Tuberculosis of nervous system Infections and Infestations Tuberculous meningitis
Conditions
Interventions
Participants are randomised (stratified by site and MRC severity grade) into one of three arms:
1. Intravenous 20mg/kg/day rifampicin for 2 weeks (followed by oral rifampicin 35mg/kg/day for 6-weeks)
Sponsors
London School of Hygiene and Tropical Medicine
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age = 18 years 2. Provision of written informed consent by participant or surrogate 3. Clinical diagnosis of TBM: meningitis symptoms, clinical signs of meningism and antituberculous chemotherapy planned by the attending physician AND 4. Bedside CSF glucose to plasma ratio <50%, or absolute CSF glucose <40mg/dl or 2.2 mmol/L OR 5. Positive CSF AFB smear or Xpert MTB/ Rif or Ultra
Exclusion criteria
Exclusion criteria: 1. Presence of jaundice or known liver cirrhosis (Due to emergent need to begin TBM therapy to reduce mortality, enrolment will not be delayed and participants will be replaced a posteriori if baseline ALT>3x ULN) 2. Greater than 3 doses of TB treatment received within the previous 3 days (induction of cytochrome P450 enzymes occurs after 3-5 days of rifampicin therapy which would affect PK data) 3. Discontinued TB treatment in the prior 14 days (induction of cytochrome P450 enzymes persists for up to 2-weeks after cessation of R and would make interpretation of the PK data challenging) 4. Known allergy to Rifamycins, H, Z, E or study drug excipients 5. Known current/previous rifampicin drug-resistant M. tuberculosis infection 6. Current cryptococcal meningitis: India ink stain positive or culture positive or cryptococcal antigen positive in the absence of prior effective treatment and prophylaxis. 7. Use of any drug that has a clinically relevant interaction with rifampicin or other first-line TB drugs, including ritonavir, atazanavir or darunavir (see appendix 2 for further detail) 8. Cannot or unlikely to attend regular clinic visits 9. Pregnancy / Breastfeeding. Women of childbearing potential must agree to use barrier contraception or abstinence for 8 weeks. Hormonal contraception is unacceptable as rifampicin induces metabolism. 10. Lack of consent from participant or family member 11. Known porphyria 12. Known chronic renal failure with eGFR <10 ml/min
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Individual pharmacokinetic parameters (plasma and CSF AUC0-24h, Cmax) are measured using intensive PK sampling of blood at 0, 2, 4 and 8 hours and a single CSF sample on day 2 and by sparse PK sampling on day 12. 2. Safety composite endpoint is assessed during the intervention period by measuring: 2.1. Adverse Events, Clinical Grade 3-5 as classified by Division of AIDS Toxicity Scale, or 2.2. All serious adverse events, or 2.3. Drug-induced liver injury, grade 3-5, (ALT >5x ULN; or Bilirubin >2.6x ULN) or 2.4. Discontinuation of rifampicin for >5 days in the first 8 weeks for any cause | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Survival time is measured at 8 and 24 weeks after randomisation 2. Time to normalization of mental status is measured using the Glasgow Coma Scale score (GCS) of 15 which is maintained for >2 days 3. Degree of disability/dependence is measured using the Modified Rankin Scale score at 8 and 24 weeks 4. Neurocognitive performance is measured using detailed quantitative neurocognitive performance Z-score (QNPZ-8) at 8 and 24 weeks 5. Paradoxical TB-related immune reconstitution inflammatory syndrome (TB-IRIS) is assessed using published case definition at 4 weekly follow up. | — |
Countries
Uganda
Outcome results
None listed