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

NCT05383742 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: A5384
• Study Type: interventional
• Target: 330
• Locations: 12 countries
• Sites: 18

Brief 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).

Conditions

Tuberculous Meningitis

Keywords

Tuberculosis, meningeal; Tuberculosis; CNS Disease

Outcome Measures

Primary Outcomes (1)

• 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)

  At 48 weeks

Secondary Outcomes (21)

• Modified Rankin Scale (all 7 levels)

  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)

  At 12, 24, 36, 48 and 72 weeks

• Modified Rankin Scale 5 or 6

  At 12, 24, 36, 48 and 72 weeks

• Time to death through 48 and 72 weeks

  At weeks 48 and 72

• Proportion of participants with Grade 3 or higher AEs

  At 4, 8 and 24 weeks

Other Outcomes (10)

• Proportion of participants with recurrence

  At 36 and 48 weeks

• Positive or negative CSF Xpert Ultra

  At screening, Day 3 and week 2 or week 6 or week 8

• Positive or negative CSF and urine LAM

  At screening, Day 3 and week 2 or week 6 or week 8

Study Arms (2)

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.

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.

Drug: Pyrazinamide (PZA); Drug: ethambutol (EMB); Drug: Rifampicin; Drug: Isoniazid

Interventions

Rifampicin (RIF) DRUG

Rifampicin 35 mg/kg

Arm A

Isoniazid (INH) DRUG

Isoniazid 10 or15 mg/kg

Arm A

Linezolid (LZD) DRUG

1200 mg

Arm A

Pyrazinamide (PZA) DRUG

25 mg/kg

Arm A; Arm B

ethambutol (EMB) DRUG

20 mg/kg

Arm B

Rifampicin DRUG

10 mg/kg

Arm B

Isoniazid DRUG

5 mg/kg

Arm B

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (18)

Hospital Nossa Senhora da Conceicao CRS (Site ID: 12201)

Porto Alegre, 91350-200, Brazil

RECRUITING

Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS (Site ID: 12101)

Rio de Janeiro, Brazil

RECRUITING

Byramjee Jeejeebhoy Government Medical College (BJMC) CRS (Site ID: 31441)

Pune, 411001, India

RECRUITING

Moi University Clinical Research Center (MUCRC) CRS (Site ID: 12601)

Eldoret, 30100, Kenya

RECRUITING

Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS (Site ID: 12501)

Kericho, Kenya

RECRUITING

Malawi CRS (Site ID: 12001)

Lilongwe, Malawi

RECRUITING

Nutrición-Mexico CRS (Site ID: 32078)

Mexico City, 14080, Mexico

NOT YET RECRUITING

Socios en Salud Sucursal Peru CRS (Site ID: 31985)

Lima, 15046, Peru

NOT YET RECRUITING

Barranco CRS (Site ID:11301)

Lima, 4, Peru

NOT YET RECRUITING

TB HIV Innovations and Clinical Research Foundation Corp (Site ID: 31981)

Cavite, 4114, Philippines

NOT YET RECRUITING

Durban International CRS (Site ID:11201)

Durban, 4091, South Africa

NOT YET RECRUITING

University of the Witwatersrand Helen Joseph (WITS HJH) CRS (Site ID: 11101)

Johannesburg, 2193, South Africa

NOT YET RECRUITING

Kilimanjaro Christian Medical Centre (KCMC) (Site ID: 5118)

Moshi, Tanzania

NOT YET RECRUITING

Siriraj Hospital, Mahidol University NICHD CRS (Site ID: 5115)

Bangkok, Bangkoknoi, 10700, Thailand

NOT YET RECRUITING

Thai Red Cross AIDS Research Centre (TRC-ARC) CRS (Site ID: 31802)

Bangkok, Pathumwan, 10330, Thailand

NOT YET RECRUITING

Chiangrai Prachanukroh Hospital NICHD CRS (Site ID: 5116)

Chiang Mai, 50100, Thailand

RECRUITING

National Lung Hospital CRS (Site ID: 32483)

Vĩnh Phúc, Hanoi, 100000, Vietnam

RECRUITING

Milton Park CRS (Site ID: 30313)

Harare, Zimbabwe

RECRUITING

MeSH Terms

Conditions

Tuberculosis, Meningeal; Tuberculosis; Central Nervous System Diseases

Interventions

Rifampin; Isoniazid; Linezolid; Pyrazinamide; Ethambutol

Condition Hierarchy (Ancestors)

Meningitis, Bacterial; Central Nervous System Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Tuberculosis, Central Nervous System; Tuberculosis, Extrapulmonary; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Central Nervous System Infections; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Acetamides; Amides; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Pyrazines; Ethylenediamines; Diamines; Polyamines; Amines

Central Study Contacts

ACTG Clinicaltrials.gov Coordinator

CONTACT

(301) 628-3348; ACTGCT.gov@fstrf.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 8, 2022
• First Posted: May 20, 2022
• Study Start: December 7, 2023
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): September 15, 2029
• Last Updated: December 2, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) by NIH
• Access Criteria: * With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the ACTG. * For what types of analyses? To achieve aims in the proposal approved by the ACTG. * By what mechanism will data be made available? Researchers may submit a request for access to data using the ACTG "Data Request" form at: https://submit.mis.s-3.net/. Researchers of approved proposals will need to sign an ACTG Data Use Agreement before receiving the data

Locations

IN (1); TA (1); VN (1); ZI (1); ME (1); PH (1); BR (2); TH (3); ZA (2); PE (2); MA (1); KE (2)