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 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).

Study Overview

• Status: Recruiting
• Conditions: Tuberculous Meningitis
• Intervention / Treatment: Drug: Rifampicin (RIF); Drug: Isoniazid (INH); Drug: Linezolid (LZD); Drug: Pyrazinamide (PZA); Drug: ethambutol (EMB); Drug: Rifampicin; Drug: Isoniazid

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 BMRC criteria.

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 disease severity 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).

• Study Type: Interventional
• Enrollment (Estimated): 330
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: ACTG Clinicaltrials.gov Coordinator; Phone Number: (301) 628-3348; Email: ACTGCT.gov@fstrf.org

Study Locations

• Brazil
  • Porto Alegre, Brazil, 91350-200
    • Recruiting
    • Hospital Nossa Senhora da Conceicao CRS (12201)
    • Contact: Rita Lira, MD; Phone Number: +55 51-33572603; Email: lrita@ghc.com.br
  • Rio De Janeiro, Brazil
    • Recruiting
    • Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS (12101)
    • Contact: Brenda Hoagland, MD; Phone Number: 55 21 38659122; Email: E-mbrenda.hoagland@ipec.fiocruz.br
• India
  • Pune, India, 411001
    • Recruiting
    • Byramjee Jeejeebhoy Government Medical College (BJMC) CRS (31441)
    • Contact: Nishi Suryavanshi, MD; Phone Number: 91-20-26052419; Email: nishi@jhumitpune.com
• Kenya
  • Eldoret, Kenya, 30100
    • Not yet recruiting
    • Moi University Clinical Research Center (MUCRC) CRS (12601)
    • Contact: Viola Kirui; Phone Number: 254-711-729856; Email: viola.kirui@gmail.com
  • Kericho, Kenya
    • Recruiting
    • Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS (12501)
    • Contact: Samwel Chirchir; Phone Number: 254-52-2030686; Email: samwel.chirchir@usamru-k.org
• Malawi
  • Lilongwe, Malawi
    • Not yet recruiting
    • Malawi CRS
    • Contact: Thokozani Makuhunga; Phone Number: 265-175-5056; Email: E-mtmakuhunga@unclilongwe.org
• Mexico
  • Mexico City, Mexico, 14080
    • Not yet recruiting
    • Nutrición-Mexico CRS
    • Contact: Brenda Crabtree-Ramirez, MD; Phone Number: 52-5555130010; Email: brenda.crabtree@infecto.mx
• Peru
  • Lima, Peru, 4
    • Not yet recruiting
    • Barranco CRS
    • Contact: María Caballero, MD; Phone Number: +51 206-7800; Email: mestrella@impactaperu.org
• Philippines
  • Cavite, Philippines, 4114
    • Not yet recruiting
    • De La Salle Health Science Institute Angelo King Medical Research Center (DLSHSI-AKMRC) (Site ID: 31981)
    • Contact: Maricelle S. Gler; Phone Number: 63-9178230431; Email: tarcelasg@yahoo.com
• South Africa
  • Durban, South Africa, 4091
    • Not yet recruiting
    • Durban International CRS
    • Contact: Rosie Mngqibisa, MD; Phone Number: 27-31-2611093; Email: mngqibisa@ecarefoundation.com
  • Johannesburg, South Africa, 2193
    • Not yet recruiting
    • University of the Witwatersrand Helen Joseph (WITS HJH) CRS
    • Contact: Sharlaa Badel-Faesen, MBBCh, MSc; Email: sfaesen@witshealth.co.za
• Tanzania
  • Moshi, Tanzania
    • Not yet recruiting
    • Kilimanjaro Christian Medical Centre (KCMC) (Site ID: 5118)
    • Contact: Cynthia A. Asiyo; Phone Number: 255-753698484; Email: cynthia.asiyo@duke.edu
• Thailand
  • Chiang Mai, Thailand, 50100
    • Not yet recruiting
    • Chiangrai Prachanukroh Hospital NICHD CRS
    • Contact: Pra-ornsuda Sukrakanchana; Phone Number: 66-81-7468858; Email: Pra-ornsuda.Sukrakanchana@phpt.org
  • Bangkoknoi
    • Bangkok, Bangkoknoi, Thailand, 10700
      • Not yet recruiting
      • Siriraj Hospital, Mahidol University NICHD CRS (Site ID: 5115)
      • Contact: Watcharee Lermankul; Phone Number: 5695 66-2-4197000; Email: watchareeped@gmail.com
• Vietnam
  • Hanoi
    • Vĩnh Phúc, Hanoi, Vietnam, 100000
      • Not yet recruiting
      • National Lung Hospital CRS (Site ID: 32483)
      • Contact: Tran V Viet Ha; Phone Number: 84-912-785886; Email: vietha@live.unc.edu
• Zimbabwe
  • Harare, Zimbabwe
    • Not yet recruiting
    • Milton Park CRS
    • Contact: Pamela Marimbe-Mukwekwerere, MD; Phone Number: +263-242-257066; Email: pmukwekwerere@uz-ctrc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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
• Persons aged ≥15 years
• 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:
• Grade I: Glasgow Coma Score 15, no focal neurological deficits
• Grade II: Glasgow Coma Score 11-14 or 15 with focal neurological deficits
• Grade III: Glasgow Coma Score ≤10

