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

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

Sponsors

Lead Sponsor: Universitas Padjadjaran

Collaborator: United States Agency for International Development (USAID)
Radboud University

Source Universitas Padjadjaran
Brief Summary

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.

Overall Status Completed
Start Date 2014-12-01
Completion Date 2017-05-05
Primary Completion Date 2016-11-05
Phase Phase 2/Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Rifampicin concentrations in plasma and cerebrospinal fluid (CSF) Day 2 (+/- 1) after administration of study drugs
Secondary Outcome
Measure Time Frame
Rifampicin concentrations in plasma and CSF at steady-state Day 10 (+/- 1) after starting treatment with study drugs
Grade 3 and 4 and serious adverse events Within 60 days
Mortality 180 days
Neurological response Within 60 days
Neuroradiological response 60 days
Resolution of blood and CSF inflammatory response 7 days
Sensitivity of GeneXpert for diagnosing TBM Within 6 weeks
Enrollment 60
Condition
Intervention

Intervention Type: Drug

Intervention Name: Placebo

Description: 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.

Intervention Type: Drug

Intervention Name: Rifampicin

Description: 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

Intervention Type: Drug

Intervention Name: Other TB drugs

Description: 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)

Intervention Type: Drug

Intervention Name: Adjuvant dexamethasone

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

Eligibility

Criteria:

Inclusion Criteria: 1. Male or Female, aged 15 years or above. 2. Clinical suspicion of TBM and CSF/blood glucose ratio < 0.5. 3. None or less than 3 days of anti-tuberculosis chemotherapy taken for the current infection. 4. Patient or representative (if the patient is incapacitated) is willing and able to give informed consent for participation in the study. 5. Willingness to allow storage of specimens. Exclusion Criteria: Patients may not enter the study if any of the following apply: 1. Liver dysfunction (ALT > 5 times upper limit); kidney dysfunction (eGFR < 50 ml/min) 2. Pregnancy or breastfeeding (negative urine pregnancy test for all females of child-bearing age). 3. Confirmed cryptococcus meningitis (LFA), or confirmed bacterial meningitis (microscopy). 4. Rapid clinical deterioration at time of presentation (e.g. signs of sepsis, decreasing consciousness or signs of cerebral oedema, or herniation)

Gender:

All

Minimum Age:

15 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Rovina Ruslami, M.D., PhD Principal Investigator Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia
Location
Facility: Hasan Sadikin General Hospital
Location Countries

Indonesia

Verification Date

2016-12-01

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 3
Arm Group

Label: Rifampicin 450 mg (standard dose)

Type: Active Comparator

Description: 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)

Label: Rifampicin 900 mg per oral

Type: Experimental

Description: 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)

Label: Rifampicin 1350 mg per oral

Type: Experimental

Description: 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)

Acronym ReDEFINe
Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

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