Recombinant factor VIIa versus placebo for spontaneous intracerebral haemorrhage within 2 h of symptom onset (FASTEST): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

We aimed to evaluate the safety, clinical efficacy, and effect on growth of ICH and intraventricular haemorrhage (IVH) of recombinant factor VIIa in patients with acute spontaneous ICH who were most likely to benefit from treatment with this agent.

我们的目标是评估重组凝血因子VIIa在急性自发性ICH患者中的安全性、临床疗效以及对ICH和脑室内出血(IVH)生长的影响，这些患者最有可能从使用该药物治疗中受益。

Methods

We conducted a multicentre, prospective, double-blind, randomised, placebo-controlled, adaptive, phase 3 trial (FASTEST) at 93 sites across the USA, Japan, Canada, Spain, Germany, and the UK.

我们在美国、日本、加拿大、西班牙、德国和英国的93个地点进行了一项多中心、前瞻性、双盲、随机、安慰剂对照、自适应的3期临床试验（FASTEST）。

Adults aged 18-80 years with a spontaneous ICH of 2-60 mL, IVH in less than two-thirds of one lateral ventricle or in less than a third of both lateral ventricles, a Glasgow Coma Scale score of at least 8, no evidence of recent ischaemic stroke or myocardial infarction, no recent use of anticoagulation medication or other structural cause of ICH, and who had been treated with study medication within 2 h of stroke onset or last known well were eligible for inclusion.

年龄在18-80岁之间的成年人，自发性脑内出血（ICH）量为2-60毫升，单侧脑室的脑室内出血（IVH）不超过一侧脑室的三分之二，或两侧脑室的三分之一，格拉斯哥昏迷评分至少为8分，没有近期缺血性中风或心肌梗死的证据，没有近期使用抗凝药物或其他导致ICH的结构性原因，并且在中风发作或最后已知良好状态后2小时内接受了研究药物治疗，符合纳入标准。

Patients were randomly assigned (1:1) by a simple randomisation scheme to either 80 μg/kg recombinant factor VIIa (intervention group) or an identical placebo (placebo group), administered intravenously over 2 min.

患者按1:1的比例通过简单的随机化方案随机分配到80 μg/kg重组因子VIIa（干预组）或外观相同的安慰剂（安慰剂组），静脉注射2分钟内完成。

All investigators and participants were masked to allocated group assignment.

所有研究者和参与者对分配的组别均不知情。

The primary outcome was functional outcome at 180 days, measured by modified Rankin Scale (mRS; score 0-2, 3, and 4-6) and analysed by intention to treat in all randomly assigned patients.

主要结果是180天时的功能结果，通过改良Rankin量表（mRS；评分0-2、3和4-6）测量，并对所有随机分配的患者进行意向治疗分析。

The primary safety outcome was life-threatening thromboembolic events during the first 4 days, assessed in all randomly assigned participants.

主要安全性结果是在前4天内发生的威胁生命的血栓栓塞事件，评估所有随机分配的参与者。

The secondary aim was change in ICH volume and ICH plus IVH volume between baseline and 24 h of treatment administration.

次要目标是治疗开始前和治疗后24小时内ICH体积及ICH加IVH体积的变化。

We performed an ordinal logistic regression, adjusted for age, baseline ICH volume, baseline IVH volume, and pre-stroke mRS.

我们进行了有序逻辑回归分析，调整了年龄、基线ICH体积、基线IVH体积和卒中前mRS评分。

Preplanned interim analyses, including adaptive sample size re-estimation and enrichment to a younger subgroup (aged ≤70 years), were also conducted.

预先计划的中期分析，包括自适应样本量重新估计和向年轻亚组（年龄≤70岁）的富集，也进行了。

This trial is registered with ClinicalTrials.gov (NCT03496883) and is closed to new participants.

这项试验已在ClinicalTrials.gov上注册（NCT03496883），并已对新参与者关闭。

Results

Between Dec 3, 2021, and Oct 1, 2025, we screened 3288 patients, of whom 626 participants were randomly assigned and included in the intention-to-treatanalyses: 298 (48%) in the placebo group and 328 (52%) in the intervention group. 216 (35%) participants were female and 410 (65%) were male, with a mean age of 61 years (SD 12).

在2021年12月3日至2025年10月1日期间，我们筛查了3288名患者，其中626名参与者被随机分配并纳入意向治疗分析：安慰剂组298人（占48%），干预组328人（占52%）。216名（35%）参与者为女性，410名（65%）为男性，平均年龄为61岁（标准差12）。

Mean time from stroke onset to administration of study drug was 100 min (SD 22).

从中风发作到研究药物给药的平均时间为100分钟（标准差22）。

The trial met the prespecified stopping criteria for futility at the second interim analysis.

该试验在第二次中期分析时达到了预先设定的无效性停止标准。

There was no differential effect in the primary clinical outcome measure of mRS at 180 days between the intervention group and placebo group (adjusted common odds ratio 1·09 [95% CI 0·79-1·51]; p=0·61).

在主要临床结果指标mRS的180天测量中，干预组与安慰剂组之间没有差异效应（调整后的共同比值比为1.09 [95%置信区间0.79-1.51]；p=0.61）。

Life-threatening thromboembolic complications within 4 days occurred in 15 (<5%) participants in the intervention group and in four (1%) in the placebo group (relative risk 3·41 [95% CI 1·14-10·15]; p=0·020).

干预组中有15名（<5%）参与者在4天内发生了致命的血栓栓塞并发症，而安慰剂组有4名（1%）（相对风险3.41 [95% 置信区间 1.14-10.15]；p=0.020）。

Compared with placebo, recombinant factor VIIa was associated with decreased growth of ICH (-3·7 mL [95% CI -5·4 to -1·9]) and of ICH plus IVH growth (-5·2 mL [-7·6 to -2·8]) between baseline and CT scan at 24 h.

与安慰剂相比，重组活化因子VIIa与24小时CT扫描时ICH体积增长减少（-3.7 mL [95% 置信区间 -5.4至-1.9]）以及ICH加上IVH体积增长减少（-5.2 mL [-7.6至-2.8]）有关。

interpretation

Recombinant factor VIIa administered within 2 h of ICH onset slowed haematoma growth, but did not improve functional outcomes and showed a small increased risk of life-threatening thromboembolic complications.

在脑出血（ICH）发病后2小时内使用重组凝血因子VIIa可以减缓血肿增长，但并未改善功能结果，并显示出轻微增加致命性血栓栓塞并发症的风险。

Further testing of recombinant factor VIIa in patients with the greatest risk of continued bleeding is ongoing.

对于继续出血风险最大的患者，重组凝血因子VIIa的进一步测试正在进行中。

funding

National Institute of Neurological Diseases and Stroke, Japan Agency for Medical Research and Development, and Novo Nordisk.

日本神经疾病与中风研究所、日本医药研究开发机构以及诺和诺德公司。