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). Davis, A. G, Wasserman, S., Stek, C., Maxebengula, M., Liang, C. J., Stegmann, S., Koekemoer, S., Jackson, A., Kadenani, Y., Bremer, M., Daroowala, R., Aziz, S., Goliath, R. T, Sai, L. L., Sihoyiya, T., Denti, P., Lai, R. P., Crede, T., Naude, J., Szymanski, P., Vallie, Y., Banderker, I. A., Moosa, M. S, Raubenheimer, P., Candy, S., Offiah, C., Wahl, G., Vorster, I., Maartens, G., Black, J., Meintjes, G., & Wilkinson, R. J medRxiv, Cold Spring Harbor Laboratory Press, jul, 2022.
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) [link]Paper  doi  abstract   bibtex   
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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03927313 ### Clinical Protocols \textlesshttps://wellcomeopenresearch.org/articles/6-136\textgreater ### Funding Statement This study and the investigators listed are supported by Wellcome, EDCTP, Department of Science and Technology (South Africa), Research Councils UK, Cancer Research UK, Meningitis Now and National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval for the trial was granted by the University of Cape Town Human Research Ethics Committee (293/2018), Walter Sisulu University Human Research Committee (012/2019) and the South African Health Products Regulatory Authority (20180622). The trial was registered on the South African National Clinical Trials Register (DOH-27-0319-6230), Pan African National Clinical Trials Register (PACTR201902921101705) and clinicaltrials.gov ([NCT03927313][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03927313&atom=%2Fmedrxiv%2Fearly%2F2022%2F07%2F26%2F2022.07.26.22278065.atom
@article{Davis2022,
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. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Clinical Trial NCT03927313 {\#}{\#}{\#} Clinical Protocols {\textless}https://wellcomeopenresearch.org/articles/6-136{\textgreater} {\#}{\#}{\#} Funding Statement This study and the investigators listed are supported by Wellcome, EDCTP, Department of Science and Technology (South Africa), Research Councils UK, Cancer Research UK, Meningitis Now and National Institutes of Health. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval for the trial was granted by the University of Cape Town Human Research Ethics Committee (293/2018), Walter Sisulu University Human Research Committee (012/2019) and the South African Health Products Regulatory Authority (20180622). The trial was registered on the South African National Clinical Trials Register (DOH-27-0319-6230), Pan African National Clinical Trials Register (PACTR201902921101705) and clinicaltrials.gov ([NCT03927313][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript [1]: /lookup/external-ref?link{\_}type=CLINTRIALGOV{\&}access{\_}num=NCT03927313{\&}atom={\%}2Fmedrxiv{\%}2Fearly{\%}2F2022{\%}2F07{\%}2F26{\%}2F2022.07.26.22278065.atom},
author = {Davis, Angharad G and Wasserman, Sean and Stek, Cari and Maxebengula, Mpumi and Liang, C. Jason and Stegmann, Stephani and Koekemoer, Sonya and Jackson, Amanda and Kadenani, Yakub and Bremer, Marise and Daroowala, Remy and Aziz, Saalikha and Goliath, Rene T and Sai, Louise Lai and Sihoyiya, Thandi and Denti, Paolo and Lai, Rachel PJ and Crede, Thomas and Naude, Jonathan and Szymanski, Patryk and Vallie, Yakoob and Banderker, Ismail Abbas and Moosa, Muhammed S and Raubenheimer, Peter and Candy, Sally and Offiah, Curtis and Wahl, Gerda and Vorster, Isak and Maartens, Gary and Black, John and Meintjes, Graeme and Wilkinson, Robert J},
doi = {10.1101/2022.07.26.22278065},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Davis et al. - 2022 - A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or wit.pdf:pdf},
journal = {medRxiv},
keywords = {HIV,OA,Tuberculous meningitis,aspirin,fund{\_}ack,linezolid,original,rifampicin},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jul},
pages = {2022.07.26.22278065},
publisher = {Cold Spring Harbor Laboratory Press},
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)}},
url = {https://www.medrxiv.org/content/10.1101/2022.07.26.22278065v1 https://www.medrxiv.org/content/10.1101/2022.07.26.22278065v1.abstract},
year = {2022}
}
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