• 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 and ART-naïve, planned initiation of ART during the first 4 weeks after randomization
• 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Rifampicin (RIF); Rifampicin 35 mg/kg; Drug: Isoniazid (INH); Isoniazid 10 or15 mg/kg; Drug: Linezolid (LZD); 1200 mg; Drug: Pyrazinamide (PZA); 25 mg/kg
Active Comparator: Arm B; 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); 25 mg/kg; Drug: ethambutol (EMB); 20 mg/kg; Drug: Rifampicin; 10 mg/kg; Drug: Isoniazid; 5 mg/kg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale (all 7 levels)		At weeks 12,24,36 and 72
Modified Rankin Scale using collapsed categories at 12, 24, 36, 48 and 72 weeks: mRS (0 or 1), (2 or 3), (4 or 5), (6)		12, 24, 36, 48 and 72 weeks
Modified Rankin Scale 5 or 6		At 12, 24, 36, 48 and 72 weeks
Change in mRS from baseline to each of 12, 24, 36, 48, and 72 weeks		At 12, 24, 36, 48, and 72 weeks
Time to death over 48 and 72 weeks		At weeks 48 and 72
Proportion of participants with Grade 3 or higher AEs over 8 weeks		At 8 weeks
Proportion of participants with a serious adverse event (SAE) over 8 weeks		At 8 weeks
Proportion of participants who complete study treatments, which is defined as completing 168 doses within 185 days for Arm A and 252 doses in 278 days for Arm B		At day 185 and day 278
Proportion of participants with TBM IRIS (as defined in protocol) over 48 weeks		At week 48
Wechsler Adult Intelligence Scale Digit Symbol or Symbol Digit Modalities	Neurocognitive battery performance	At week 24 and 48
Color Trails 1, 2	Neurocognitive battery performance	At week 24 and 48
Category Fluency	Neurocognitive battery performance	At week 24 and 48
Hopkins Verbal Learning Test-Revised	Neurocognitive battery performance	At week 24 and 48
Grooved Pegboard Bilateral	Neurocognitive battery performance	At week 24 and 48
Finger-tapping Bilateral	Neurocognitive battery performance	At week 24 and 48
Patient Health Questionnaire (PHQ-9) total score	defined as Glasgow Coma Score of 15 for ≥48 hours for hospitalized participants over 4 weeks	At 24, 48, and 72 weeks
WHO DAS score	defined as Glasgow Coma Score of 15 for ≥48 hours for hospitalized participants over 4 weeks	At 24, 48, and 72 weeks
Change in BMRC TBM grade at week 1. BMRC TBM grade is defined as:	Grade I: Glasgow Coma Score 15, no focal neurological deficits; Grade II: Glasgow Coma Score 11-14 or 15 with focal neurological deficits; Grade III: Glasgow Coma Score ≤10	At week 1
Time to coma clearance, which is defined as Glasgow Coma Score of 15 for ≥48 hours for hospitalized participants, over 4 weeks.		At week 4
Time to new neurological event, which is defined as fall in Glasgow Coma Score of ≥2 points for ≥48 hours for hospitalized participants or since last visit for non-hospitalized participants, new onset seizures, new focal neurologic deficit		At week 48
CSF to plasma ratio		At Day 3, Week 2, 6 or 8
Rate of CSF uptake		At Day 3, Week 2, 6 or 8
Plasma absorption rate constant (ka)		At Day 3, Week 2, 6 or 8
Drug clearance (Cl/F)		At Day 3, Week 2, 6 or 8
Volume of distribution (Vd)		At Day 3, Week 2, 6 or 8
Post-hoc Bayesian predictions of secondary parameters Cmax		At Day 3, Week 2, 6 or 8
Time to Cmax		At Day 3, Week 2, 6 or 8
Time to AUC0-24		At Day 3, Week 2, 6 or 8
Time to plasma elimination half-life		At Day 3, Week 2, 6 or 8
Time to CSF elimination half-life		At Day 3, Week 2, 6 or 8

Other Outcome Measures

Outcome Measure	Time Frame
Proportion of participants who relapsed by 12 and 24 weeks after completion of study treatments	At week 12 and 24
Positive or negative CSF Xpert Ultra	At Day 3, week 2 and week 8
Positive or negative CSF and urine LAM	At Day 3, weeks 2, 8 and 12
Change in sterilization of CSF culture	At Weeks 2 and 6-8
Change in CSF white blood cell count	At Weeks 2 and 6-8
Change in CSF glucose	At Weeks 2 and 6-8
Change in CSF blood glucose ratio	At Weeks 2 and 6-8
Change in CSF protein	At Weeks 2 and 6-8

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2023
• Primary Completion (Estimated): May 10, 2027
• Study Completion (Estimated): May 10, 2027

Study Registration Dates

• First Submitted: April 8, 2022
• First Submitted That Met QC Criteria: May 16, 2022
• First Posted (Actual): May 20, 2022

Study Record Updates

• Last Update Posted (Actual): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Tuberculosis; Tuberculosis, meningeal; CNS Disease
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis, Central Nervous System; Neuroinflammatory Diseases; Tuberculosis, Extrapulmonary; Tuberculosis; Meningitis; Tuberculosis, Meningeal; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Protein Synthesis Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Fatty Acid Synthesis Inhibitors; Linezolid; Rifampin; Isoniazid; Pyrazinamide; Ethambutol
• Other Study ID Numbers: A5384

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie results in the publication, after deidentification
• IPD Sharing Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH

IPD Sharing Access Criteria

With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.

For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group.

By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/submit-a-proposal/. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No