{"doi":"10.1101/2022.07.26.22278065","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)","abstract":"ABSTRACT 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 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 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% ‘possible’ or 25% ‘probable’. AESI or death occurred in 10/16 (arm 3) vs 4/14 (arm 2) vs 6/20 (arm 1) ( p=0 . 083 ). The cumulative proportion of AESI or death (Kaplan-Meier method) 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 the three 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 aspirin, is outweighed by mortality or morbidity benefit. SUMMARY 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.","journal":"medRxiv","year":2022,"id":300314,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9334,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":308893,"name":"Sean Wasserman","orcid":"0000-0002-3508-6719","position":1,"is_corresponding":false},{"id":560703,"name":"Cari Stek","orcid":"0000-0001-8813-0819","position":2,"is_corresponding":false},{"id":685847,"name":"Mpumi Maxebengula","orcid":null,"position":3,"is_corresponding":false},{"id":49901,"name":"Chen Liang","orcid":"0000-0002-9803-9880","position":4,"is_corresponding":false},{"id":756583,"name":"Stephani Stegmann","orcid":null,"position":5,"is_corresponding":false},{"id":685848,"name":"Sonya Koekemoer","orcid":null,"position":6,"is_corresponding":false},{"id":402052,"name":"Amanda Jackson","orcid":"0000-0003-4056-3337","position":7,"is_corresponding":false},{"id":755884,"name":"Yakub Kadernani","orcid":"0000-0003-3787-7167","position":8,"is_corresponding":false},{"id":419271,"name":"Marise Bremer","orcid":null,"position":9,"is_corresponding":false},{"id":110207,"name":"Remy Daroowala","orcid":null,"position":10,"is_corresponding":false},{"id":756582,"name":"Saalikha Aziz","orcid":null,"position":11,"is_corresponding":false},{"id":330709,"name":"René Goliath","orcid":"0000-0001-9818-4634","position":12,"is_corresponding":false},{"id":756584,"name":"Louise Lai Sai","orcid":null,"position":13,"is_corresponding":false},{"id":756585,"name":"Thandi Sihoyiya","orcid":null,"position":14,"is_corresponding":false},{"id":308900,"name":"Paolo Denti","orcid":"0000-0001-7494-079X","position":15,"is_corresponding":false},{"id":418472,"name":"Rachel Lai","orcid":"0000-0003-3418-850X","position":16,"is_corresponding":false},{"id":685849,"name":"Thomas Crede","orcid":null,"position":17,"is_corresponding":false},{"id":685850,"name":"Jonathan Naudé","orcid":null,"position":18,"is_corresponding":false},{"id":685851,"name":"Patryk Szymanski","orcid":null,"position":19,"is_corresponding":false},{"id":685852,"name":"Yakoob Vallie","orcid":null,"position":20,"is_corresponding":false},{"id":755885,"name":"Ismail Abbas Banderker","orcid":"0000-0002-5104-1326","position":21,"is_corresponding":false},{"id":685067,"name":"Muhammed Shiraz Moosa","orcid":"0000-0003-4354-3817","position":22,"is_corresponding":false},{"id":755687,"name":"Peter Raubenheimer","orcid":"0000-0002-5416-1286","position":23,"is_corresponding":false},{"id":756589,"name":"Sally Candy","orcid":null,"position":24,"is_corresponding":false},{"id":756587,"name":"Curtis Offiah","orcid":null,"position":25,"is_corresponding":false},{"id":756586,"name":"Gerda Wahl","orcid":null,"position":26,"is_corresponding":false},{"id":756588,"name":"Isak Vorster","orcid":null,"position":27,"is_corresponding":false},{"id":110248,"name":"Gary Maartens","orcid":"0000-0003-3080-6606","position":28,"is_corresponding":false},{"id":342201,"name":"John Black","orcid":"0000-0002-7845-4972","position":29,"is_corresponding":false},{"id":292884,"name":"Graeme Meintjes","orcid":"0000-0003-1196-4414","position":30,"is_corresponding":false},{"id":266683,"name":"Robert J. Wilkinson","orcid":"0000-0002-2753-1800","position":31,"is_corresponding":false},{"id":418470,"name":"Angharad Davis","orcid":"0000-0001-8914-5094","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-19T00:31:53.559757Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}