an ischaemic stroke in the previous 72 h with a National Institutes of Health Stroke Scale (NIHSS) score ranging from 4 to 25 and a level of consciousness score (subscale 1a of the NIHSS) of 1 or less were randomly assigned in a 1:1 ratio to receive minocycline or placebo in addition to routine treatment.

在过去72小时内发生缺血性中风的患者，其美国国立卫生研究院卒中量表（NIHSS）评分为4至25分，意识水平评分为1分或以下（NIHSS的1a分项），按照1:1的比例随机分配接受米诺环素或安慰剂治疗，除常规治疗外。

Minocycline (loading dose of 200 mg, followed by 100 mg every 12 h for the subsequent 4 days) or matching placebo was administered orally.

米诺环素（首剂200 mg，随后每12小时100 mg，持续4天）或匹配安慰剂通过口服给药。

Block randomisation with a fixed block size of four stratified by study site was done with a computer-generated randomisation sequence.

采用分层的分块随机化方法，每组固定为四人，按研究地点进行分层，并使用计算机生成的随机序列进行分组。

All patients, treating clinicians, and investigators involved in the trial were fully masked to treatment allocation.

所有患者、治疗医生和参与试验的研究人员对治疗分配完全不知情。

The primary outcome was an excellent functional outcome at 90 days (with a modified Rankin Scale [mRS] score of 0-1) and was analysed in all patients who were randomised and received at least one dose of the study drug, without imputation for missing data.

主要结果是在90天时取得极佳的功能结果（改良Rankin量表[mRS]评分为0-1），并且在所有被随机分配并至少接受一次研究药物治疗的患者中进行分析，未对缺失数据进行估算。

Safety outcomes were assessed in participants who received at least one dose of the study drug and had at least one safety evaluation and included symptomatic intracranial haemorrhage at 24 h and 6 days.

在至少接受一次研究药物并进行至少一次安全性评估的参与者中评估了安全性结果，包括24小时和6天时的症状性颅内出血。

This trial was registered with ClinicalTrials.gov (NCT05836740) and is now completed.

该试验已在ClinicalTrials.gov注册（NCT05836740），目前已完成。

Results

Between May 19, 2023, and May 20, 2024, 1724 patients were randomly assigned to minocycline (n=862) or placebo (n=862) groups.

在2023年5月19日至2024年5月20日期间，1724名患者被随机分配到米诺环素(n=862)或安慰剂(n=862)组。

Median age was 65 years (IQR 57-71). 1151 (66·8%) patients were male and 573 (33·2%) were female.

中位年龄为65岁（四分位数间距57-71）。1151名（66.8%）患者为男性，573名（33.2%）为女性。

Median NIHSS score at baseline was 5 (IQR 4-7).

基线时的中位NIHSS评分为5（四分位数间距4-7）。

Four patients withdrew consent (three in the minocycline group and one in the placebo group) and 19 patients were lost to follow-up (nine in the minocycline group and ten in the placebo group).

四名患者撤回了同意（三名在米诺环素组和一名在安慰剂组），19名患者失访（米诺环素组九名，安慰剂组十名）。

At 90 days, 447 (52·6%) of 850 patients with minocycline and 403 (47·4%) of 851 with placebo had an mRS score of 0-1 (adjusted risk ratio 1·11, 95% CI 1·03-1·20; p=0·0061).

在90天时，使用米诺环素的850名患者中有447名（52.6%）和使用安慰剂的851名患者中有403名（47.4%）的mRS评分为0-1（调整后风险比为1.11，95%置信区间为1.03-1.20；p=0.0061）。

Ordinal analysis across the full range of mRS scores also favoured minocycline, with an adjusted common odds ratio of 1·19 (95% CI 1·03-1·38; p=0·018).

在mRS评分的全范围内进行的等级分析也倾向于米诺环素，调整后的共同优势比为1.19（95%置信区间为1.03-1.38；p=0.018）。

The incidenceof symptomatic intracranial haemorrhage was similar between the minocycline and placebo groups at 24 h (1/860 [0·1%] vs 0/861 [0%]) and 6 days (3/859 [0·3%] vs 0/861 [0%]).

在24小时时，米诺环素组和安慰剂组的有症状颅内出血发生率相似（1/860 [0.1%] 对比 0/861 [0%]），在6天时也是（3/859 [0.3%] 对比 0/861 [0%]）。

No significant differences were observed in other safety outcomes, including serious adverse events (40/862 [4·6%] in the minocycline group vs 51/862 [5·9%] in the placebo group; p=0·24).

其他安全性结果，包括严重不良事件，未观察到显著差异（米诺环素组为40/862 [4.6%]，安慰剂组为51/862 [5.9%]；p=0.24）。

interpretation

Minocycline therapy initiated within 72 h of acute ischaemic stroke provided a significant functional outcome benefit compared with placebo at 90 days, without safety concerns.

在急性缺血性中风发生后72小时内开始的米诺环素治疗，在90天时与安慰剂相比，提供了显著的功能性结果益处，且没有安全方面的担忧。

Future studies are needed to confirm these findings and to establish whether the benefits extend to patients with more severe or minor strokes.

需要进一步的研究来确认这些发现，并确定这些益处是否延伸至更严重或较轻微中风的患者。

funding

National Natural Science Foundation of China, Beijing Healthunion Cardio-cerebrovascular Disease Prevention and Treatment Foundation, Noncommunicable Chronic Diseases-National Science and Technology Major Project, Beijing Municipal Science & Technology Commission, Chinese Institutes for Medical Research, Capital's Funds for Health Improvement and Research, and National Key R&D Program of China.

中国国家自然科学基金、北京健康联盟心脑血管疾病防治基金会、非传染性慢性疾病-国家科技重大专项、北京市科学技术委员会、中国医学研究机构、首都健康改善与研究基金以及国家重点研发计划。