Clinical trial NCT03537495: Pharmacokinetic Study of Linezolid for TB Meningitis
Official title: Short Intervention and Measurement of Pharmacokinetics of Linezolid in Tuberculosis Meningitis: a Pharmacokinetics and Safety/Tolerability Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis, Meningeal
Linezolid
Keywords: tuberculous meningitis
linezolid
pharmacokinetic study
Lead sponsor: Universitas Padjadjaran
Sponsor class: OTHER
Collaborators: name: Radboud University Medical Center
name: Global Alliance for TB Drug Development
First posted: 2018-05-25
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Detailed description: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Linezolid exposure in blood and CSF
timeFrame: day 2 and day 11
Secondary outcomes:
measure: Serious adverse event
timeFrame: Day 3, 7, 10 and 14
measure: Clinical response
timeFrame: Day 3, 7 and 14.
measure: Neurological response
timeFrame: Day 3, 7 and 14.
measure: Mortality
timeFrame: Within 14 days and 1 month after starting treatment
measure: Blood inflammatory response
timeFrame: at PK days (day 2 and 11), and day 7 and 14
measure: CSF inflammatory response
timeFrame: at PK sampling days (day 2 and 11)
Other outcomes:
Locations:
city: Bandung
country: Indonesia
facility: Hasan Sadikin General Hospital
state: Jawa Barat
Study officials:
affiliation: Hasan Sadikin General Hospital, Bandung, Indonesia
name: Ahmad R Ganiem, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.