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

This study has been completed.
Sponsor:
Collaborator:
Radboud University
Information provided by (Responsible Party):
Ahmad Rizal Ganiem, Universitas Padjadjaran
ClinicalTrials.gov Identifier:
NCT01158755
First received: July 7, 2010
Last updated: June 6, 2012
Last verified: June 2012
  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

Resource links provided by NLM:


Further study details as provided by Universitas Padjadjaran:

Primary Outcome Measures:
  • 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



Secondary Outcome Measures:
  • 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
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01158755

Locations
Indonesia
Hasan Sadikin General Hospital
Bandung, West Java, Indonesia, 40161
Sponsors and Collaborators
Universitas Padjadjaran
Radboud University
Investigators
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
Meningitis, Bacterial
Tuberculosis
Tuberculosis, Meningeal
Central Nervous System Infections
Central Nervous System Diseases
Nervous System Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Central Nervous System Bacterial Infections
Tuberculosis, Central Nervous System
Moxifloxacin
Norgestimate, ethinyl estradiol drug combination
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 16, 2014