Tuberculous MeningitisPhase 2NCT05383742
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
A Phase 2 study testing Rifampicin (RIF), Isoniazid (INH) and Linezolid (LZD) in people with Tuberculous Meningitis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 18 sites in 12 countries.
Trial summary
The purpose of this study is to compare a 6-month regimen of high-dose rifampicin (RIF), high-dose isoniazid (INH), linezolid (LZD), and pyrazinamide (PZA) versus the World Health Organization (WHO) standard of care (SOC) treatment for tuberculosis meningitis (TBM). Read more about this study
- Who is it for?
- Ages 15 years and older
- Conditions the study is for
- Tuberculous Meningitis
- What is being tested?
- Rifampicin (RIF), Isoniazid (INH) and Linezolid (LZD)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 330 participants
- Where
- 18 sitesin 12 countries
- Study dates
- 7 Dec 2023to 15 Sep 2029
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 15 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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)
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- 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
Who cannot join
- 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
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- 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).
Trial locations and contacts
18 sites in 12 countries. Contact the study team or a site near you to ask about taking part.
18 sites in 12 countries
Thailand3 sites, 3 recruiting
- Not yet recruiting
Siriraj Hospital, Mahidol University NICHD CRS (Site ID: 5115)
Bangkok, Bangkoknoi, 10700
Watcharee Lermankul, 66-2-4197000 ext. 5695, watchareeped@gmail.com
- Not yet recruiting
Thai Red Cross AIDS Research Centre (TRC-ARC) CRS (Site ID: 31802)
Bangkok, Pathumwan, 10330
Parawee Thongpaeng, M.Ed, 66-2-6523040, parawee.t@hivnat.org
- Recruiting
Chiangrai Prachanukroh Hospital NICHD CRS (Site ID: 5116)
Chiang Mai, 50100
Pra-ornsuda Sukrakanchana, 66-81-7468858, Pra-ornsuda.Sukrakanchana@phpt.org
Brazil2 sites, 2 recruiting
- Recruiting
Hospital Nossa Senhora da Conceicao CRS (Site ID: 12201)
Porto Alegre, 91350-200
Rita Lira, MD, +55 51-33572603, lrita@ghc.com.br
- Recruiting
Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS (Site ID: 12101)
Rio de Janeiro
Brenda Hoagland, MD, 55 21 38659122, E-mbrenda.hoagland@ipec.fiocruz.br
Kenya2 sites, 2 recruiting
- Recruiting
Moi University Clinical Research Center (MUCRC) CRS (Site ID: 12601)
Eldoret, 30100
Viola Kirui, 254-711-729856, viola.kirui@gmail.com
- Recruiting
Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS (Site ID: 12501)
Kericho
Samwel Chirchir, 254-52-2030686, samwel.chirchir@usamru-k.org
Peru2 sites, 2 recruiting
- Not yet recruiting
Socios en Salud Sucursal Peru CRS (Site ID: 31985)
Lima, 15046
Bruno Martel, RN, MSc, 51-945230659, bmartel_ses@pih.org
- Not yet recruiting
Barranco CRS (Site ID:11301)
Lima, 4
María Caballero, MD, +51 206-7800, mestrella@impactaperu.org
South Africa2 sites, 2 recruiting
- Not yet recruiting
Durban International CRS (Site ID:11201)
Durban, 4091
Rosie Mngqibisa, MD, 27-31-2611093, mngqibisa@ecarefoundation.com
- Not yet recruiting
University of the Witwatersrand Helen Joseph (WITS HJH) CRS (Site ID: 11101)
Johannesburg, 2193
Sharlaa Badel-Faesen, MBBCh, MSc, sfaesen@witshealth.co.za
India1 site, 1 recruiting
- Recruiting
Byramjee Jeejeebhoy Government Medical College (BJMC) CRS (Site ID: 31441)
Pune, 411001
Nishi Suryavanshi, MD, 91-20-26052419, nishi@jhumitpune.com
Malawi1 site, 1 recruiting
- Recruiting
Malawi CRS (Site ID: 12001)
Lilongwe
Thokozani Makuhunga, 265-175-5056, E-mtmakuhunga@unclilongwe.org
Mexico1 site, 1 recruiting
- Not yet recruiting
Nutrición-Mexico CRS (Site ID: 32078)
