{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T09:21:27Z","timestamp":1768555287897,"version":"3.49.0"},"posted":{"date-parts":[[2022,7,26]]},"group-title":"Neurology","reference-count":27,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2022,7,26]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We conducted a phase 2 open-label parallel-design RCT to assess safety of high-dose rifampicin, linezolid and 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)\n                    <jats:italic>or<\/jats:italic>\n                    death was assessed.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    52 participants were randomised. 59% had mild disease (MRC Grade 1) vs 39% (Grade 2) vs 2% (Grade 3). 33% of participants had microbiologically-confirmed TBM; vs 41% \u2018possible\u2019 or 25% \u2018probable\u2019. AESI or death occurred in 10\/16 (arm 3) vs 4\/14 (arm 2) vs 6\/20 (arm 1) (\n                    <jats:italic>p=0<\/jats:italic>\n                    .\n                    <jats:italic>083<\/jats:italic>\n                    ). The cumulative proportion of AESI or death (Kaplan-Meier method) demonstrated worse outcomes in arm 3 vs arm 1 (\n                    <jats:italic>p=0<\/jats:italic>\n                    .\n                    <jats:italic>04<\/jats:italic>\n                    ), 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 the three arms.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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 aspirin, is outweighed by mortality or morbidity benefit.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>SUMMARY<\/jats:title>\n                  <jats:p>In this phase 2a randomised control trial we demonstrate that high-doserifampicin and adjunctive linezolid is safe in adult HIV-associated tuberculous meningitis. Larger studies are required to evaluate potential toxicity with aspirin, in relation to benefit on morbidity and mortality.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2022.07.26.22278065","type":"posted-content","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T01:59:09Z","timestamp":1658973549000},"source":"Crossref","is-referenced-by-count":2,"title":["A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis (The LASER-TBM Trial)"],"prefix":"10.64898","author":[{"given":"Angharad G","family":"Davis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Wasserman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cari","family":"Stek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mpumi","family":"Maxebengula","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. 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