Adjunctive Linezolid for the Treatment of Tuberculous Meningitis

NCT ID: NCT04021121

Last Updated: 2024-10-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-05
• Study Completion Date: 2023-12-04

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

High Dose RIF with LZD

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.

Group Type: EXPERIMENTAL

LZD

Intervention Type: DRUG

LZD 1200 mg daily

High dose RIF

Intervention Type: DRUG

RIF 35 mg/kg/day

Standard dose RIF with LZD

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.

Group Type: EXPERIMENTAL

LZD

Intervention Type: DRUG

LZD 1200 mg daily

Standard dose RIF

Intervention Type: DRUG

RIF 10 mg/kg/day

High Dose RIF

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.

Group Type: EXPERIMENTAL

High dose RIF

Intervention Type: DRUG

RIF 35 mg/kg/day

Standard Dose RIF

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

Group Type: ACTIVE_COMPARATOR

Standard dose RIF

Intervention Type: DRUG

RIF 10 mg/kg/day

Interventions

LZD

LZD 1200 mg daily

Intervention Type: DRUG

High dose RIF

RIF 35 mg/kg/day

Intervention Type: DRUG

Standard dose RIF

RIF 10 mg/kg/day

Intervention Type: DRUG

Other Intervention Names

Linezolid

Eligibility Criteria

Inclusion Criteria

1. Age > 18 years

2. Written informed consent from participant or proxy

3. 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

1. >5 doses of TB treatment received within previous 5 days

2. Discontinued TB treatment in prior 14 days

3. Known current/previous drug resistant TB infection

4. Known allergy to RIF, INH, PZA, EMB, LZD

5. Previous treatment of TB or TBM with LZD

6. 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)

7. 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.

8. Unwillingness to be an inpatient for 2 weeks for initial treatment or to attend follow up clinic visits

9. Lack of informed consent from participant or next of kin/caregiver

10. 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.

11. 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).

12. 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

MRC/UVRI and LSHTM Uganda Research Unit

OTHER

Sponsor Role: collaborator

London School of Hygiene and Tropical Medicine

OTHER

Sponsor Role: collaborator

Fogarty International Center of the National Institute of Health

NIH

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Felicia C Chow, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

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

Masaka, , Uganda

Countries

Uganda

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

R21TW011035

Identifier Type: NIH

Identifier Source: secondary_id

View Link

18-26068

Identifier Type: -

Identifier Source: org_study_id