High-dose Rifampicin for the Treatment of Tuberculous Meningitis: a Dose-finding Study (ReDEFINe)
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ClinicalTrials.gov Identifier: NCT02169882 |
Recruitment Status :
Completed
First Posted : June 23, 2014
Last Update Posted : June 1, 2017
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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:
- 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.
- 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
- 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.
- There is a need to explore relevant treatment endpoints besides mortality including neurological, neuroradiological and inflammatory response.
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Tuberculosis, Meningeal | Drug: Placebo Drug: Rifampicin Drug: Other TB drugs Drug: Adjuvant dexamethasone | Phase 2 Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 60 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
Primary Purpose: | Treatment |
Official 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 |
Actual Study Start Date : | December 1, 2014 |
Actual Primary Completion Date : | November 5, 2016 |
Actual Study Completion Date : | May 5, 2017 |

Arm | Intervention/treatment |
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Active Comparator: Rifampicin 450 mg (standard dose)
Twenty patients will receive 1 tablet of 450 mg Rifampicin and 2 tablets of placebo once daily for 30 days. Unconscious subjects will receive oral drugs via nasogastric tubes (NGT). After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin. 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. Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission) |
Drug: Placebo
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. Drug: Other TB drugs 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) Drug: Adjuvant dexamethasone Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission) |
Experimental: Rifampicin 900 mg per oral
Twenty patients will receive 2 tablets of 450 mg Rifampicin and 1 tablet of placebo once daily for 30 days. Unconscious subjects will receive oral drugs via nasogastric tubes (NGT) After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin. 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. Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission) |
Drug: Placebo
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. Drug: Rifampicin 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 Name: Rifampisin - Kimia Farma Drug: Other TB drugs 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) Drug: Adjuvant dexamethasone Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission) |
Experimental: Rifampicin 1350 mg per oral
Twenty patients will receive 3 tablets of 450 mg Rifampicin and 0 tablet of placebo once daily for 30 days. Unconscious subjects will receive oral drugs via nasogastric tubes (NGT) After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin. 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. Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission) |
Drug: Rifampicin
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 Name: Rifampisin - Kimia Farma Drug: Other TB drugs 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) Drug: Adjuvant dexamethasone Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission) |
- 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.
- 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.
- 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
- Mortality [ Time Frame: 180 days ]
- 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.
- 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
- Resolution of blood and CSF inflammatory response [ Time Frame: 7 days ]Inflammatory response will be measured at day 0 and day 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.

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Ages Eligible for Study: | 15 Years and older (Child, Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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)

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02169882
Indonesia | |
Hasan Sadikin General Hospital | |
Bandung, Jawa Barat, Indonesia, 40161 |
Principal Investigator: | Rovina Ruslami, M.D., PhD | Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | Universitas Padjadjaran |
ClinicalTrials.gov Identifier: | NCT02169882 |
Other Study ID Numbers: |
TB-201406.01 PGA-2000003601 ( Other Identifier: PEER Health ) |
First Posted: | June 23, 2014 Key Record Dates |
Last Update Posted: | June 1, 2017 |
Last Verified: | December 2016 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Tuberculous meningitis Rifampicin Dose finding study Pharmacokinetics |
Tuberculosis Meningococcal Infections Tuberculosis, Meningeal Meningitis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Central Nervous System Diseases Nervous System Diseases Neisseriaceae Infections Gram-Negative Bacterial Infections Meningitis, Bacterial Central Nervous System Bacterial Infections Tuberculosis, Central Nervous System |
Central Nervous System Infections Rifampin Dexamethasone Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs Gastrointestinal Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Antineoplastic Agents, Hormonal Antineoplastic Agents Antibiotics, Antitubercular |