Improving diagnosis and treatment of HIV-associated Tuberculous meningitis
- Conditions
- Tuberculosis of nervous systemInfections and InfestationsTuberculous meningitis
- Registration Number
- ISRCTN42218549
- Lead Sponsor
- ondon School of Hygiene and Tropical Medicine
- Brief Summary
2018 Protocol article in https://pubmed.ncbi.nlm.nih.gov/30175245/ protocol (added 06/01/2021) 2021 Results article in https://pubmed.ncbi.nlm.nih.gov/33693537/ (added 08/11/2021)
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- All
- Target Recruitment
- 61
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
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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <br> 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.<br> 2. Safety composite endpoint is assessed during the intervention period by measuring:<br> 2.1. Adverse Events, Clinical Grade 3-5 as classified by Division of AIDS Toxicity Scale, or<br> 2.2. All serious adverse events, or<br> 2.3. Drug-induced liver injury, grade 3-5, (ALT >5x ULN; or Bilirubin >2.6x ULN) or<br> 2.4. Discontinuation of rifampicin for >5 days in the first 8 weeks for any cause<br>
- Secondary Outcome Measures
Name Time Method <br> 1. Survival time is measured at 8 and 24 weeks after randomisation<br> 2. Time to normalization of mental status is measured using the Glasgow Coma Scale score (GCS) of 15 which is maintained for >2 days<br> 3. Degree of disability/dependence is measured using the Modified Rankin Scale score at 8 and 24 weeks<br> 4. Neurocognitive performance is measured using detailed quantitative neurocognitive performance Z-score (QNPZ-8) at 8 and 24 weeks<br> 5. Paradoxical TB-related immune reconstitution inflammatory syndrome (TB-IRIS) is assessed using published case definition at 4 weekly follow up.<br>