Linezolid, Aspirin and Enhanced Dose Rifampicin in HIV-TBM
Summary
LASER-TBM is a parallel group, randomized, multi-arm phase IIa trial evaluating the safety of increased dose rifampicin (RIF) plus linezolid (LZD), with or without aspirin (ASA), for the treatment of HIV-infected adults with tuberculous meningitis (TBM). The study will recruit 100 HIV-infected adults with TBM across four sites in South Africa. The primary endpoint is the occurrence of solicited treatment-related adverse events. Secondary endpoints include death and disability (including neurocognitive impairment), radiological outcomes, and the occurrence of immune reconstitution inflammatory syndrome (IRIS). A nested pharmacokinetic (PK) substudy aims to: 1. Describe the plasma and cerebrospinal fluid (CSF) PK of LZD and high dose RIF. 2. Evaluate the relationship between drug exposures, toxicity and efficacy. 3. Compare exposures between intravenous and oral RIF administration. 4. Investigate the impact of high dose RIF on LZD and dolutegravir (DTG).
Timeline
- Start
- 2019-06-12
- Primary completion
- 2021-03-30
- Completion
- 2021-03-31
Publications
- Abdelgawad N, Wasserman S, Abdelwahab MT, Davis A, Stek C, Wiesner L, Black J, Meintjes G, Wilkinson RJ, Denti P. Linezolid Population Pharmacokinetic Model in Plasma and Cerebrospinal Fluid Among Patients With Tuberculosis Meningitis. J Infect Dis. 2024 Apr 12;229(4):1200-1208. doi: 10.1093/infdis/jiad413.
- Davis AG, Wasserman S, Stek C, Maxebengula M, Jason Liang C, Stegmann S, Koekemoer S, Jackson A, Kadernani Y, Bremer M, Daroowala R, Aziz S, Goliath R, Lai Sai L, Sihoyiya T, Denti P, Lai RPJ, Crede T, Naude J, Szymanski P, Vallie Y, Banderker IA, Moosa MS, Raubenheimer P, Candy S, Offiah C, Wahl G, Vorster I, Maartens G, Black J, Meintjes G, Wilkinson RJ. A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus-Associated Tuberculous Meningitis: The LASER-TBM Trial. Clin Infect Dis. 2023 Apr 17;76(8):1412-1422. doi: 10.1093/cid/ciac932.
- Davis AG, Wasserman S, Maxebengula M, Stek C, Bremer M, Daroowala R, Aziz S, Goliath R, Stegmann S, Koekemoer S, Jackson A, Lai Sai L, Kadernani Y, Sihoyiya T, Liang CJ, Dodd L, Denti P, Crede T, Naude J, Szymanski P, Vallie Y, Banderker I, Moosa S, Raubenheimer P, Lai RPJ, Joska J, Nightingale S, Dreyer A, Wahl G, Offiah C, Vorster I, Candy S, Robertson F, Meintjes E, Maartens G, Black J, Meintjes G, Wilkinson RJ. Study protocol for 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 [LASER-TBM]. Wellcome Open Res. 2021 Jun 1;6:136. doi: 10.12688/wellcomeopenres.16783.1. eCollection 2021.
- Wasserman S, Davis A, Stek C, Chirehwa M, Botha S, Daroowala R, Bremer M, Maxebengula M, Koekemoer S, Goliath R, Jackson A, Crede T, Naude J, Szymanski P, Vallie Y, Moosa MS, Wiesner L, Black J, Meintjes G, Maartens G, Wilkinson RJ. Plasma Pharmacokinetics of High-Dose Oral versus Intravenous Rifampicin in Patients with Tuberculous Meningitis: a Randomized Controlled Trial. Antimicrob Agents Chemother. 2021 Jul 16;65(8):e0014021. doi: 10.1128/AAC.00140-21. Epub 2021 Jul 16.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Aspirin | Small molecule | 1000 mg | Oral |
| Subject | Linezolid | Other / unclassified | 600 mg | Oral |
| Subject | Rifampin | Small molecule | 10 mg/kg | Oral |
| Subject | Rifampin | Small molecule | 20 mg/kg | Oral |
| Subject | Rifampin | Small molecule | 35 mg/kg | Oral |
| Background | Dexamethasone | Small molecule | — | Oral |
| Background | Ethambutol | Small molecule | 15 mg/kg | Oral |
| Background | Isoniazid | Small molecule | 5 mg/kg | Oral |
| Background | Pyrazinamide | Small molecule | 25 mg/kg | Oral |