Clinical trial NCT02169882: High-dose Rifampicin for the Treatment of Tuberculous Meningitis: a Dose-finding Study
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Tuberculosis, Meningeal
Keywords: Tuberculous meningitis
Rifampicin
Dose finding study
Pharmacokinetics
Lead sponsor: Universitas Padjadjaran
Sponsor class: OTHER
Collaborators: name: United States Agency for International Development (USAID)
name: Radboud University Medical Center
First posted: 2014-06-23
Enrollment: 60
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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)

Primary outcomes:
measure: Rifampicin concentrations in plasma and cerebrospinal fluid (CSF)
timeFrame: Day 2 (+/- 1) after administration of study drugs
Secondary outcomes:
measure: Rifampicin concentrations in plasma and CSF at steady-state
timeFrame: Day 10 (+/- 1) after starting treatment with study drugs
measure: Grade 3 and 4 and serious adverse events
timeFrame: Within 60 days
measure: Mortality
timeFrame: 180 days
measure: Neurological response
timeFrame: Within 60 days
measure: Neuroradiological response
timeFrame: 60 days
measure: Resolution of blood and CSF inflammatory response
timeFrame: 7 days
measure: Sensitivity of GeneXpert for diagnosing TBM
timeFrame: Within 6 weeks
Other outcomes:
Locations:
city: Bandung
country: Indonesia
facility: Hasan Sadikin General Hospital
state: Jawa Barat
Study officials:
affiliation: Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia
name: Rovina Ruslami, M.D., PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, Borm G, Aarnoutse RE, van Crevel R. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis. 2013 Jan;13(1):27-35. doi: 10.1016/S1473-3099(12)70264-5. Epub 2012 Oct 25.
citation: Dian S, Yunivita V, Ganiem AR, Pramaesya T, Chaidir L, Wahyudi K, Achmad TH, Colbers A, Te Brake L, van Crevel R, Ruslami R, Aarnoutse R. Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis. Antimicrob Agents Chemother. 2018 Nov 26;62(12):e01014-18. doi: 10.1128/AAC.01014-18. Print 2018 Dec.