Mexico City, 14080
Brenda Crabtree-Ramirez, MD, 52-5555130010, brenda.crabtree@infecto.mx
Philippines1 site, 1 recruiting
- Not yet recruiting
TB HIV Innovations and Clinical Research Foundation Corp (Site ID: 31981)
Cavite, 4114
Maricelle S. Gler, 63-9178230431, tarcelasg@yahoo.com
Tanzania1 site, 1 recruiting
- Not yet recruiting
Kilimanjaro Christian Medical Centre (KCMC) (Site ID: 5118)
Moshi
Cynthia A. Asiyo, 255-753698484, cynthia.asiyo@duke.edu
Vietnam1 site, 1 recruiting
- Recruiting
National Lung Hospital CRS (Site ID: 32483)
Vĩnh Phúc, Hanoi, 100000
Tran V Viet Ha, 84-912-785886, vietha@live.unc.edu
Zimbabwe1 site, 1 recruiting
- Recruiting
Milton Park CRS (Site ID: 30313)
Harare
Pamela Marimbe-Mukwekwerere, MD, +263-242-257066, pmukwekwerere@uz-ctrc.org
About this study
Official title: 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)
The purpose of this study is to compare a 6-month regimen of high-dose rifampicin (RIF), high-dose isoniazid (INH), linezolid (LZD), and pyrazinamide (PZA) versus the World Health Organization (WHO) standard of care (SOC) treatment for tuberculosis meningitis (TBM).
Read the detailed description
Rationale: TBM is a devastating illness with high risk of mortality and severe neurologic morbidity. Although recent data suggest that significant dose increases in RIF may improve outcomes in TBM, mortality remains high, and enhanced treatment strategies are needed. In addition, limited data are available to guide treatment duration in adults with TBM. The overall goal of this Phase II, randomized, open-label trial is to assess the PK, safety, and longitudinal treatment outcomes of an optimized 6-month regimen of high-dose RIF, high-dose INH, LZD, and PZA to the WHO 9-month SOC regimen for the treatment of TBM.
Primary objective: To determine if a regimen of high-dose RIF, high-dose INH, LZD, and PZA improves functional outcomes measured by the modified Rankin Scale (mRS) at 48 weeks compared with WHO SOC for the treatment of TBM.
Design: Participants with definite, probable, or possible TBM will be randomized to one of the two study arms below and randomization will be stratified by HIV status and stage of disease as defined by the modified British Medical Research Council (BMRC) Classification TBM Grade.
Arm A: RIF 35 mg/kg + INH 15 mg/kg + LZD 1200 mg + PZA 25 mg/kg for 2 weeks, followed by RIF 35 mg/kg + INH 10 mg/kg + LZD 1200 mg + PZA 25 mg/kg for 6 weeks, and then RIF 35 mg/kg and INH 10 mg/kg for 16 weeks, for a total of 24 weeks of study treatment.
Arm B: WHO SOC: RIF 10 mg/kg + INH 5 mg/kg + EMB 20 mg/kg + PZA 25 mg/kg for 8 weeks, followed by RIF 10 mg/kg and INH 5 mg/kg for 28 weeks, for a total of 36 weeks of study treatment. Up to 15 mg/kg or a maximum of 900 mg daily of oral RIF will be permitted in this arm at clinician's discretion.
All participants in Arms A and B will receive pyridoxine, while receiving INH, and adjunctive corticosteroids according to BMRC TBM grade for at least 6 weeks.
All participants in Arms A and B will be followed from randomization to week 72.
Procedures: Study visits will include interval history, blood collection for laboratory testing, peripheral neuropathy screening, visual acuity, color vision, and contrast sensitivity visual testing to monitor for AEs. Lumbar puncture will be performed for assessments of CSF microbiology, LAM and other biomarkers. Optional collection and storage of blood and storage of remaining CSF for future testing will occur. Urine will be obtained for LAM assessment. Plasma and CSF PK assessments will be performed. Participants will undergo assessment of functional status with the mRS and WHO DAS 2.0. Participants will also be assessed with a neurocognitive battery and depression questionnaire (PHQ-9).
