Intensified Treatment Regimens for TB Meningitis: PK, PD and Tolerability Study

Study Overview
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Brief Summary
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Tuberculous meningitis (TBM) is the most lethal form of tuberculosis infection, and is diagnosed in approximately 5-10% of TB patients. The incidence of TBM has increased considerably during the last decade, partly due to the HIV epidemic. Without treatment, virtually all patients with TB meningitis will die. With the current treatment regimens, TBM is fatal in approximately 30-50% of cases, and responsible for severe disability in a similar proportion of survivors. Worldwide, Indonesia the third highest case load of tuberculosis with an estimated 500,000 new patients / year. Representative data are lacking, but it is clear that TBM is a growing problem. For instance, in Hasan Sadikin Hospital, the top-referral hospital for West Java Province (population 40 million), Indonesia, 40-50 cases of TBM were treated yearly in the late 90's compared to approximately 100 in recent years. There is very little evidence for the current treatment regimen for TBM, which dates back to the late 60's. Therefore, there is an urgent need to evaluate intensified treatment of TBM in randomized trials. We hypothesize that higher dose rifampicin, moxifloxacin (possibly also at high dose), or both will improve outcome of TBM. To determine the experimental regimen(s) which should be compared with current regimen in phase 3 trials, we want to evaluate pharmacokinetic aspects and toxicity of candidate regimens in a phase 2 clinical trial in 60 patients with TBM in Indonesia.

Official Title
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Comparison of Intensive Treatment Regimens and Standard Treatment Regimen for Tuberculous Meningitis: Pharmacokinetics, Pharmacodynamics and Tolerability Study

Conditions
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Meningitis, Tuberculous, Pharmacokinetics, Pharmacodynamics, Tolerability

Intervention / Treatment
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* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Tuberculous meningitis, diagnosed based on clinical and/or CSF criteria Age 15 years old or more Hospitalized for the treatment Exclusion Criteria: Pregnancy/lactation On TB treatment within 7 days before inclusion Elevated liver enzyme (> 5x than normal values) Known hypersensitivity/intolerance to rifampicin or moxifloxacin Prolonged QTc interval in ECG or other detectable cardiac arrythmias, in the absence of hypokalemia Refusal to be included in the study

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard dose rifampisin<br>Subjects in this arm receive 450 mg rifampicin orally. In accordance with national TB treatment standard that encourages the use of 4 drugs, all subjects -both in active comparator and experimental arm- will also receive isoniazide 300 mg p.o. and pyrazinamide 1500 mg p.o. Unconscious subjects will receive oral drugs via nasogastric tubes (NGT) | Drug: Moxifloxacin<br>* Subjects on both arms will further be randomized into receiving moxifloxacin either in standard dose (400 mg p.o.), high dose (800 mg p.o.) of moxifloxacin, or not receiving moxifloxacin (ethambutol 750 mg p.o., instead) Intervention drug will be given for 14 days, and the drug will be switched to ethambutol 750 mg p.o. (in accordance with National TB Program)<br>* Other names: Avelox (r);|
| Experimental: High dose rifampisin<br>Subjects in this arm receive 600 mg Rifampisin i.v. for 14 days, and the dosage will be switched to 450 mg Rifampisin p.o afterwards until completion of TB medication (in accordance with National TB Program) In accordance with national TB treatment standard that encourages the use of 4 drugs, all subjects -both in active comparator and experimental arm- will also receive isoniazide 300 mg p.o. and pyrazinamide 1500 mg p.o. Unconscious subjects will receive oral drugs via nasogastric tubes (NGT) | Drug: Moxifloxacin<br>* Subjects on both arms will further be randomized into receiving moxifloxacin either in standard dose (400 mg p.o.), high dose (800 mg p.o.) of moxifloxacin, or not receiving moxifloxacin (ethambutol 750 mg p.o., instead) Intervention drug will be given for 14 days, and the drug will be switched to ethambutol 750 mg p.o. (in accordance with National TB Program)<br>* Other names: Avelox (r);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rifampicin and Moxifloxacin concentration in plasma and CSF | On sampling day (one of the first 3 days of hospitalization), we will measure plasma and CSF drug concentration at several time points. Plasma drug concentration will be measured at 6 time points (hour 0, 1, 2, 4, 6 and 12). CSF drug concentration at 2 time points: (1) hour 3-6 post dose on the same blood sampling day and (2) within 5 days after the 1st day of TB drug administration, 1-3 hours after drug intake | Plasma drug concentration samplings at 0, 1, 2, 4, 6 and 24h post dose (6 time points). CSF samples at 2 time points. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early and late mortality | We will measure early (within first month of TB treatment) and late (after 6 months of TB treatment) mortality | 1st and 6th month of TB treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Meningitis, tuberculous, Intensified Regimen, PK/PD and tolerability, Outcome