Phase 2
N=40
Adjunctive Linezolid for the Treatment of Tuberculous Meningitis
Tuberculosis, Meningeal
Bottom Line
View on ClinicalTrials.gov: NCT04021121 ↗Enrolled (actual)
40
Serious AEs
55.0%
Results posted
Oct 2024
Primary outcome: Primary: Drug Clearance (CL/F) — 6.24 L/hr
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- LZD (Drug); High dose RIF (Drug); Standard dose RIF (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- University of California, San Francisco
- Primary completion
- Jul 2023
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Drug Clearance (CL/F) |
6.24 | — |
| PRIMARY Volume of Distribution (Vd) |
24.97 | — |
| PRIMARY Plasma Absorption Rate Constant (ka) |
0.35 | — |
| PRIMARY Rate of CSF Uptake (kPC) |
0.382 | — |
| PRIMARY CSF to Plasma Ratio (PC) |
.5381 | — |
| SECONDARY Proportion of Participants With Grade 3 or Higher Adverse Events (AE). |
— | — |
| SECONDARY Proportion of Participants Who Complete LZD Treatment. |
— | — |
| SECONDARY Modified Rankin Scale (MRS) Performance. |
— | — |
| SECONDARY Neurocognitive Battery Performance: Wechsler Adult Intelligence Scale-III Digit Symbol (WAIS-III). |
— | — |
| SECONDARY Neurocognitive Battery Performance: Color Trails, Part 1 |
— | — |
| SECONDARY Neurocognitive Battery Performance: Color Trails, Part 2 |
— | — |
| SECONDARY Neurocognitive Battery Performance: Category Fluency |
— | — |
| SECONDARY Neurocognitive Battery Performance: Hopkins Verbal Learning Test-Revised (HVLT-R) |
— | — |
| SECONDARY Neurocognitive Battery Performance: World Health Organization-University of California-Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT). |
— | — |
| SECONDARY Neurocognitive Battery Performance: Grooved Pegboard Bilateral |
— | — |
| SECONDARY Neurocognitive Battery Performance: Finger Tapping Bilateral |
— | — |
| SECONDARY Montreal Cognitive Assessment Performance (Conditional). |
— | — |
Summary
This is a phase II randomized open-label trial of high versus standard dose rifampin (RIF) with or without linezolid (LZD) for the first 4 weeks of treatment for Tuberculosis Meningitis (TBM) at Masaka Regional Referral Hospital in Uganda. Initial randomization will be to high (35 mg/kg/day) versus standard (10 mg/kg/day) dose oral rifampin for the first 4 weeks of intensive therapy. Participants will then undergo a second randomization to linezolid 1200 mg daily versus no linezolid for the first 4 weeks of therapy. The primary aims are (1) to determine the cerebrospinal fluid and plasma pharmacokinetics of adjunctive LZD 1200 mg daily in TBM patients receiving high or standard dose RIF and (2) to evaluate the tolerability of a 4-week course of LZD in TBM patients.
Eligibility Criteria
Inclusion Criteria
- Age > 18 years
- Written informed consent from participant or proxy
- Definite, probable, possible, or suspected TBM diagnosis wherein the patient is being committed to a full course of anti-TB treatment for TBM in the setting of routine care.
All participants must have at least one of the following signs/symptoms: headache, irritability, vomiting, fever, neck stiffness, convulsions, focal neurological deficits, altered consciousness, or lethargy. In addition, participants must have CSF glucose to plasma ratio 5 doses of TB treatment received within previous 5 days
- Discontinued TB treatment in prior 14 days
- Known current/previous drug resistant TB infection
- Known allergy to RIF, INH, PZA, EMB, LZD
- Previous treatment of TB or TBM with LZD
- Concomitant or planned use of monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, HIV protease inhibitors, or any other drug with significant interaction with RIF, LZD, or any TB drugs (see Appendices C and D)
- Women who are pregnant or breastfeeding, or women or men of reproductive potential who are unwilling to use at least one reliable form of barrier contraception or to abstain from sexual activity while receiving study drug treatment and for 30 days after stopping study treatment. Acceptable forms of contraception include: condoms (male or female) with or without a spermicidal agent, or diaphragm or cervical cap with spermicide. Hormonal contraception is not recommended as it may be ineffective due to induction of metabolism when receiving rifampicin.
- Unwillingness to be an inpatient for 2 weeks for initial treatment or to attend follow up clinic visits
- Lack of informed consent from participant or next of kin/caregiver
- Serum creatinine >1.8 times upper limit of normal, hemoglobin 3 times the upper limit of normal, total bilirubin >2 times the upper limit of normal.
- Severe peripheral neuropathy defined by Grade 3 symptoms AND vibratory loss OR absent ankle jerks for participants able to undergo the Brief Peripheral Neuropathy Screen (see Appendix B).
- Contraindication to LP, including PLT <50 cells/mm3 or unequal pressures between intracranial compartments (e.g., due to mass lesion, non-communicating hydrocephalus), or unwillingness to undergo or consent to LP
Data sourced from ClinicalTrials.gov (NCT04021121). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.