A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus-Associated Tuberculous Meningitis: The LASER-TBM Trial.
A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus-Associated Tuberculous Meningitis: The LASER-TBM Trial.
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DOI：
10.1093/cid/ciac932
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发表时间：
2023-04-17
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包括强化抗生素和有效抗炎治疗在内的药物治疗方案可能会改善结核性脑膜炎（TBM）的预后。需要关于其联合使用和在人类免疫缺陷病毒（HIV）背景下使用的安全性数据，以告知临床试验设计。我们进行了一项II期、开放标签、平行设计、随机对照试验，以评估高剂量利福平、利奈唑胺和高剂量阿司匹林治疗HIV相关TBM的安全性。受试者被随机（1.4：1：1）分配至3个治疗组（1，标准治疗[SOC]; 2，SOC +额外利福平[高达35 mg/kg/d] +利奈唑胺1200 mg/d，28天后降至600 mg/d; 3，根据第2组+阿司匹林1000 mg/d），持续56天，评估特别关注的不良事件（AESI）或死亡的主要结局。共有52名HIV相关TBM受试者接受随机分组; 59%的受试者患有轻度疾病（英国医学研究理事会（MRC）1级），39%（2级）和2%（3级）。10/16例（63%;第3组）vs 4/14例（29%;第2组）vs 6/20例（30%;第1组; P = 0.083）发生AESI或死亡。AESI或死亡（Kaplan-Meier）的累积比例显示，第3组的结局比第1组更差（P = .04）;然而，第3组中仅1起事件可归因于阿司匹林，且为轻度事件。两组之间的疗效（改良兰金量表）无差异。高剂量利福平和抗感染利奈唑胺可安全地添加到HIV相关TBM的标准治疗中。需要进行更大规模的研究，以确定与这些干预措施相关的潜在毒性，特别是高剂量阿司匹林，是否超过死亡率或发病率的好处。NCT 03927313。在这项2A期随机对照试验中，我们证明了大剂量利福平和利奈唑胺联合治疗成人人类免疫缺陷病毒相关结核性脑膜炎是安全的。需要更大规模的研究来评估高剂量阿司匹林的潜在毒性与发病率和死亡率的相关性。
Drug regimens that include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in tuberculous meningitis (TBM). Safety data on their use in combination and in the context of human immunodeficiency virus (HIV) are needed to inform clinical trial design. We conducted a phase 2, open-label, parallel-design, randomized, controlled trial to assess the safety of high-dose rifampicin, linezolid, and high-dose aspirin in HIV-associated TBM. Participants were randomized (1.4:1:1) to 3 treatment arms (1, standard of care [SOC]; 2, SOC + additional rifampicin [up to 35 mg/kg/d] + linezolid 1200 mg/d reducing after 28 days to 600 mg/d; 3, as per arm 2 + aspirin 1000 mg/d) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. A total of 52 participants with HIV-associated TBM were randomized; 59% had mild disease (British Medical Research Council (MRC) grade 1) vs 39% (grade 2) vs 2% (grade 3). AESI or death occurred in 10 of 16 (63%; arm 3) vs 4 of 14 (29%; arm 2) vs 6 of 20 (30%; arm 1; P = .083). The cumulative proportion of AESI or death (Kaplan–Meier) demonstrated worse outcomes in arm 3 vs arm 1 (P = .04); however, only 1 event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) between arms. High-dose rifampicin and adjunctive linezolid can safely be added to the standard of care in HIV-associated TBM. Larger studies are required to determine whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit. NCT03927313. In this phase 2A, randomized, controlled trial, we demonstrate that high-dose rifampicin and adjunctive linezolid is safe in adult human immunodeficiency virus–associated tuberculous meningitis. Larger studies are required to evaluate potential toxicity with high-dose aspirin in relation to benefit on morbidity and mortality.
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增加剂量利福平和辅助利奈唑胺（联合或不联合阿司匹林）治疗 HIV 相关结核性脑膜炎的安全性和耐受性的 2A 期试验研究方案 [LASER-TBM]。
影响因子：
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作者：
Davis AG;Wasserman S;Maxebengula M;Stek C;Bremer M;Daroowala R;Aziz S;Goliath R;Stegmann S;Koekemoer S;Jackson A;Lai Sai L;Kadernani Y;Sihoyiya T;Liang CJ;Dodd L;Denti P;Crede T;Naude J;Szymanski P;Vallie Y;Banderker I;Moosa S;Raubenheimer P;Lai RPJ;Joska J;Nightingale S;Dreyer A;Wahl G;Offiah C;Vorster I;Candy S;Robertson F;Meintjes E;Maartens G;Black J;Meintjes G;Wilkinson RJ
通讯作者：
Wilkinson RJ
DOI：
10.1093/cid/ciab162
发表时间：
2021-09-07
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
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作者：
Cresswell FV;Meya DB;Kagimu E;Grint D;Te Brake L;Kasibante J;Martyn E;Rutakingirwa M;Quinn CM;Okirwoth M;Tugume L;Ssembambulidde K;Musubire AK;Bangdiwala AS;Buzibye A;Muzoora C;Svensson EM;Aarnoutse R;Boulware DR;Elliott AM
通讯作者：
Elliott AM
影响因子：
158.5
作者：
Conradie, Francesca;Diacon, Andreas H.;Spigelman, Melvin
通讯作者：
Spigelman, Melvin
影响因子：
4.4
作者：
Misra, U. K.;Kalita, J.;Nair, P. P.
通讯作者：
Nair, P. P.
影响因子：
7.7
作者：
Mai, Nguyen T. H.;Dobbs, Nicholas;Thwaites, Guy E.
通讯作者：
Thwaites, Guy E.