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Tuberculosis, MeningealPhase 2SIMPLENCT03537495

Pharmacokinetic Study of Linezolid for TB Meningitis

A Phase 2 study testing Linezolid in people with Tuberculosis, Meningeal and Linezolid, run by Universitas Padjadjaran at 1 site in Indonesia.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Tuberculosis, Meningeal, Linezolid
What is being tested?
Linezolid
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
36 participants
Where
1 siteIndonesia
Study dates
21 Jun 2021to 20 Jul 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 12Show fewer
  • 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)

Trial locations and contacts

1 site in 1 country.

Indonesia1 site

  • Hasan Sadikin General Hospital

    Bandung, West Java, 40161

Other trials in Indonesia

About this study

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

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.

Read more

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.

Read the 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.

Being tested
Linezolid
Keywords
tuberculous meningitis, linezolid, pharmacokinetic study
Medical subject headings
Tuberculosis, Meningeal

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LinezolidDrug

    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.

Study groups in NCT03537495
Study groupRoleWhat they receive
Control armNo interventionSubjects 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 600ExperimentalSubjects 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.
Receives: Drug: Linezolid
Linezolid 1200ExperimentalSubjects 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.
Receives: Drug: Linezolid

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: day 2 and day 11

Secondary outcomes (6)

  1. Serious adverse event

    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.

    Measured: Day 3, 7, 10 and 14

  2. Clinical response

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

    Measured: Day 3, 7 and 14.

  3. Neurological response

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

    Measured: Day 3, 7 and 14.

  4. Mortality

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

    Measured: Within 14 days and 1 month after starting treatment

  5. Blood inflammatory response

    Profile of inflammatory response in blood

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

  6. CSF inflammatory response

    inflammatory response in CSF at PK sampling days

    Measured: at PK sampling days (day 2 and 11)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 May 2018
  2. Study start21 Jun 2021
  3. Primary completion1 Mar 2023
  4. Study completion20 Jul 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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)
Enrolment
36 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03537495
Sponsor's protocol ID
TB-201805.01
Acronym
SIMPLE
Status last verified
Sep 2023
First submitted
2 May 2018
Last updated
6 Sep 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 23103177

  • 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.

    PubMed 30224533

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Linezolid in people with Tuberculosis, Meningeal and Linezolid, run by Universitas Padjadjaran at 1 site in Indonesia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Indonesia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Linezolid exposure in blood and CSF (time frame: day 2 and day 11). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03537495, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Sep 2023.

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