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Pharmacokinetic Study of Linezolid for TB Meningitis (SIMPLE)

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ClinicalTrials.gov Identifier: NCT03537495
Recruitment Status : Not yet recruiting
First Posted : May 25, 2018
Last Update Posted : April 18, 2019
Sponsor:
Collaborators:
Radboud University
Global Alliance for TB Drug Development
Information provided by (Responsible Party):
Ahmad Rizal Ganiem, Universitas Padjadjaran

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.


Condition or disease Intervention/treatment Phase
Tuberculosis, Meningeal Linezolid Drug: Linezolid Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Short Intervention and Measurement of Pharmacokinetics of Linezolid in Tuberculosis Meningitis: a Pharmacokinetics and Safety/Tolerability Study
Estimated Study Start Date : June 2019
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : June 2020


Arm Intervention/treatment
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.
Drug: Linezolid

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.


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.
Drug: Linezolid

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 Outcome Measures :
  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 Outcome Measures :
  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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03537495


Contacts
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Contact: Ahmad R Ganiem, MD, PhD +62 878 2288 3773 ahmad.rizal@unpad.ac.id

Locations
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Indonesia
Hasan Sadikin General Hospital
Bandung, Jawa Barat, Indonesia, 40161
Sponsors and Collaborators
Universitas Padjadjaran
Radboud University
Global Alliance for TB Drug Development
Investigators
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Principal Investigator: Ahmad R Ganiem, MD, PhD Hasan Sadikin General Hospital, Bandung, Indonesia

Publications:
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Responsible Party: Ahmad Rizal Ganiem, MD, PhD, Universitas Padjadjaran
ClinicalTrials.gov Identifier: NCT03537495     History of Changes
Other Study ID Numbers: TB-201805.01
First Posted: May 25, 2018    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ahmad Rizal Ganiem, Universitas Padjadjaran:
tuberculous meningitis
linezolid
pharmacokinetic study

Additional relevant MeSH terms:
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Tuberculosis
Meningitis
Tuberculosis, Meningeal
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Central Nervous System Diseases
Nervous System Diseases
Meningitis, Bacterial
Central Nervous System Bacterial Infections
Tuberculosis, Central Nervous System
Central Nervous System Infections
Linezolid
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action