HIV, Meningitis, TB - Tuberculosis, Tuberculous Meningitis
Conditions
Brief summary
This two-stage study will compare consented research participants with tuberculous meningitis receiving BPaLMZ to controls receiving SOC of rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E), known as RHZE.
Interventions
DRUGBPaLMZ Regimen
bedaquiline, pretomanid, linezolid, moxifloxacin, and pyrazinamide
Sponsors
David Boulware
Infectious Diseases Institute, Uganda
University of Minnesota
Brighton & Sussex Medical School
Mbarara University of Science and Technology
Radboud University Medical Center
Meningitis Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* First Episode definite or probable TBM with physician intent to treat * Age ≥18 years * Provision of Informed Consent by participant or surrogate * Living with HIV * Weight \> 35kg, estimate or measured
Exclusion criteria
* Additional active and confirmed CNS infection * Known rifampicin-resistant TB * Allergy or contraindication to a study medicine * More than 5 doses of any TB therapy received within the previous 14 days * Presence of jaundice, known liver cirrhosis, elevated ALT or AST \>3x ULN, or total bilirubin \>2x ULN * Estimated Glomerular Filtration Rate \<30 ml/min/1.73m2 * Significant cardiac comorbidity, heart failure, arrhythmia, or QTc \>450 ms * Pregnancy or Breastfeeding * Cryptococcal antigen positivity in blood * Condition which makes participation not in the participant's best interest
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Death | 24 Weeks | — |
| Hierarchical composite endpoint (survival + functional status) | 24 Weeks | Hierarchical composite endpoint of survival and modified Rankin score (0-6 scale) assessed by Win Ratio |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serious adverse events (SAE) | 28 weeks | Incidience of Serious adverse events |
| Clinical Adverse Events | 28 weeks | Clinical Adverse Events, by grade (1-5) associated with TB drug discontinuation, dose reduction, or interruption \>3 days |
| Laboratory abnormalities | 28 weeks | Number of participants with grade 3 or 4 abnormal laboratory values, by the Division of AIDS toxicity grading scale |
| Neuropathy | 28 weeks | Incidence of Neuropathy |
| Drug induced liver injury | 28 weeks | Drug induced liver injury with Grade \>=3 with serum alanine aminotransferase (ALT) \>5x upper limit or normal or total bilirubin \>2.5x upper limit of normal) |
| Change in CSF inflammatory markers | 14 days | Change in CSF leukocytes from baseline to day 7 and 14 visits. |
| Modified Rankin Scale | 24 weeks | Modified Rankin Score as an ordinal score (0-6 scale) of: 0 Alive: no residual symptoms or disability. 1. No significant disability: symptoms are present but do not prevent carrying out all usual duties and activities; able to carry out all pre-TBM activities. 2. Slight disability: unable to carry out all pre-TBM activities but able to look after self without daily help. 3. Moderate disability: requires some assistance with tasks but able to walk without assistance. 4. Moderately severe disability: unable attend to bodily functions or walk without assistance. 5. Severe disabilities: bedridden, incontinent, requires continuous care and attention. 6. Dead |
| Change in blood inflammatory markers | 7 days | Change in white blood cell count from baseline to day 7 visit |
| Quantitative neurocognitive performance Z-score | 24 weeks | Quantitative neurocognitive performance Z-score scaled to Ugandan population adult norms where population average = 0. Performance is Z-scored such that performance that is one standard deviation better than average is +1 and one standard deviation worse is -1. |
| Change in PCR cycle threshold (Ct) value in CSF | 14 days | Change in PCR cycle threshold (Ct) value in CSF from baseline to Day 7 and 14 visits. |
| Altered Mental Status over time | 10 days | Number of days with Glasgow Coma Scale score = 15 within the first 10 days |
| Additional corticosteroids use | 24 weeks | Additional corticosteroids use in TBM survivors (beyond initial use) |
| Change in CSF glcuose | 14 days | Change in CSF glcuose from baseline to day 7 to day 14 |
| Change in serum C-reactive protein | 7 days | Change in serum C-reactive protein (CRP) from baseline to day 7 |
Countries
Uganda
Contacts
CONTACTDavid Boulware, MD
CONTACTDarlisha Williams, MPH
PRINCIPAL_INVESTIGATORDavid Boulware, MD
University of Minnesota
Outcome results
None listed