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).

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.