Intensified Treatment Regimens for TB Meningitis: PK, PD and Tolerability Study
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Meningitis, Tuberculous Pharmacokinetics Pharmacodynamics Tolerability |
Drug: Moxifloxacin |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Factorial Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Comparison of Intensive Treatment Regimens and Standard Treatment Regimen for Tuberculous Meningitis: Pharmacokinetics, Pharmacodynamics and Tolerability Study |
- Rifampicin and Moxifloxacin concentration in plasma and CSF [ Time Frame: Plasma drug concentration samplings at 0, 1, 2, 4, 6 and 24h post dose (6 time points). CSF samples at 2 time points. ] [ Designated as safety issue: Yes ]
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
- Early and late mortality [ Time Frame: 1st and 6th month of TB treatment ] [ Designated as safety issue: No ]We will measure early (within first month of TB treatment) and late (after 6 months of TB treatment) mortality
| Enrollment: | 60 |
| Study Start Date: | October 2010 |
| Study Completion Date: | June 2012 |
| Primary Completion Date: | December 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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 Name: 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 Name: Avelox (r)
|
Eligibility| Ages Eligible for Study: | 15 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations| Indonesia | |
| Hasan Sadikin General Hospital | |
| Bandung, West Java, Indonesia, 40161 | |
| Principal Investigator: | Rovina Ruslami, PhD | Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia |
More Information
No publications provided
| Responsible Party: | Ahmad Rizal Ganiem, MD, Universitas Padjadjaran |
| ClinicalTrials.gov Identifier: | NCT01158755 History of Changes |
| Other Study ID Numbers: | TB-201006.01 |
| Study First Received: | July 7, 2010 |
| Last Updated: | June 6, 2012 |
| Health Authority: | Indonesia: Department Kesehatan (Department of Health) Indonesia: National Agency of Drug and Food Control |
Keywords provided by Universitas Padjadjaran:
|
Meningitis, tuberculous Intensified Regimen PK/PD and tolerability Outcome |
Additional relevant MeSH terms:
|
Meningitis Tuberculosis Tuberculosis, Meningeal Central Nervous System Infections Central Nervous System Diseases Nervous System Diseases Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Meningitis, Bacterial Central Nervous System Bacterial Infections |
Tuberculosis, Central Nervous System Moxifloxacin Norgestimate, ethinyl estradiol drug combination Anti-Infective Agents Therapeutic Uses Pharmacologic Actions Contraceptives, Oral, Combined Contraceptives, Oral Contraceptive Agents, Female Contraceptive Agents Reproductive Control Agents Physiological Effects of Drugs |
ClinicalTrials.gov processed this record on May 22, 2013