A5384: A Phase II, Randomized, Open-Label Trial of a Six-Month Regimen of High-Dose Rifampicin, High-Dose Isoniazid, Linezolid, and Pyrazinamide versus a Standard Nine-Month Regimen for the Treatment of Adults and Adolescents with Tuberculous Meningitis

Study Description

A5384 is a trial for people who have or might have tuberculous meningitis (TBM). TBM is an infectious disease that causes inflammation of the membranes that surround the brain and the spinal cord (meninges). TBM is caused by the bacterium Mycobacterium tuberculosis, which can be found elsewhere in the body, usually the lungs, but can travel via the bloodstream to the meninges, where the bacteria cause TBM.

This trial will compare a new experimental regimen of anti-TBM medicines taken over a 6-month time period with the current standard of care regimen of anti-TBM medicines taken over a 9-month time period.

• Better treatments for TBM are needed. This study will look at the safety and tolerability (having a reaction or side effects from the medicines) of the regimens and how well the experimental 6-month regimen does compared to the standard 9-month regimen.
• The study will also measure the level of the drugs in the blood and cerebrospinal fluid (CSF).

• Age 15 years and older
• Definite, probable, or possible TBM diagnosis from testing performed as part of routine care within 21 days of entering the study
• Cannot have taken more than 14 days of anti-TB medications
• Cannot have current or prior drug-resistant TB infection
• Living with or without HIV
• If with HIV:
• May need to switch to an acceptable anti-HIV regimen
• May not initiate anti-HIV treatment during first 4 weeks of study

Participants will be randomly selected (like the flip of a coin) to be in one of two groups:

• Experimental regimen: rifampicin (high-dose), isoniazid (high-dose), linezolid, and pyrazinamide for 6 months, OR
• Current standard of care for TBM: rifampicin, isoniazid, ethambutol, and pyrazinamide for 9 months.

All participants will also receive pyridoxine and additional corticosteroids for at least 6 weeks during the trial. All study treatments are taken orally.

Participants will complete 13 study visits over the 72-week trial. At some visits, they will receive pharmacokinetic (PK) sampling blood draws over several hours as well as lumbar punctures to measure how much of the medicines are in blood and in the CSF.

All of the standard of care and experimental TBM medications, except the corticosteroids, will be provided by the study.