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

Phase 2

Completed

• Conditions: Meningitis, Tuberculous; Pharmacokinetics; Pharmacodynamics; Tolerability
• Interventions: Drug: Moxifloxacin

• Registration Number: NCT01158755
• Lead Sponsor: Universitas Padjadjaran

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2010-07-07
• Study First Submitted QC: 2010-07-07
• Study First Posted: 2010-07-08
• Study Start: 2010-10
• Primary Completion: 2011-12
• Status Verified: 2012-06
• Study Completion: 2012-06
• Last Update Submitted: 2012-06-06
• Last Update Posted: 2012-06-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Tuberculous meningitis, diagnosed based on clinical and/or CSF criteria
• Age 15 years old or more
• Hospitalized for the treatment

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
High dose rifampisin	Moxifloxacin	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)
Standard dose rifampisin	Moxifloxacin	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)

Primary Outcome Measures

Name	Time	Method
Rifampicin and Moxifloxacin concentration in plasma and CSF	Plasma drug concentration samplings at 0, 1, 2, 4, 6 and 24h post dose (6 time points). CSF samples at 2 time points.	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

Secondary Outcome Measures

Name	Time	Method
Early and late mortality	1st and 6th month of TB treatment	We will measure early (within first month of TB treatment) and late (after 6 months of TB treatment) mortality

Trial Locations

Locations (1)

Hasan Sadikin General Hospital; 🇮🇩 Bandung, West Java, Indonesia