Adjunctive Linezolid for the Treatment of Tuberculous Meningitis

NCT04021121 | Completed Phase 2 Results DMC

• 2 other identifiers: 18-26068R21TW011035
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Tuberculosis, Meningeal

Outcome Measures

Primary Outcomes (5)

• Drug Clearance (CL/F)

  Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability).

  4 weeks

• Volume of Distribution (Vd)

  Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability).

  4 weeks

• Plasma Absorption Rate Constant (ka)

  Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability).

  4 weeks

• Rate of CSF Uptake (kPC)

  Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability).

  4 weeks

• CSF to Plasma Ratio (PC)

  Once plasma parameter estimates were finalized, these were fixed and then linked to CSF concentrations via a hypothetical effect compartment with a unidirectional rate of the entry whose rate was described by KPC and an amount, expressed as PC, or a ratio between plasma concentrations and CSF concentrations. Higher values of KPC indicate faster rates of entry, and higher values of PC indicate greater proportions of linezolid entering from the blood into the CSF. Parameters were estimated in NONMEM v7.5 using maximum likelihood estimation (MLE) by optimizing the likelihood function based on observed data. The First Order Conditional Estimation (FOCE) method was employed, which linearizes the model around individual-specific estimates to efficiently account for both fixed effects (population-level parameters) and random effects (individual variability).

  4 weeks

Secondary Outcomes (12)

• Proportion of Participants With Grade 3 or Higher Adverse Events (AE).

  4 weeks

• Proportion of Participants Who Complete LZD Treatment.

  4 weeks

• Modified Rankin Scale (MRS) Performance.

  4, 12 and 24 weeks

• Neurocognitive Battery Performance: Wechsler Adult Intelligence Scale-III Digit Symbol (WAIS-III).

  12 and 24 weeks

• Neurocognitive Battery Performance: Color Trails, Part 1

  12 and 24 weeks

Study Arms (4)

High Dose RIF with LZD

EXPERIMENTAL

Arm 1 participants will receive high dose oral RIF (35mg/kg/day) and LZD 1200 mg daily for the first 4 weeks of therapy, along with standard doses of Isoniazid (INH), Pyrazinamide (PZA), and Ethambutol (EMB). After 4 weeks, LZD will be discontinued and high dose RIF will return to standard dose for the remainder of treatment.

Drug: LZD; Drug: High dose RIF

Standard dose RIF with LZD

EXPERIMENTAL

Arm 2 participants will receive standard dose RIF, INH, PZA, and EMB along with LZD 1200 mg daily. After 4 weeks, LZD will be discontinued.

Drug: LZD; Drug: Standard dose RIF

High Dose RIF

EXPERIMENTAL

Arm 3 participants will receive high dose oral RIF (35mg/kg/day) for the first 4 weeks of therapy, along with standard doses of INH, PZA, and EMB. After 4 weeks, high dose RIF will return to standard dose for the remainder of treatment.

Drug: High dose RIF

Standard Dose RIF

ACTIVE COMPARATOR

Arm 4 participants will receive standard doses of RIF, INH, PZA, and EMB.

Drug: Standard dose RIF

Interventions

LZD DRUG

LZD 1200 mg daily

Also known as: Linezolid

High Dose RIF with LZD; Standard dose RIF with LZD

High dose RIF DRUG

RIF 35 mg/kg/day

High Dose RIF; High Dose RIF with LZD

Standard dose RIF DRUG

RIF 10 mg/kg/day

Standard Dose RIF; Standard dose RIF with LZD

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• \>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

Sponsors & Collaborators

• University of California, San Francisco: lead
• MRC/UVRI and LSHTM Uganda Research Unit: collaborator
• London School of Hygiene and Tropical Medicine: collaborator
• Fogarty International Center of the National Institute of Health: collaborator

Study Sites (1)

Masaka Regional Referral Hospital/MRC UVRI Uganda Research Unit on AIDS

Masaka, Uganda

Location

MeSH Terms

Conditions

Tuberculosis, Meningeal

Interventions

Linezolid; Rifampin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Felicia Chow
• Organization: University of California, San Francisco

felicia.chow@ucsf.edu

(628) 206-4449

Study Officials

• Felicia C Chow, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: June 3, 2019
• First Posted: July 16, 2019
• Study Start: May 5, 2021
• Primary Completion: July 5, 2023
• Study Completion: December 4, 2023
• Last Updated: October 1, 2024
• Results First Posted: October 1, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

UG (1)