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

NCT ID: NCT01158755

Last Updated: 2012-06-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-10-31
• Study Completion Date: 2012-06-30

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.

Conditions

Meningitis, Tuberculous; Pharmacokinetics; Pharmacodynamics; Tolerability

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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)

Group Type: ACTIVE_COMPARATOR

Moxifloxacin

Intervention Type: DRUG

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)

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)

Group Type: EXPERIMENTAL

Moxifloxacin

Intervention Type: DRUG

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)

Interventions

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)

Intervention Type: DRUG

Other Intervention Names

Avelox (r)

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

• Minimum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: collaborator

Universitas Padjadjaran

OTHER

Sponsor Role: lead

Responsible Party

Ahmad Rizal Ganiem

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Rovina Ruslami, PhD

Role: PRINCIPAL_INVESTIGATOR

Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia

Locations

Hasan Sadikin General Hospital

Bandung, West Java, Indonesia

Countries

Indonesia

References

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.

Reference Type: DERIVED

PMID: 25703312 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23103177 (View on PubMed)

Other Identifiers

TB-201006.01

Identifier Type: -

Identifier Source: org_study_id