Pharmacokinetic Study of Linezolid for TB Meningitis

NCT03537495 | Completed Phase 2

• 1 other identifier: TB-201805.01
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Tuberculosis, Meningeal; Linezolid

Keywords

tuberculous meningitis; linezolid; pharmacokinetic study

Outcome Measures

Primary Outcomes (1)

• Linezolid exposure in blood and CSF

  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.

  day 2 and day 11

Secondary Outcomes (6)

• Serious adverse event

  Day 3, 7, 10 and 14

• Clinical response

  Day 3, 7 and 14.

• Neurological response

  Day 3, 7 and 14.

• Mortality

  Within 14 days and 1 month after starting treatment

• Blood inflammatory response

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

Study Arms (3)

Control arm

NO INTERVENTION

Subjects in this arm will only receive high-dose rifampicin (\~35 mg/kg, based on weight), isoniazid (H) 300 mg, pyrazinamide (Z) 1500 mg and ethambutol (E) 750 mg once daily administered orally for 14 days. High-dose rifampicin will consist of weight-banded fixed-dose combination (FDC), including rifampicin (R), isoniazid (H), pyrazinamide (Z) and ethambutol (E) according to international guidelines, combined with 900 mg rifampicin (≤37 kg: two 450 mg tablets) or 1200 mg rifampicin (\>37 kg: two 600 mg tablets) to reach \~35 mg/kg rifampicin in total.

Linezolid 600

EXPERIMENTAL

Subjects in this arm will receive 600 mg linezolid QD along with high-dose rifampicin (\~35 mg/kg, based on weight), isoniazid (H) 300 mg, pyrazinamide (Z) 1500 mg and ethambutol (E) 750 mg once daily administered orally for 14 days.

Drug: Linezolid

Linezolid 1200

EXPERIMENTAL

Subjects in this arm will receive 1200 mg linezolid QD along with rifampicin 1350 mg (\~35 mg/kg, based on weight), isoniazid (H) 300 mg, pyrazinamide (Z) 1500 mg and ethambutol (E) 750 mg once daily administered orally for 14 days.

Drug: Linezolid

Interventions

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.

Linezolid 1200; Linezolid 600

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 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Universitas Padjadjaran: lead
• Radboud University Medical Center: collaborator
• Global Alliance for TB Drug Development: collaborator

Study Sites (1)

Hasan Sadikin General Hospital

Bandung, West Java, 40161, Indonesia

Location

Related Publications (2)

• Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, Borm G, Aarnoutse RE, van Crevel R. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis. 2013 Jan;13(1):27-35. doi: 10.1016/S1473-3099(12)70264-5. Epub 2012 Oct 25.

  PMID: 23103177 BACKGROUND

• Dian S, Yunivita V, Ganiem AR, Pramaesya T, Chaidir L, Wahyudi K, Achmad TH, Colbers A, Te Brake L, van Crevel R, Ruslami R, Aarnoutse R. Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis. Antimicrob Agents Chemother. 2018 Nov 26;62(12):e01014-18. doi: 10.1128/AAC.01014-18. Print 2018 Dec.

  PMID: 30224533 BACKGROUND

MeSH Terms

Conditions

Tuberculosis, Meningeal

Interventions

Linezolid

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

Study Officials

• Ahmad R Ganiem, MD, PhD

  Hasan Sadikin General Hospital, Bandung, Indonesia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Model Details: TB meningitis patients will be randomised into three treatment groups to either receive no linezolid (control group); or 600 mg QD or 1200 mg QD linezolid next to high dose rifampicin (\~35 mg/kg, based on weight), isoniazid (H) 300 mg, pyrazinamide (Z) 1500 mg and ethambutol (E) 750 mg once daily administered orally for 14 days. All patients will receive dexamethasone according to standard dosing in TBM.

Study Record Dates

• First Submitted: May 2, 2018
• First Posted: May 25, 2018
• Study Start: June 21, 2021
• Primary Completion: March 1, 2023
• Study Completion: July 20, 2023
• Last Updated: September 6, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

ID (1)