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.

BACKGROUND: Recombinant factor VIIa has been shown to slow bleeding in patients with intracerebral haemorrhage (ICH), but no haemostatic agent has been shown to improve clinical outcomes. 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.

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. 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. 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. All investigators and participants were masked to allocated group assignment. 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. The primary safety outcome was life-threatening thromboembolic events during the first 4 days, assessed in all randomly assigned participants. The secondary aim was change in ICH volume and ICH plus IVH volume between baseline and 24 h of treatment administration. We performed an ordinal logistic regression, adjusted for age, baseline ICH volume, baseline IVH volume, and pre-stroke mRS. Preplanned interim analyses, including adaptive sample size re-estimation and enrichment to a younger subgroup (aged ≤70 years), were also conducted. This trial is registered with ClinicalTrials.gov (NCT03496883) and is closed to new participants.

FINDINGS: 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-treat analyses: 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). Mean time from stroke onset to administration of study drug was 100 min (SD 22). The trial met the prespecified stopping criteria for futility at the second interim analysis. 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). 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). 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.

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

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