Clinical trial NCT01158755: Intensified Treatment Regimens for TB Meningitis: PK, PD and Tolerability Study
Official title: Comparison of Intensive Treatment Regimens and Standard Treatment Regimen for Tuberculous Meningitis: Pharmacokinetics, Pharmacodynamics and Tolerability Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Meningitis, Tuberculous
Pharmacokinetics
Pharmacodynamics
Tolerability
Keywords: Meningitis, tuberculous
Intensified Regimen
PK/PD and tolerability
Outcome
Lead sponsor: Universitas Padjadjaran
Sponsor class: OTHER
Collaborators: name: Radboud University Medical Center
First posted: 2010-07-08
Enrollment: 60
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Rifampicin and Moxifloxacin concentration in plasma and CSF
timeFrame: Plasma drug concentration samplings at 0, 1, 2, 4, 6 and 24h post dose (6 time points). CSF samples at 2 time points.
Secondary outcomes:
measure: Early and late mortality
timeFrame: 1st and 6th month of TB treatment
Other outcomes:
Locations:
city: Bandung
country: Indonesia
facility: Hasan Sadikin General Hospital
state: West Java
Study officials:
affiliation: Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
name: Rovina Ruslami, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Te Brake L, Dian S, Ganiem AR, Ruesen C, Burger D, Donders R, Ruslami R, van Crevel R, Aarnoutse R. Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis. Int J Antimicrob Agents. 2015 May;45(5):496-503. doi: 10.1016/j.ijantimicag.2014.12.027. Epub 2015 Feb 7.
citation: 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.