- Conditions
- Tuberculous Meningitis
- Being tested
- Rifampicin (RIF), Isoniazid (INH), Linezolid (LZD), Pyrazinamide (PZA), ethambutol (EMB)
- Keywords
- Tuberculosis, meningeal, Tuberculosis, CNS Disease
- Medical subject headings
- Tuberculosis, Meningeal, Tuberculosis, Central Nervous System Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rifampicin (RIF)Drug
Rifampicin 35 mg/kg
Isoniazid (INH)Drug
Isoniazid 10 or15 mg/kg
Linezolid (LZD)Drug
1200 mg
Pyrazinamide (PZA)Drug
25 mg/kg
ethambutol (EMB)Drug
20 mg/kg
RifampicinDrug
10 mg/kg
IsoniazidDrug
5 mg/kg
| Study group | Role | What they receive |
|---|---|---|
| Arm A | Experimental | RIF 35 mg/kg + INH 15 mg/kg + LZD 1200 mg + PZA 25 mg/kg for 2 weeks, followed by RIF 35 mg/kg + INH 10 mg/kg + LZD 1200 mg + PZA 25 mg/kg for 6 weeks, and then RIF 35 mg/kg and INH 10 mg/kg for 16 weeks, for a total of 24 weeks of study treatment. Receives: Drug: Rifampicin (RIF); Drug: Isoniazid (INH); Drug: Linezolid (LZD); Drug: Pyrazinamide (PZA) |
| Arm B | Active comparator | WHO SOC: RIF 10 mg/kg + INH 5 mg/kg + ethambutol (EMB) 20 mg/kg + PZA 25 mg/kg for 8 weeks, followed by RIF 10 mg/kg and INH 5 mg/kg for 28 weeks, for a total of 36 weeks of study treatment. Up to 15 mg/kg or a maximum of 900 mg daily of oral RIF will be permitted in this arm at clinician's discretion. Receives: Drug: Pyrazinamide (PZA); Drug: ethambutol (EMB); Drug: Rifampicin; Drug: Isoniazid |
What is being measured
The primary outcome is the main question the study is designed to answer.
Modified Rankin Scale (6-death, 5-severe disability, 4-moderately severe disability, 3-moderate disability, 2-slight disability, 1-no significant disability, 0-no symptoms)
Measured: At 48 weeks
Secondary outcomes (21)
Modified Rankin Scale (all 7 levels)
Measured: At 0, 12, 24, 36, 48 and 72 weeks
Modified Rankin Scale using collapsed categories: mRS (0 or 1), (2 or 3), (4 or 5), (6)
Measured: At 12, 24, 36, 48 and 72 weeks
Modified Rankin Scale 5 or 6
Measured: At 12, 24, 36, 48 and 72 weeks
Time to death through 48 and 72 weeks
Measured: At weeks 48 and 72
Proportion of participants with Grade 3 or higher AEs
Measured: At 4, 8 and 24 weeks
Proportion of participants with a serious adverse event (SAE)
Measured: At 4, 8 and 24 weeks
Proportion of participants with study treatment discontinuations
Measured: At 4, 8 and 24 weeks
Proportion of participants who complete study treatments
Measured: At 185 and 278 days
Proportion of participants with TBM IRIS or paradoxical worsening
Measured: At 48 weeks
Wechsler Adult Intelligence Scale Digit Symbol
Neurocognitive battery performance
Measured: At 24 and 48 weeks
Color Trails 1
Neurocognitive battery performance
Measured: At 24 and 48 weeks
Color Trails 2
Neurocognitive battery performance
Measured: At 24 and 48 weeks
Category Fluency
Neurocognitive battery performance
Measured: At 24 and 48 weeks
Hopkins Verbal Learning Test-Revised
Neurocognitive battery performance
Measured: At 24 and 48 weeks
Grooved Pegboard Bilateral
Neurocognitive battery performance
Measured: At 24 and 48 weeks
Finger-tapping Bilateral
Neurocognitive battery performance
Measured: At 24 and 48 weeks
Patient Health Questionnaire (PHQ-9) total score
Measured: At 24, 48, and 72 weeks
WHO DAS score
Measured: At 24, 48, and 72 weeks
Change in BMRC TBM grade at week 1
Measured: At 1 week
Time to coma clearance
Measured: At 4 weeks
Time to new neurological event
Measured: At 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 May 2022
- Study start7 Dec 2023
- Primary completion30 Apr 2028 (estimated)
- Study completion15 Sep 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Tuberculous MeningitisStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 330 participants (estimated)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05383742
- Sponsor's protocol ID
- A5384
- Status last verified
- Jun 2026
- First submitted
- 8 Apr 2022
- Last updated
- 2 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie results in the publication, after deidentification