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

Tahapan Penelitian : Awal
Sponsor:
Mitra Pelaksana:
Universitas Padjadjaran, Radboud University
No Registry
INA-BK9O54S
Tanggal Input Registry : 16-10-2014

01-11-2014
Rifampicin concentrations in plasma and cerebrospinal fluid (CSF) [Time Frame: Day 2 (+/- 1) after administration of study drugs] [Designated as safety issue: Yes] 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] [Designated as safety issue: Yes ] 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] [Designated as safety issue: Yes] 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] [Designated as safety issue: No] Neurological response [Time Frame: Within 60 days] [Designated as safety issue: No] 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 ] [ Designated as safety issue: No ] 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 ] [ Designated as safety issue: No ] Inflammatory response will be measured at day 0 and day 7 Sensitivity of GeneXpert for diagnosing TBM [ Time Frame: Within 6 weeks ] [ Designated as safety issue: No ] 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.
 
High-dose Rifampicin for the Treatment of Tuberculous Meningitis: a Dose-finding Study (ReDEFINe)
A Randomized Double Blinded Phase 2b Clinical Trial Comparing Standard Dose With Two Higher Doses of Rifampicin for Treatment of Adults With Tuberculous Meningitis
Eksperimental
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) 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)
60
 

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:

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)
 
No. 1234/ETIK/IX/2014, tanggal 7 Sep 2014
No. 567/MTA/X/2014, tanggal 2 Okt 2014
No. 89/PPUK/X/2014, tanggal 10 Okt 2014
TIDAK ADA
A.R Ganiem, M.D., PhD, +62 878 2288 6773, rzl@gmail.com, Sofi Din, M.D., +62 812 2134 519, sofi@gmail.com