Adding Doxycycline to Treatment for Brain Tuberculosis

AI summary

From the trial's eligibility criteria. Machine-read from the registry text on this page, so it can be wrong. The registry text below and the trial team decide who can take part.

The trial is looking for adults with tuberculosis infection of the brain and its linings (central nervous system TB) who have just started or are about to start TB treatment. It tests doxycycline against placebo.

Age

21 years and above.

Sex

All sexes can join.

Disease stage

Definite, probable or possible TB meningitis (TB of the central nervous system), by set diagnostic criteria. A lumbar puncture and a brain scan (CT or MRI) are needed at the start.

Earlier treatment

No more than 7 days of TB treatment so far, or about to start combination TB treatment.

Biomarker or test result

Liver test ALT below 3 times the upper limit of normal.

Main reasons for not taking part

• Active cancer
• Pregnant or breastfeeding
• Allergy to tetracyclines
• Autoimmune disease or taking medicines that suppress the immune system
• Cannot take steroids

The registry criteria, word for word

What the trial wants to find out

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.

The 2 groups in the trial

• Doxycycline + standard anti-tuberculous treatment + corticosteroid therapyTreatment being tested

  Doxycycline 100 mg twice daily with once daily anti-tuberculous treatment comprising of at least three agents, including rifampicin 10 mg/kg, isoniazid 5 mg/kg, ethambutol 15 - 20 mg/kg, ± pyrazinamide 25 mg/kg and pyridoxine 10-50 mg per day, or aminoglycosides or quinolones according to managing physicians' discretion. 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 e.g. hydrocortisone, methylprednisolone at the equivalent dosage. Where needed, the drugs will be adjusted according to renal function. These will be given daily for 8 weeks. Subsequently doxycycline will be ceased and patients are to continue with their standard anti-tuberculous treatment and duration according to their managing physician.

  Treatment: Doxycycline, Anti Tuberculosis Drug, and Adjunctive corticosteroid

• Placebo + standard anti-tuberculous treatment + corticosteroid therapyPlacebo, for comparison

  Placebo twice daily with once daily anti-tuberculous treatment comprising of at least three agents, including rifampicin 10 mg/kg, isoniazid 5 mg/kg, ethambutol 15-20 mg/kg, ± pyrazinamide 25 mg/kg and pyridoxine 10-50 mg per day, or aminoglycosides or quinolones according to managing physicians' discretion. 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 e.g. hydrocortisone, methylprednisolone at the equivalent dosage. Where needed, the drugs will be adjusted according to renal function. These will be given daily for 8 weeks. Subsequently placebo will be ceased and patients are to continue with their standard anti-tuberculous treatment and duration according to their managing physician.

  Treatment: Placebo, Anti Tuberculosis Drug, and Adjunctive corticosteroid