背景:XI因子缺乏症患者的缺血性卒中发生率低于普通人群,且自发性出血很少,提示XI因子在血栓形成中的作用比在止血中的作用更重要。Milvexian,一种口服小分子活化因子XI抑制剂,加入标准抗血小板治疗,可能会降低非心源性缺血性卒中的风险,而不会增加出血风险.我们旨在评估近期缺血性卒中或短暂性脑缺血发作(TIA)患者的复发性缺血性脑事件和大出血的剂量反应。
方法:AXIOMATIC-SSP是第2阶段,随机,双盲,安慰剂对照,在27个国家的367家医院进行的剂量发现试验.40岁或以上的合格参与者,急性(<48小时)缺血性卒中或高危TIA,由基于网络的交互式响应系统以1:1:1:1:1:2的比例随机分配,以接受五剂米尔维西(每天一次25毫克,25毫克,每天两次,50毫克,每天两次,每天两次100毫克,或200毫克,每天两次)或匹配安慰剂,每天两次,持续90天。所有参与者在前21天每天服用75毫克氯吡格雷,在前90天每天服用100毫克阿司匹林。调查人员,现场工作人员,参与者被蒙面接受治疗分配。主要疗效终点是90天MRI上缺血性卒中或隐性脑梗塞的复合结果,在所有分配给完成随访MRI脑部扫描的治疗参与者中进行评估,主要分析采用多重比较程序模型(MCP-MOD)评估剂量-反应关系。主要的安全性结果是90天的大出血,在接受至少一剂研究药物的所有参与者中进行评估。该试验已在ClinicalTrials.gov(NCT03766581)和欧盟临床试验注册(2017-005029-19)注册。
结果:在2019年1月27日至2021年12月24日之间,2366名参与者被随机分配到安慰剂组(n=691);米维西安25毫克每天一次(n=328);或每日两次剂量的米维西安25毫克(n=318),50毫克(n=328),100毫克(n=310),或200毫克(n=351)。参与者的平均年龄为71(IQR62-77)岁,859(36%)为女性。90天,安慰剂组患者有症状性缺血性卒中或隐性脑梗塞的比例估计为16·8(90·2%CI14·5-19·1),16·7(14·8-18·6),每日一次25毫克米维西人,16·6(14·8-18·3)每天两次25毫克,15·6(13·9-17·5),每天两次50毫克,15·4(13·4-17·6),每天两次100毫克,和15·3(12·8-19·7),每天两次200毫克。对于主要的复合疗效结果,在五个米维西剂量中未观察到显着的剂量反应。与安慰剂相比,基于模型的milvexian的相对风险估计为每天25mg的0·99(90·2%CI0·91-1·05),0·99(0·87-1·11),每天两次25毫克,0·93(0·78-1·11),每天两次50毫克,0·92(0·75-1·13),每天两次100毫克,和0·91(0·72-1·26),每天两次200毫克。大出血没有观察到明显的剂量反应(682名安慰剂参与者中有4名[1%],325个中的2个[1%],米尔维西亚人25毫克,每天一次,313中的两个[1%],每天两次25毫克,325个中的5个[2%],每天两次50毫克,306中的五个[2%],每天两次100毫克,和5[1%]的344与200毫克每天两次)。发生了5例治疗紧急死亡,研究者认为其中4种与研究药物无关.
结论:米尔维西安症抑制因子XIa,加入双重抗血小板治疗,没有显著降低症状性缺血性卒中或隐性脑梗死的复合结局,也没有显著增加大出血的风险.我们的研究结果为预防急性缺血性卒中或TIA患者缺血性卒中的III期临床试验的设计提供了依据。
背景:百时美施贵宝和扬森研发。
BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA).
METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19).
RESULTS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator.
CONCLUSIONS: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA.
BACKGROUND: Bristol Myers Squibb and Janssen Research & Development.