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

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

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.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics; Pharmacodynamics; Tolerability; Meningitis, Tuberculous
• Intervention / Treatment: Drug: Moxifloxacin

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Indonesia
  • West Java
    • Bandung, West Java, Indonesia, 40161
      • Hasan Sadikin General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Standard dose rifampisin; 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; 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); Other Names: Avelox (r)
EXPERIMENTAL: High dose rifampisin; 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; 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); Other Names: Avelox (r)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Universitas Padjadjaran
• Collaborators: Radboud University Medical Center
• Investigators: Principal Investigator: Rovina Ruslami, PhD, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (ACTUAL): December 1, 2011
• Study Completion (ACTUAL): June 1, 2012

Study Registration Dates

• First Submitted: July 7, 2010
• First Submitted That Met QC Criteria: July 7, 2010
• First Posted (ESTIMATE): July 8, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): June 7, 2012
• Last Update Submitted That Met QC Criteria: June 6, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: Outcome; Meningitis, tuberculous; Intensified Regimen; PK/PD and tolerability
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis, Central Nervous System; Tuberculosis; Meningitis; Tuberculosis, Meningeal; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Moxifloxacin
• Other Study ID Numbers: TB-201006.01