Pharmacokinetic Study of Linezolid for TB Meningitis

Watumiaji waliosajiliwa tu ndio wanaweza kutafsiri nakala

Ingia / Ingia

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HaliBado kuajiri

Wadhamini

Universitas Padjadjaran

Washirika

Radboud University

Global Alliance for TB Drug Development

JARIBIO LA KLINIKI: NCT03537495

BioSeek: nct03537495

Maneno muhimu

Kikemikali

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.

Maelezo

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.

Tarehe

Imethibitishwa Mwisho:	06/30/2020
Iliyowasilishwa Kwanza:	05/01/2018
Uandikishaji uliokadiriwa Uliwasilishwa:	05/13/2018
Iliyotumwa Kwanza:	05/24/2018
Sasisho la Mwisho Liliwasilishwa:	07/01/2020
Sasisho la Mwisho Lilichapishwa:	07/06/2020
Tarehe halisi ya kuanza kwa masomo:	07/31/2020
Tarehe ya Kukamilisha Msingi iliyokadiriwa:	12/31/2020
Tarehe ya Kukamilisha Utafiti:	03/31/2021

Hali au ugonjwa

Tuberculosis, Meningeal

Linezolid

Uingiliaji / matibabu

Drug: Linezolid

Awamu

Awamu 2

Vikundi vya Arm

Mkono	Uingiliaji / matibabu
No Intervention: Control arm 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.
Experimental: Linezolid 600 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.
Experimental: Linezolid 1200 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.

Vigezo vya Kustahiki

Zama zinazostahiki Kujifunza	18 Years Kwa 18 Years
Jinsia Inastahiki Kujifunza	All
Hupokea Wajitolea wa Afya	Ndio
Vigezo	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)

Matokeo

Hatua za Matokeo ya Msingi

1. Linezolid exposure in blood and CSF [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.

Hatua za Matokeo ya Sekondari

1. Serious adverse event [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 [Day 3, 7 and 14.]

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

3. Neurological response [Day 3, 7 and 14.]

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

4. Mortality [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 [at PK days (day 2 and 11), and day 7 and 14]

Profile of inflammatory response in blood

6. CSF inflammatory response [at PK sampling days (day 2 and 11)]

inflammatory response in CSF at PK sampling days

Pharmacokinetic Study of Linezolid for TB Meningitis

Maneno muhimu

kifua kikuu

meningitis

antibacterial

antibaotiki