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Six-month high-dose rifampicin and isoniazid with linezolid and pyrazinamide versus standard nine-month therapy for adult and adolescent tuberculous meningitis

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: Improved Management With Antimicrobial AGents Isoniazid rifampiciN LinEzolid for TBM (IMAGINE-TBM)

Phase 2 Interventional National Institute of Allergy and Infectious Diseases (NIAID) · NCT05383742

This study tests whether a six-month, high-dose antibiotic regimen (rifampicin, isoniazid, linezolid, and pyrazinamide) works better than the WHO nine-month treatment for adults and adolescents with tuberculous meningitis.

Quick facts

PhasePhase 2
Study typeInterventional
Enrollment330 (estimated)
Ages15 Years and up
SexAll
SponsorNational Institute of Allergy and Infectious Diseases (NIAID) NIH
Locations18 sites (Porto Alegre and 17 other locations)
Trial IDNCT05383742 on ClinicalTrials.gov

What this trial studies

This is a Phase II, randomized, open-label trial comparing an optimized six-month high-dose regimen (high-dose rifampicin and isoniazid with linezolid and pyrazinamide) to the WHO nine-month standard of care for tuberculous meningitis. Participants with definite, probable, or possible TB meningitis are randomized with stratification by HIV status and disease stage (modified BMRC grade). The trial will collect pharmacokinetic data, monitor safety, and measure longitudinal clinical outcomes, with the primary endpoint being functional status by the modified Rankin Scale at 48 weeks. The design aims to determine whether dose escalation and inclusion of linezolid can shorten therapy while maintaining or improving survival and neurologic outcomes.

Who should consider this trial

Good fit: Adults and adolescents diagnosed with definite, probable, or possible tuberculous meningitis who are beginning a full course of anti‑TB therapy, including people with or without HIV, are the intended candidates.

Not a fit: Patients with known contraindications or intolerance to high‑dose rifampicin, isoniazid, linezolid, or pyrazinamide, or with severe hepatic, hematologic, or other conditions that prevent use of these drugs, are unlikely to benefit from this regimen.

Why it matters

Potential benefit: If successful, the regimen could shorten treatment to six months and reduce death and long-term neurologic disability from tuberculous meningitis.

How similar studies have performed: Prior data suggest higher-dose rifampicin may improve outcomes in TB meningitis, but combining high-dose rifampicin and isoniazid with linezolid in a shortened six-month regimen is a novel approach with limited direct evidence to date.

Eligibility criteria

Show full inclusion / exclusion criteria 
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).

Where this trial is running

Porto Alegre and 17 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Tuberculous MeningitisTuberculosis, meningealTuberculosisCNS Disease
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.