Although tuberculosis is now considered a treatable disease, central nervous system tuberculosis (CNS-TB) when managed with the current standard-of-care (SOC), still has mortality rates ranging from 30-50% even in tertiary hospital centers. At present, the SOC for the management of CNS-TB is anti-tuberculous therapy with adjunctive corticosteroids. In CNS-TB, the activity of pathogenic host matrix metalloproteinases (MMPs) is unopposed to tissue inhibitors of metalloproteinases (TIMPs), resulting in a matrix-degrading phenotype which may drive worse outcomes in CNS-TB. In a prior established CNS-TB murine model, the investigators have demonstrated that adjunctive MMP inhibition using doxycycline, a widely available and cheap drug, in addition to standard TB treatment, compared with standard TB treatment alone, improved murine survival (Manuscript in preparation). The investigators previously showed that in humans with pulmonary TB, doxycycline with anti-TB treatment is safe, accelerates the resolution of inflammation, and suppresses systemic and respiratory MMPs. Hence, the investigators are now ideally positioned to determine if adjunctive doxycycline in patients with CNS-TB can improve clinical outcomes. The investigators will perform a Phase 2 double-blind randomized-controlled trial (RCT) of adjunctive doxycycline versus placebo with standard TB treatment and steroids for 8 weeks, with the primary outcome of 8-week mortality or severe neurological deficits.
Aged 21 years and above.
Patients receiving ≤ 7 days of TB treatment or about to start combination TB treatment, including injectable agents, where required.
"Definite" CNS-TB would be defined if acid-fast bacilli (AFB) or a positive nucleic acid amplification test for M. tuberculosis in the cerebrospinal fluid of patients.
"Probable" CNS-TB would be defined if the patient exhibit one or more of the following: suspected pulmonary tuberculosis on chest radiography, acid-fast bacilli found in any specimen other than the cerebrospinal fluid or clinical evidence of other extrapulmonary tuberculosis.
Active Cancer
Pregnant or breastfeeding
Allergies to tetracyclines
Patients on retinoic acid, neuromuscular blocking agents or pimozide which may increase the risk of drug toxicity.
Parallel
Doxycycline
Drugadjunctive doxycycline to standard anti-tuberculous treatment and corticosteroid therapy
Placebo
DrugPlacebo
Anti Tuberculosis Drug
DrugStandard anti-tuberculous therapy
Adjunctive corticosteroid
DrugAdjunctive corticosteroids to be dosed at 0.4mg/kg/day of dexamethasone or equivalent for week 1, then 0.3mg/kg/day for week 2, 0.2mg/kg/day for week 3, 0.1mg/kg/day for week 4, then tapered to stop over the next 4 weeks. Other forms of corticosteroids are also acceptable eg. hydrocortisone, methylprednisolone at the equivalent dosage
Mortality or severe neurological deficits (modified Rankin scale of 3 or more) at 8 weeks, from time of randomization.
Patients who survived at 8 weeks, from time of randomization, OR Persistent neurological disability at 8 weeks, from time of randomization, defined as a modified Rankin score of 3 or greater.
Mortality at 8 weeks, from time of randomization
Mortality at 8 weeks, from time of randomization
Persistent neurological disability at 8 weeks, from time of randomization
Persistent neurological disability at 8 weeks, from time of randomization
Magnetic resonance imaging or Computed tomography brain at 8 weeks, from time of randomization, showing persistent changes associated with CNS-TB at 8 weeks, from time of randomization
Magnetic resonance imaging or Computed tomography brain at 8 weeks from time of randomization, showing persistent changes associated with CNS-TB, at 8 weeks, from time of randomization
The pattern of change of host transcriptome at week 8 from time of randomization
Whole blood will be collected in Tempus tubes and processed in a biosafety level-3 laboratory. Library preparation and bulk RNA sequencing will be performed as previously described. In addition, in the subset of patients recruited from Singapore, single-cell RNA sequencing (scRNAseq) will be performed from the doxycycline and placebo arm, analysing 10,000 cells per sample. In this subset of patients, blood for bulk RNAseq will also be stored as a backup. Single-cell RNAsequencing from the CSF will also be performed. Bioinformatic analyses will be performed to evaluate the pattern of change of host transcriptome at week 8, in established pipelines.
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National University Hospital, Singapore
Lead sponsor
National Medical Research Council (NMRC), Singapore
Collaborator
