Genotype-stratified adjunctive dexamethasone for tuberculous meningitis in HIV-negative adults: a randomized controlled phase 3 trial.

Leukotriene A4 hydrolase (LTA4H) genotypes associate with distinct intracerebral inflammatory phenotypes and may determine corticosteroid response in tuberculous meningitis, with benefit observed in hyperinflammatory TT genotype but uncertain benefit in lower inflammation CC and CT genotypes.

白三烯A4水解酶（LTA4H）基因型与不同的脑内炎症表型相关，并可能决定结核性脑膜炎中皮质类固醇的反应，其中高炎症TT基因型观察到有益效果，而炎症较低的CC和CT基因型的益处尚不确定。

Here, in a phase 3, placebo-controlledtrial of human immunodeficiency virus-negative Vietnamese adults with tuberculous meningitis, we randomized 613 LTA4H CC- and CT-genotype participants to 6-8 weeks of dexamethasone or placebo, aiming to show noninferiority of placebo (hazard ratiomargin of 0.75) or its superiority.

在这里，我们在一项针对HIV阴性越南成人的结核性脑膜炎的III期安慰剂对照试验中，将613名LTA4H CC-和CT-基因型参与者随机分配到6-8周的地塞米松或安慰剂治疗，旨在证明安慰剂的非劣效性（风险比边际为0.75）或其优越性。

Given the significant survival benefit of dexamethasone previously seen in LTA4H TT-genotype individuals, TT-genotype participants all received open-label dexamethasone and were not randomized.

鉴于之前在LTA4H TT-基因型个体中看到的地塞米松显著的生存益处，所有TT-基因型参与者均接受了开放标签的地塞米松治疗，并未进行随机分配。

A total of 89 TT-genotype participants received open-label dexamethasone.

共有89名TT基因型参与者接受了开放标签的地塞米松治疗。

In CC- and CT-genotype participants, the primary endpoint of all-cause death or new neurological event over 12 months from randomization occurred in 108/305 (35.4%) given dexamethasone and 110/308 (35.7%) given placebo (hazard ratioof 0.99, 96% confidence interval(adjusted for multiple testing) 0.748-1.31).

在CC和CT基因型参与者中，从随机分组起12个月内，接受地塞米松治疗的108/305人（35.4%）和接受安慰剂治疗的110/308人（35.7%）发生了主要终点事件，即全因死亡或新发神经系统事件（校正多重检验后的风险比为0.99，96%置信区间为0.748-1.31）。

The number of observed primary endpoints (n = 218) exceeded the prespecified number (n = 184) used to calculate the trial's sample size and power.

观察到的主要终点事件数量（n = 218）超过了用于计算试验样本量和功效的预定数量（n = 184）。

Placebo noninferiority was not established in the CC and CT population or in individual genotype subpopulations.

在CC和CT人群或各个基因型亚人群中，未确立安慰剂的非劣效性。

Benefit or heterogeneity of effect was not observed by any prespecified subgroup.

通过任何预先设定的亚组均未观察到益处或效应异质性。

In TT-genotype participants, the primary endpoint occurred in 28/89 (31.5%) participants, similar to CC and CT participants.

在TT基因型参与者中，主要终点事件发生在89名参与者中的28名（31.5%），与CC和CT基因型参与者相似。

Outcomes were not significantly better in TT-genotype participants versus CC- or CT-genotype participants.

TT基因型参与者与CC型或CT型参与者相比，结果没有显著改善。

In CC- and CT-genotype participants, serious adverse events occurred in 161/305 (52.8%) dexamethasone-treated participants and 160/308 (51.9%) placebo-treated participants.

在CC型和CT型基因型参与者中，严重不良事件发生在305名接受地塞米松治疗的参与者中有161人（52.8%），在308名接受安慰剂治疗的参与者中有160人（51.9%）。

In conclusion, neither noninferiority nor superiority of placebo was established in human immunodeficiency virus-negative LTA4H CC- and CT-genotype adults with tuberculous meningitis, and dexamethasone was safe.

总之，在HIV阴性的LTA4H CC和CT基因型成人结核性脑膜炎患者中，安慰剂既没有显示出非劣效性也没有显示出优越性，地塞米松是安全的。

The modest and heterogeneous benefit of dexamethasone indicates that greater understanding of tuberculous meningitis pathophysiology is needed, alongside better targeted, more effective anti-inflammatory agents than corticosteroids (ClinicalTrials.gov NCT03100786 ).

地塞米松的适度且异质性的益处表明，需要更深入地了解结核性脑膜炎的病理生理学，并且需要比皮质类固醇更有效、更有针对性的抗炎药物（ClinicalTrials.gov NCT03100786）。