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

Study Overview
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Brief Summary
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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).

Detailed Description
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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).

Official Title
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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)

Conditions
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Tuberculous Meningitis

Intervention / Treatment
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* Drug: Rifampicin (RIF)
* Drug: Isoniazid (INH)
* Drug: Linezolid (LZD)
* Drug: Pyrazinamide (PZA)
* Drug: ethambutol (EMB)
* Drug: Rifampicin
* Drug: Isoniazid


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>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)<br>* Rifampicin 35 mg/kg<br>Drug: Isoniazid (INH)<br>* Isoniazid 10 or15 mg/kg<br>Drug: Linezolid (LZD)<br>* 1200 mg<br>Drug: Pyrazinamide (PZA)<br>* 25 mg/kg<br>|
| Active Comparator: Arm B<br>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)<br>* 25 mg/kg<br>Drug: ethambutol (EMB)<br>* 20 mg/kg<br>Drug: Rifampicin<br>* 10 mg/kg<br>Drug: Isoniazid<br>* 5 mg/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, meningeal, Tuberculosis, CNS Disease