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Completed

NCT Number: NCT03537495

Pharmacokinetic Study of Linezolid for TB Meningitis

Tuberculosis meningitis (TBM) is the most severe manifestation of TB, resulting in death or neurological disability in up to 50% of affected patients, despite antibacterial treatment. This TBM treatment follows the model for pulmonary TB by using the same first-line TB drugs (a combination of rifampicin, isoniazid, pyrazinamide and ethambutol) and the same dosing guidelines, although it is known that penetration of two of these drugs (rifampicin and ethambutol) into cerebrospinal fluid (CSF) is limited. Improvement of treatment of TBM is urgently needed.

To do so, a combination of two interventions will be investigated in this study. A series of phase II clinical trials on higher doses of the pivotal TB drug rifampicin in Indonesian patients with TBM have shown that the dose of rifampicin can be increased from 10 mg/kg orally (standard dose) up to 30 mg/kg orally, resulting in a strong increase in exposure to this drug in plasma and CSF, no increase in grade III or IV adverse effects, and a reduction in mortality. Similarly, higher doses of rifampicin up to 35 mg/kg resulted in strong increases in plasma concentrations; the doses were well tolerated and reduced time to sputum conversion in African pulmonary TB patients.

Next to a higher dose of rifampicin, the approved antibacterial drug linezolid seems a good candidate for a new TBM regimen. The drug penetrates well into the CSF and is applied successfully against other central nervous system (CNS) infections (e.g. caused by penicillin-nonsusceptible Streptococcus pneumoniae, vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus). In a study in China, linezolid in a dose of 600 mg BID orally strongly increased recovery of patients with TBM response. Linezolid is also being investigated as a new drug for (drug-resistant) pulmonary TB in numerous studies, in a dose of 1200 mg once daily. More severe adverse effects to this drug typically occur only after prolonged treatment during several months, not during short-term treatment.

Overall, linezolid is expected to be a promising and tolerable candidate for a new intensified TBM treatment regimen consisting of a backbone of high dose rifampicin plus linezolid.

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Key information

Conditions

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

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Hasan Sadikin General Hospital

Bandung, West Java, 40161, Indonesia

About this study

Overall aim is to determine the most appropriate dose of linezolid in the treatment of TB meningitis, when combined with high-dose rifampicin (35 mg/kg orally), to be tested in larger clinical follow-up studies.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age: 18 years old or older
  • Clinically diagnosed as TB meningitis patient
  • CSF/blood glucose ratio < 0.5
  • Willing to participate in the study by signing informed consent

Exclusion criteria

Patients who have one of the following criteria will be excluded:

  • Failure to diagnostic lumbar puncture
  • Confirmed cryptococcus meningitis (LFA) in HIV-positive patients; or diagnosed as bacterial meningitis based on clinical assessment and routine CSF examination.
  • Treatment for tuberculosis for more than 3 days before admission
  • History of TBM
  • Current treatment with: MAO inhibitors, direct and indirect acting sympathomimetic drugs, vasopressive drugs, dopaminergic compounds, buspiron, serotonin reuptake inhibitors, tricyclic antidepressants, triptans, tramadol and meperidine
  • History (< 2 weeks before start of linezolid) of taking any MAO inhibitors
  • Pregnant or lactating females
  • Hepatic insufficiency (ALT>5x upper normal limit)
  • Kidney dysfunction (eGFR <50ml/min)
  • Known hypersensitivity to rifampicin and/or linezolid
  • Rapid clinical deterioration at time of presentation (sepsis, decreasing consciousness, or signs of cerebral oedema or herniation)

Treatment and study plan

Linezolid

Drug

Overall, there is an urgent need for improvement of TBM treatment. LInezolid is known to be well-penetrated to blood brain barrier. A combination of high-dose rifampicin and linezolid as an intensified add-on therapy in the management of TB meningitis has never been studied.

The goal is to assess the most appropriate dose of linezolid for larger follow-up studies and to evaluate the feasibility of a linezolid-containing TBM regimen.

Primary outcomes

  1. Linezolid exposure in blood and CSF

    Time frame: day 2 and day 11

    Linezolid exposure in blood (full plasma concentration-versus-time profiles (0-24h)) will be measured in 2 days, i.e. day 2 (+/- 1) and at day 11 (+/- 1) of TB treatment. In each sampling day, there will be 6 sampling points i.e. at 0 (pre-dose), 1, 2, 4, 8, and 12 h after study medication intake

    One CSF sample per patient will be taken at the same day as PK sampling i.e. at 2, 4 or 8 hours post dose.

Secondary outcomes

  1. Serious adverse event

    Time frame: Day 3, 7, 10 and 14

    Serious adverse events assessed daily during the 14 days of intensified treatment (e.g. gastro-intestinal intolerance), and grade 1-4 adverse events (e.g. liver function and hematology) assessed at day 3, 7, 10 and 14.

  2. Clinical response

    Time frame: Day 3, 7 and 14.

    Clinical response includes resolution of fever, resolution of hyponatremia etc.

  3. Neurological response

    Time frame: Day 3, 7 and 14.

    Neurological response includes resolution of consciousness, development of raised intracranial pressure, etc.

  4. Mortality

    Time frame: Within 14 days and 1 month after starting treatment

    mortality during the first month will be recorded and cause of death will be classified as neurologic or non-neurologic, if applicable

  5. Blood inflammatory response

    Time frame: at PK days (day 2 and 11), and day 7 and 14

    Profile of inflammatory response in blood

  6. CSF inflammatory response

    Time frame: at PK sampling days (day 2 and 11)

    inflammatory response in CSF at PK sampling days

Sponsors and collaborators

Lead sponsor

Universitas Padjadjaran

Other

Collaborators

  • Global Alliance for TB Drug Development
  • Radboud University Medical Center

Registry information

Official study title

Short Intervention and Measurement of Pharmacokinetics of Linezolid in Tuberculosis Meningitis: a Pharmacokinetics and Safety/Tolerability Study

Acronym: SIMPLE

Important dates

Study start
2021
Primary completion
2023
Study completion
2023
First posted
May 25, 2018
Registry last updated
Sep 6, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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