Adjunctive Linezolid for the Treatment of Tuberculous Meningitis

  • STATUS
    Recruiting
  • End date
    Nov 17, 2023
  • participants needed
    60
  • sponsor
    University of California, San Francisco
Updated on 17 June 2021

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.

Details
Condition Tuberculous meningitis
Treatment LZD, High dose RIF, Standard dose RIF
Clinical Study IdentifierNCT04021121
SponsorUniversity of California, San Francisco
Last Modified on17 June 2021

Eligibility

Yes No Not Sure

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 < 0.5 OR positive CSF acid-
fast bacilli (AFB) smear OR positive CSF GeneXpert or Xpert Ultra OR clinician
intent to initiate TB treatment for suspected TB meningitis
Definite, probable and possible TBM will be defined as
Definite TBM is defined by the presence of one or more of the following
Acid- fast bacilli (AFB) seen in the CSF, M tuberculosis cultured from CSF, or a CSF M tuberculosis-positive nucleic acid amplification test (e.g., Gene Xpert Ultra) performed within 14 days of entry
AFB seen in the context of histological changes consistent with tuberculosis in the brain with suggestive symptoms or signs and CSF changes
Probable and possible TBM are defined using previously published consensus
criteria as shown in Appendix A45
Probable TBM is defined as a total score of 12 when neuroimaging is available or total score of 10 when neuroimaging is unavailable. At least two points should either come from CSF or cerebral imaging criteria
Possible TBM is defined as a total score of 6-11 when neuroimaging is available, or total score of 6-9 when neuroimaging is unavailable
Exclusion of the most likely alternative diagnoses is also required (e.g
negative cryptococcal antigen). Because culture confirmation is rarely
available or often delayed in TBM, patients with probable or possible TBM will
be recruited based on these predefined criteria, and CSF will be collected for
mycobacterial culture and molecular testing. Classification of participants as
definite, probable, or possible TBM will be made retrospectively once all
necessary data are available

Exclusion Criteria

>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 <7.0 g/dL for men, <6.5 g/dL for women, platelet count <50,000/mm3, absolute neutrophil count <600/mm3, alanine aminotransferase (ALT) >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
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