A randomised trial of 6 months enhanced anti-tuberculosis and 2 months anti-inflammatory treatment for HIV-infected and HIV-uninfected African and Asian children with tuberculous meningitis
Tuberculous meningitis
Participants in this study will either be given the antibiotic medicines that are usually used to treat children with TB meningitis for 12 months (standard of care treatment) OR the higher dose medicines for 6 months (test treatment). Participants will be randomly allocated to receive the test treatment or the standard of care in a 1:1 ratio, with minimisation by TBM stage (stages 1 and 2 versus stage 3), HIV status, age (<2 years of age versus ≥2 years) and study centre. This stage is open-label. The standard of care treatment uses 4 medicines at the WHO recommended dosages (rifampicin 15 mg/kg, isoniazid 10 mg/kg, pyrazinamide 35 mg/kg and ethambutol 20 mg/kg) once daily for 2 months followed by 2 medicines (rifampicin 15 mg/kg and isoniazid 10 mg/kg ) daily for 10 months. The test treatment uses 4 medicines (rifampicin 30 mg/kg, isoniazid 20 mg/kg, pyrazinamide 40 mg/kg and levofloxacin 20 mg/kg) once daily for 6 months. Participants in both groups will then be randomised again (using the same methodology as before) to receive either aspirin to be taken once daily for 8 weeks (20 mg/kg) or a placebo once daily for 8 weeks. Whilst taking the aspirin or the placebo, participants will be given ranitidine to protect the stomach. This stage will be double-blinded. Participants will also receive steroid medication for around the first 4 weeks of their TBM treatment (standard of care for TBM). Following screening assessments, eligible children will be randomised and enrolled into the trial. The randomisations will occur immediately after screening procedures have been completed and before commencing trial treatment, provided that results of CSF microscopy and results from screening are available, and the participant/carer feels they have adequate time to consider trial participation. Before treatment allocations, the patient's eligibility will be confirmed, including the results of safety screening laboratory tests, and the minimisation factors entered into the data
Current inclusion criteria as of 22/08/2024: 1. Aged between 29 days and <18 years old 2. Weight ≥3 kg 3. Symptoms compatible with tuberculosis meningitis (TBM), including fever, vomiting, anorexia, listlessness and headache 4. Cerebrospinal fluid (CSF) result with abnormalities compatible with TBM (elevated cell count and/or protein with or without M. tuberculosis detected by microscopy or GeneXpert). Physician believes the child needs immediate initiation of anti-TB drugs. 5. Known (or pending confirmation of) HIV status 6. Parent/carer give informed, written consent 7. CSF sample processed for chemistry, microscopy, Ziehl–Nielsen or auramine stain and, mycobacterial culture (in process) and, where available, Xpert (Gene Xpert/Rif or Xpert Ultra) prior to commencing treatment. Where patients have already been started on ATT, pre-screening CSF results should be available. 8. Carer/parent can comply with the protocol requirements in the opinion of the site investigator 9. Home address accessible for visiting and intending to remain within the recruitment area for follow up period of at least 18 months _____ Previous inclusion criteria: 1. Aged between 29 days and 15 years 2. Weight ≥3 kg 3. Symptoms compatible with tuberculosis meningitis (TBM), including fever, vomiting, anorexia, listlessness and headache 4. Cerebrospinal fluid (CSF) result with abnormalities compatible with TBM (elevated cell count and/or protein with or without M. tuberculosis detected by microscopy or GeneXpert). Physician believes the child needs immediate initiation of anti-TB drugs. 5. Known (or pending confirmation of) HIV status 6. Parent/carer give informed, written consent 7. CSF sample processed for chemistry, microscopy, Ziehl–Nielsen or auramine stain and, mycobacterial culture (in process) and, where available, Xpert (Gene Xpert/Rif or Xpert Ultra) prior to commencing treatment. Where patients have already been started on ATT, pre-screening CSF results should be available. 8. C
1. Recent contact (last 12 months) with known or suspected rifampicin-resistant TB 2. Proven drug resistance to rifampicin in the child 3. On ATT for >7 days 4. Severely moribund - high risk of death within 24 hours 5. History or presence of known allergy or other contraindication to any of the following: 5.1. First-line anti-tuberculosis drugs 5.2. Corticosteroids 5.3. Aspirin 6. Pregnancy 7. History of gastrointestinal (GI) bleeding or bleeding diathesis 8. Active clinical infection with influenza or varicella 9. Grade 4 liver toxicity or other contraindications for taking part in the trial