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

Pharmacokinetics Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01158755
• Other study ID #: TB-201006.01
• Status: Completed
• Phase: Phase 2
• First received: July 7, 2010
• Last updated: June 6, 2012
• Start date: October 2010
• Est. completion date: June 2012

Study information

• Verified date: June 2012
• Source: Universitas Padjadjaran
• Contact: n/a
• Is FDA regulated: No
• Health authority: Indonesia: Department Kesehatan (Department of Health)Indonesia: National Agency of Drug and Food Control
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: June 2012
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 15 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Meningitis
• Meningitis, Tuberculous
• Pharmacodynamics
• Pharmacokinetics
• Tolerability
• Tuberculosis
• Tuberculosis, Meningeal

Intervention

Drug:
• Moxifloxacin
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)

Locations

Country	Name	City	State
Indonesia	Hasan Sadikin General Hospital	Bandung	West Java

Sponsors (2)

Lead Sponsor	Collaborator
Universitas Padjadjaran	Radboud University

Country where clinical trial is conducted

Indonesia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Yes
Secondary	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	No