DIRECT: Doxycycline Adjunctive Therapy to Reduce Excess Mortality and Complications From Central Nervous System Tuberculosis - Phase II Randomized Clinical Trial
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.
• Patients with clinical evidence of TB meningitis, as per established diagnostic criteria, defined as either definite, probable or possible CNS-TB:
‣ 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.
⁃ Possible CNS-TB would be defined if the patients exhibit at least four of the following: a history of tuberculosis, predominance of lymphocytes in the cerebrospinal fluid, a duration of illness of more than five days, a ratio of cerebrospinal fluid glucose to plasma glucose of less than 0.5, altered consciousness, yellow cerebrospinal fluid, or focal neurologic signs.
• Alanine aminotransferase (ALT) level \< 3 times the upper limit of normal.
• Able to provide informed consent. If the patient has no mental capacity to give consent, then consent may be provided for by the patient's next of kin.
• Lumbar puncture and brain imaging (either computed tomography or magnetic resonance imaging, with or without contrast) is required at baseline for enrolment