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

Inclusion Criteria: * Definite, probable, or possible TBM diagnosis wherein the participant is being committed to a full course of SOC anti-TB treatment for TBM in the setting of routine care. CSF, imaging, laboratory, and other results used to determine definite, probable, or possible TBM can be from testing performed as part of routine care, as long as obtained within 21 days prior to study entry * Absence of HIV-1 infection, as documented by any licensed rapid HIV test or HIV-1 enzyme or chemiluminescence immunoassay (E/CIA) test kit, within 30 days prior to study entry, OR * HIV-1 infection, documented by any licensed rapid HIV test or HIV-1 E/CIA test kit at any time prior to entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral load. Two or more HIV-1 RNA viral loads of \>1,000 copies/mL are also acceptable as documentation of HIV-1 infection, or documentation of HIV diagnosis in the medical record by a healthcare provider * Documentation within 3 days prior to study entry of stage of disease using BMRC TBM grade. * The following laboratory values obtained within 3 days prior to study entry: * Serum creatinine ≤1.8 times upper limit of normal (ULN) * Hemoglobin ≥8.0 g/dL for men, ≥7.5 g/dL for women * Absolute neutrophil count ≥600/mm3 * Platelet count ≥60,000/mm3 * Alanine aminotransferase (ALT) ≤3 x ULN * Total bilirubin ≤2 x ULN * For participants of reproductive potential who have not been post-menopausal for at least 24 consecutive months (i.e., no menses within the preceding 24 months), or participants who have not undergone surgical sterilization, hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or tubal ligation, documentation of a serum or urine pregnancy test result (positive or negative; see protocol for test sensitivity requirement) within 21 days prior to study entry * Participants with documentation of a positive pregnancy test will be consented using the consent form for pregnant participants. Participants of reproductive potential with documentation of a negative pregnancy test must agree to use at least one acceptable form of contraception, or abstain from sexual activity that could lead to pregnancy while receiving study treatment and for 30 days after stopping study treatment. Participants who are not of reproductive potential or whose partner(s) has documented azoospermia are not required to use contraception. Any statement of self-reported sterility or that of the partner's must be entered in the source documents * Ability and willingness of participant or parent or legally authorized representative (for adolescents or participants unable to provide consent) to provide informed consent/assent * Ability to comply with the protocol requirements in the opinion of the site investigator Exclusion Criteria: * More than 14 cumulative days of first-line TB medications, including but not limited to INH, RIF, EMB, and PZA, received within 90 days prior to study entry * Known current or previous drug resistant TB infection (i.e., resistance to one or more first-line TB medications, including but not limited to INH, RIF, EMB, LZD and PZA) * Known allergy/sensitivity or any hypersensitivity to components of study TB drugs (INH, RIF, LZD, PZA, and EMB) or their formulation * For participants who are able to undergo the Brief Peripheral Neuropathy Screen (BPNS) within 21 days prior to study entry, Grade 3 subjective peripheral neuropathy score on the BPNS AND EITHER vibratory loss OR absent ankle jerks * Expected concomitant use or use up to 21 days prior to study entry of monoamine oxidase inhibitors or selective serotonin reuptake inhibitors, or concomitant use of any other drug with significant interaction with the study drugs (See protocol) * For participants with HIV who are ART-naïve or who are not regularly taking ART, planned initiation or reinitiation of ART during screening or during the first 4 weeks after initiation of TB therapy * For participants with HIV and on ART that includes a protease inhibitor, nevirapine, or other prohibited ART (see protocol), contraindication to switching to an acceptable alternative regimen (e.g., efavirenz, high-dose raltegravir or dolutegravir with nucleoside reverse transcriptase inhibitors, as per local SOC) prior to randomization. TB treatment, including study drugs, should be started as soon as possible * Contraindication to LP at discretion of treating clinician (e.g., unequal pressures between intracranial compartments due to mass lesion, non-communicating hydrocephalus) * Positive cryptococcal antigen, gram stain, bacterial culture, or other test result obtained from a CSF specimen collected within 21 days prior to entry as part of routine care indicating CNS infection with a pathogen other than Mtb (e.g., cryptococcal meningitis, bacterial meningitis).