Adjunctive Doxycycline for Central Nervous System Tuberculosis

Condition(s) studied

Investigational drug(s) / intervention(s)

Doxycycline: adjunctive doxycycline to standard anti-tuberculous treatment and corticosteroid therapy

Placebo: Placebo

Anti Tuberculosis Drug: Standard anti-tuberculous therapy

Adjunctive corticosteroid: Adjunctive 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

Study summary

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.

Eligibility

Primary outcome measure(s)

• Mortality or severe neurological deficits (modified Rankin scale of 3 or more) at 8 weeks, from time of randomization. — 8 weeks
  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.

Trial sites (6)

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