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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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journal contribution
posted on 2023-04-20, 12:02 authored by Angharad G Davis, Sean Wasserman, Cari Stek, Mpumi Maxebengula, C Jason Liang, Stephani Stegmann, Sonya Koekemoer, Amanda Jackson, Yakub Kadernani, Marise Bremer, Remy Daroowala, Saalikha Aziz, Rene Goliath, Louise Lai Sai, Thandi Sihoyiya, Paolo Denti, Rachel PJ Lai, Thomas Crede, Jonathan Naude, Patryk Szymanski, Yakoob Vallie, Ismail Abbas Banderker, Muhammed S Moosa, Peter Raubenheimer, Sally Candy, Curtis Offiah, Gerda Wahl, Isak Vorster, Gary Maartens, John Black, Graeme Meintjes, Robert J Wilkinson
BACKGROUND: Drug regimens which 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 HIV is needed to inform clinical trial design. METHODS: We conducted a phase 2 open-label parallel-design RCT to assess safety of high-dose rifampicin, linezolid and high-dose aspirin in HIV-associated TBM. Participants were randomised (1.4:1:1) to three treatment arms (arm 1, standard of care (SOC); arm 2 SOC + additional rifampicin (up to 35mg/kg/day)) + linezolid 1200mg/day reducing after 28/7 to 600mg/day; arm 3, as per arm 2 + aspirin 1000mg/day) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. RESULTS: 52 participants with HIV-associated TBM were randomised. 59% had mild disease (MRC Grade 1) vs 39% (Grade 2) vs 2% (Grade 3). 33% had microbiologically-confirmed TBM; 41% 'possible', 25% 'probable'. AESI or death occurred in 10/16 (63%) (arm 3) vs 4/14 (29%) (arm 2) vs 6/20 (30%) (arm 1) (p = 0.083). The cumulative proportion of AESI or death (Kaplan-Meier) demonstrated worse outcomes in arm 3 vs arm 1 (p = 0.04), however only one event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) at day 56 between arms. CONCLUSIONS: High-dose rifampicin and adjunctive linezolid can safely be added to SOC in HIV-associated TBM. Larger studies are required to evaluate whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit.


Crick (Grant ID: 10218, Grant title: Wilkinson, R FC001218)