{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T02:28:02Z","timestamp":1774492082420,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.22498.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000}}],"reference-count":18,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["110179"],"award-info":[{"award-number":["110179"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>\n                    Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Corticosteroids are currently recommended as an adjunctive therapy in HIV-negative adults with TBM. However, benefit from corticosteroids in TBM may depend upon host\n                    <ns3:italic>leukotriene A4 hydrolase<\/ns3:italic>\n                    (\n                    <ns3:italic>LTA4H<\/ns3:italic>\n                    ) genotype and the corresponding inflammatory phenotypes. This article describes the planned analyses for the primary publication of the results of the LAST ACT clinical trial (NCT03100786): \u2018Leukotriene A4 hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-negative adults with Tuberculous meningitis\u2019. The primary hypothesis addressed by the trial is that\n                    <ns3:italic>LTA4H<\/ns3:italic>\n                    genotype, in particular CC or CT genotype, determines whether adjunctive dexamethasone benefits or harms adults with TBM. The trial was an\n                    <ns3:italic>LTA4H<\/ns3:italic>\n                    genotype stratified, parallel group, randomised, double blind, placebo-controlled multi-centre Phase III trial of dexamethasone given for 6\u20138 weeks in addition to standard anti-tuberculosis drugs.\n                    <ns3:italic>LTA4H<\/ns3:italic>\n                    genotype (CC, CT, TT) was determined in all participants prior to randomisation; only those with CC or CT genotype were randomised to dexamethasone or placebo. All TT genotype participants received dexamethasone because prior data indicated survival was increased by dexamethasone in this genotype. The primary endpoint was all-cause death or new neurological event over the first 12 months after randomisation. We took a hybrid trial-design approach which aims to prove non-inferiority of placebo first but also allows claiming superiority of placebo in case dexamethasone causes substantial harm. This statistical analysis plan expands upon and updates the analysis plan outlined in the published study protocol.\n                  <\/ns3:p>","DOI":"10.12688\/wellcomeopenres.22498.2","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T10:35:06Z","timestamp":1738751706000},"page":"695","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Statistical analysis plan for the LAST ACT clinical trial; a Leukotriene A4 hydrolase Stratified non-inferiority Trial of Adjunctive Corticosteroids for HIV-negative adults with Tuberculous meningitis"],"prefix":"10.12688","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5893-336X","authenticated-orcid":false,"given":"Joseph","family":"Donovan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel","family":"Wolbers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8733-692X","authenticated-orcid":false,"given":"Nguyen Thuy Thuong","family":"Thuong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong Huu Khanh","family":"Trinh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Le Thanh Hoang","family":"Nhat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-2087","authenticated-orcid":false,"given":"Guy 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.24790.r117075, Ryan Dinkele, University of Cape Town, Cape Town, 18 Jan 2025, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-695\/v1#referee-response-117075","order":0,"name":"referee-response-117075","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.24790.r116763, Michael Thy, Universit\u00e9 Paris Cit\u00e9, Paris, 21 Jan 2025, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-695\/v1#referee-response-116763","order":1,"name":"referee-response-116763","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.24790.r117077, Fajri Gafar, Unit of PharmacoTherapy, -Epidemiology and -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, 04 Feb 2025, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-695\/v1#referee-response-117077","order":2,"name":"referee-response-117077","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by Wellcome [110179 <a href=https:\/\/doi.org\/10.35802\/110179> https:\/\/doi.org\/10.35802\/110179<\/a>], an Investigator Award to Professor Guy Thwaites. \r\nThe funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}