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NCT Number: NCT02169882

High-dose Rifampicin for the Treatment of Tuberculous Meningitis: a Dose-finding Study

Tuberculous meningitis (TBM) is the most severe form of tuberculosis infection with high mortality. Current treatment regimens are not based on clinical trials. Rifampicin is a key drug for TBM, but its penetration into the brain is limited, suggesting that a higher dose may be more effective.

There are several highly relevant, outstanding questions related to the appropriate dose of rifampicin for TBM, before a multicenter phase 3 trial can be performed. These are:

1. Previous phase 2a randomized clinical trial (done in the same setting as this proposed study) suggests that high doses of intravenous rifampicin (600mg, circa 13 mg/mg) for TBM is safe and associated with a survival benefit in adults. Given that i.v. rifampicin is not readily available, this needs to be confirmed using an equivalent higher oral dose of rifampicin. 2. Recent pharmacokinetic analysis of a continuation trial comparing 600 mg i.v. rifampicin with 750 mg and 900 mg oral rifampicin suggests that an even higher dose may be needed; but this has not been examined 3. Based on those previous data, there is a need to explore a longer duration of high-dose rifampicin for a subsequent phase 3 randomized clinical trial; treatment response in the investigators previous trial suggest that the optimal duration may be > 14 days. 4. There is a need to explore relevant treatment endpoints besides mortality including neurological, neuroradiological and inflammatory response.

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Key information

Conditions

Tuberculosis, Meningeal Actinomycetales Infections Bacterial Infections Bacterial Infections and Mycoses Central Nervous System Bacterial Infections Central Nervous System Diseases Central Nervous System Infections Gram-Positive Bacterial Infections Infections Meningitis Meningitis, Bacterial Mycobacterium Infections Nervous System Diseases Neuroinflammatory Diseases Tuberculosis Tuberculosis, Central Nervous System Tuberculosis, Extrapulmonary

Age range

15 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Hasan Sadikin General Hospital

Bandung, West Java, 40161, Indonesia

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Male or Female, aged 15 years or above.
  • Clinical suspicion of TBM and CSF/blood glucose ratio < 0.5.
  • None or less than 3 days of anti-tuberculosis chemotherapy taken for the current infection.
  • Patient or representative (if the patient is incapacitated) is willing and able to give informed consent for participation in the study.
  • Willingness to allow storage of specimens.

Exclusion criteria

Patients may not enter the study if any of the following apply:

  • Liver dysfunction (ALT > 5 times upper limit); kidney dysfunction (eGFR < 50 ml/min)
  • Pregnancy or breastfeeding (negative urine pregnancy test for all females of child-bearing age).
  • Confirmed cryptococcus meningitis (LFA), or confirmed bacterial meningitis (microscopy).
  • Rapid clinical deterioration at time of presentation (e.g. signs of sepsis, decreasing consciousness or signs of cerebral oedema, or herniation)

Treatment and study plan

Placebo

Drug

Patients receiving 450 mg rifampicin will receive additional 2 placebo tablets, while those who receive 900 mg rifampicin will receive 1 placebo tablet.

Patients receiving 1350 mg rifampicin will not receive any placebo tablet.

With this arrangement, every subject will receive 3 tablets of study drugs.

rifampicin

Drug

Patients in experimental arms will receive either 1 or 2 additional tablets of rifampicin.

Placebo tablets will be added accordingly, so that every study subject will receive 3 tablets of rifampicin plus placebo as described in the Arms section.

Other names: Rifampisin - Kimia Farma

Other TB drugs

Drug

Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.

Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)

Adjuvant dexamethasone

Drug

Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Primary outcomes

  1. Rifampicin concentrations in plasma and cerebrospinal fluid (CSF)

    Time frame: Day 2 (+/- 1) after administration of study drugs

    The rifampicin concentrations in plasma are measured from blood samples that are obtained by intensive pharmacokinetic sampling at 6 sampling time points (h0, 1, 2, 4, 8, 12 post dose). CSF rifampicin concentration will be measured using CSF sample taken by means of lumbar puncture at hour 3-6 post dose at the same day of blood sampling.

Secondary outcomes

  1. Rifampicin concentrations in plasma and CSF at steady-state

    Time frame: Day 10 (+/- 1) after starting treatment with study drugs

    The rifampicin concentrations in plasma are measured from blood samples that are obtained by intensive pharmacokinetic sampling at 6 sampling time points (h0, 1, 2, 4, 8, 12 post dose). CSF rifampicin concentration will be measured using CSF sample taken by means of lumbar puncture at hour 3-6 post dose at the same day of blood sampling.

  2. Grade 3 and 4 and serious adverse events

    Time frame: Within 60 days

    Determined by measurement of liver function, hematology, gastrointestinal intolerance and hypersensitivity at days 3, 7, 10, 14, 30, 45, and 60

  3. Mortality

    Time frame: 180 days

  4. Neurological response

    Time frame: Within 60 days

    Neurological responses that show both improvement (e.g. time to resolution of comma, time to fever resolution) and worsening (time to development of neurological deficits) will be measured and recorded at days 3, 7, 30 and 60.

  5. Neuroradiological response

    Time frame: 60 days

    Development of infarction or other complication of TBM will documented by performing and comparing brain MRIs that will be done within the first 5 day and 60 day (+/- 5 days) after randomization

  6. Resolution of blood and CSF inflammatory response

    Time frame: 7 days

    Inflammatory response will be measured at day 0 and day 7

  7. Sensitivity of GeneXpert for diagnosing TBM

    Time frame: Within 6 weeks

    Every CSF sample from patients who come with suspicion of TBM will be inoculated in GeneXpert cartridge and standard culture measures (MODS), and the result will be compared.

Sponsors and collaborators

Lead sponsor

Universitas Padjadjaran

Other

Collaborators

  • Radboud University Medical Center
  • United States Agency for International Development (USAID)

Registry information

Official study title

A Randomized Double Blinded Phase 2b Clinical Trial Comparing Standard Dose With Two Higher Doses of Rifampicin for Treatment of Adults With Tuberculous Meningitis

Acronym: ReDEFINe

Important dates

Study start
2014
Primary completion
2016
Study completion
2017
First posted
Jun 23, 2014
Registry last updated
Jun 1, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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