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 [version 2; peer review: 2 approved, 1 approved with reservations]
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 leukotriene A4 hydrolase (LTA4H) genotype and the corresponding...
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Wellcome
2025-02-01
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| Online Access: | https://wellcomeopenresearch.org/articles/9-695/v2 |
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| author | Joseph Donovan Dong Huu Khanh Trinh Ronald B. Geskus Marcel Wolbers Guy E. Thwaites Nguyen Thuy Thuong Thuong Le Thanh Hoang Nhat |
| author_facet | Joseph Donovan Dong Huu Khanh Trinh Ronald B. Geskus Marcel Wolbers Guy E. Thwaites Nguyen Thuy Thuong Thuong Le Thanh Hoang Nhat |
| author_sort | Joseph Donovan |
| collection | DOAJ |
| description | 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 leukotriene A4 hydrolase (LTA4H) 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): ‘Leukotriene A4 hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-negative adults with Tuberculous meningitis’. The primary hypothesis addressed by the trial is that LTA4H genotype, in particular CC or CT genotype, determines whether adjunctive dexamethasone benefits or harms adults with TBM. The trial was an LTA4H genotype stratified, parallel group, randomised, double blind, placebo-controlled multi-centre Phase III trial of dexamethasone given for 6–8 weeks in addition to standard anti-tuberculosis drugs. LTA4H 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. |
| format | Article |
| id | doaj-art-99df0b0d17f54fa49384a7006f80d183 |
| institution | Kabale University |
| issn | 2398-502X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wellcome |
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| series | Wellcome Open Research |
| spelling | doaj-art-99df0b0d17f54fa49384a7006f80d1832025-02-06T01:00:00ZengWellcomeWellcome Open Research2398-502X2025-02-01926233Statistical 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 [version 2; peer review: 2 approved, 1 approved with reservations]Joseph Donovan0https://orcid.org/0000-0002-5893-336XDong Huu Khanh Trinh1Ronald B. Geskus2https://orcid.org/0000-0002-2740-3155Marcel Wolbers3Guy E. Thwaites4https://orcid.org/0000-0002-2858-2087Nguyen Thuy Thuong Thuong5https://orcid.org/0000-0001-8733-692XLe Thanh Hoang Nhat6Oxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Centre for Tropical Medicine, Ho Chi Minh City, VietnamTuberculous 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 leukotriene A4 hydrolase (LTA4H) 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): ‘Leukotriene A4 hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-negative adults with Tuberculous meningitis’. The primary hypothesis addressed by the trial is that LTA4H genotype, in particular CC or CT genotype, determines whether adjunctive dexamethasone benefits or harms adults with TBM. The trial was an LTA4H genotype stratified, parallel group, randomised, double blind, placebo-controlled multi-centre Phase III trial of dexamethasone given for 6–8 weeks in addition to standard anti-tuberculosis drugs. LTA4H 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.https://wellcomeopenresearch.org/articles/9-695/v2tuberculous meningitis corticosteroids clinical trial analysis plan leukotriene A4 hydrolase (LTA4H) personalised medicineeng |
| spellingShingle | Joseph Donovan Dong Huu Khanh Trinh Ronald B. Geskus Marcel Wolbers Guy E. Thwaites Nguyen Thuy Thuong Thuong Le Thanh Hoang Nhat 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 [version 2; peer review: 2 approved, 1 approved with reservations] Wellcome Open Research tuberculous meningitis corticosteroids clinical trial analysis plan leukotriene A4 hydrolase (LTA4H) personalised medicine eng |
| 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 [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_full | 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 [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_fullStr | 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 [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_full_unstemmed | 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 [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_short | 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 [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_sort | 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 version 2 peer review 2 approved 1 approved with reservations |
| topic | tuberculous meningitis corticosteroids clinical trial analysis plan leukotriene A4 hydrolase (LTA4H) personalised medicine eng |
| url | https://wellcomeopenresearch.org/articles/9-695/v2 |
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