A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults
A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults
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DOI：
10.7554/elife.33478
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发表时间：
2018-02-27
期刊：
影响因子：
7.7
通讯作者：
Thwaites, Guy E.
中科院分区：
文献类型：
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作者：
Mai, Nguyen T. H.;Dobbs, Nicholas;Thwaites, Guy E.
辅助地塞米松可降低结核性脑膜炎(TBM)的死亡率，但不能降低与脑梗塞相关的残疾。我们假设阿司匹林通过其抗血栓、抗炎和促进分解的特性来预防与TBM相关的脑梗塞。我们在未感染HIV的成年人中进行了一项随机对照试验，在抗结核药物和地塞米松(NCT02237365)的头60天中，每天服用81毫克或1000毫克的阿司匹林或安慰剂。主要的安全终点是60天后的胃肠道或脑出血；主要的疗效终点是磁共振成像确认的新的脑梗塞或60天后死亡。次要终点包括8个月的存活期和神经功能障碍；3级和4级和严重不良事件的数量；以及脑脊液(CSF)炎性脂质介质的情况。在2014年10月至2016年5月期间，41名参与者随机服用安慰剂，39名服用阿司匹林81毫克/天，40名服用阿司匹林1000 mg/天。92/120(76.7%)的患者经微生物学检查证实为脑血栓形成，而基线脑成像显示40/114(35.1%)的患者有1级脑梗塞。服用安慰剂的36人中，有5人(13.9%)出现了主要的安全结果，而服用81 mg和1000 mg阿司匹林的人中，分别有8人(22.9%)和8人(20.0%)出现了主要的安全结果(p=0.59)。安慰剂组11/38例(28.9%)，阿司匹林81 mg组8/36例(22.2%)，阿司匹林1000 mg组6例(15.8%)(p=0.40)。计划中的亚组分析显示，阿司匹林的治疗效果和诊断类别之间存在显著的相互作用(P异质性=0.01)，并表明接受阿司匹林治疗的微生物确诊为TBM的参与者在60天前可能减少新的梗塞和死亡(安慰剂组11/32(34.4%)，阿司匹林81 mg组4/27(14.8%)，阿司匹林1000 mg组3/28(10.7%)；p=0.06)。脑脊液分析显示阿司匹林剂量依赖地抑制血栓素A(2)和上调前分解脑脊液保护素。地塞米松中加入阿司匹林可能会改善TBM的预后，值得在大型3期试验中进行研究。
Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain infarction through its anti-thrombotic, anti-inflammatory, and pro-resolution properties. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365). The primary safety endpoint was gastro-intestinal or cerebral bleeding by 60 days; the primary efficacy endpoint was new brain infarction confirmed by magnetic resonance imaging or death by 60 days. Secondary endpoints included 8-month survival and neurodisability; the number of grade 3 and 4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. 41 participants were randomised to placebo, 39 to aspirin 81 mg/day, and 40 to aspirin 1000 mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120 (76.7%) and baseline brain imaging revealed >1 infarct in 40/114 (35.1%) participants. The primary safety outcome occurred in 5/36 (13.9%) given placebo, and in 8/35 (22.9%) and 8/40 (20.0%) given 81 mg and 1000 mg aspirin, respectively (p=0.59). The primary efficacy outcome occurred in 11/38 (28.9%) given placebo, 8/36 (22.2%) given aspirin 81 mg, and 6/38 (15.8%) given 1000 mg aspirin (p=0.40). Planned subgroup analysis showed a significant interaction between aspirin treatment effect and diagnostic category (P heterogeneity = 0.01) and suggested a potential reduction in new infarcts and deaths by day 60 in the aspirin treated participants with microbiologically confirmed TBM (11/32 (34.4%) events in placebo vs. 4/27 (14.8%) in aspirin 81 mg vs. 3/28 (10.7%) in aspirin 1000 mg; p=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A(2) and upregulation of pro-resolving CSF protectins. The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trail.