Doxycycline added to standard treatment for central nervous system tuberculosis

DIRECT: Doxycycline Adjunctive Therapy to Reduce Excess Mortality and Complications From Central Nervous System Tuberculosis - Phase II Randomized Clinical Trial

This trial tests whether adding doxycycline to standard anti‑TB therapy and corticosteroids helps adults with central nervous system tuberculosis live longer or have less severe neurological disability.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 200 (estimated)
• Ages: 21 Years and up
• Sex: All
• Sponsor: National University Hospital, Singapore (other)
• Locations: 5 sites (Medan and 4 other locations)
• Trial ID: NCT06446245 on ClinicalTrials.gov

What this trial studies

This Phase 2 interventional trial gives adults with CNS tuberculosis standard combination anti‑TB therapy and adjunctive corticosteroids, with participants randomized to receive either adjunctive doxycycline or placebo. Enrollment is limited to patients starting TB treatment or within seven days of starting combination therapy. The primary outcome is mortality or severe neurological disability at 8 weeks (modified Rankin score ≥3), while secondary outcomes include measurement of MMPs/TIMPs in plasma and cerebrospinal fluid, functional CSF MMP activity, and whole‑blood and single‑cell RNA transcriptomics. Safety monitoring includes liver function tests and tracking of grade 3–4 and serious adverse events to compare doxycycline plus SOC with placebo.

Who should consider this trial

Good fit: Adults aged 21 and older with definite, probable, or possible CNS tuberculosis who are starting or within seven days of starting combination TB treatment are the intended participants.

Not a fit: People without central nervous system involvement (for example pulmonary TB only), those already on TB treatment for substantially longer than seven days, children under 21, or anyone with contraindications to doxycycline are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, adding doxycycline could reduce deaths and long‑term neurological disability from CNS‑TB using an inexpensive, widely available drug.

How similar studies have performed: Preclinical mouse models showed improved survival with adjunctive doxycycline, and prior human work in pulmonary TB has suggested doxycycline is safe when given with anti‑TB therapy.

Eligibility criteria

Inclusion Criteria:

1. Aged 21 years and above.
2. Patients receiving ≤ 7 days of TB treatment or about to start combination TB treatment, including injectable agents, where required.
3. Patients with clinical evidence of TB meningitis, as per established diagnostic criteria, defined as either definite, probable or possible CNS-TB:

   1. "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.
   2. "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.
   3. "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.
4. Alanine aminotransferase (ALT) level \< 3 times the upper limit of normal.
5. 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.
6. Lumbar puncture and brain imaging (either computed tomography or magnetic resonance imaging, with or without contrast) is required at baseline for enrolment

Exclusion Criteria:

1. Active Cancer
2. Pregnant or breastfeeding
3. Allergies to tetracyclines
4. Patients on retinoic acid, neuromuscular blocking agents or pimozide which may increase the risk of drug toxicity.
5. Autoimmune disease and/or on systemic immunosuppressants.
6. Use of any investigational or non-registered drug, vaccine or medical device other than the study drug within 182 days preceding dosing of the study drug or planned use during the study period.
7. Enrolment in any other clinical trial involving a systemic drug or intervention involving the CNS.
8. Contraindications to the use of steroids.
9. Investigators' assessment of lack of willingness to participate and comply with all requirements including follow-up of the protocol or identification of any factor presumed to significantly increase the participant's risk of suffering an adverse outcome.

Where this trial is running

Medan and 4 other locations

• Adam Malik Hospital — Medan, Indonesia (NOT_YET_RECRUITING)
• Universitas Sumatera Utara — Medan, Indonesia (NOT_YET_RECRUITING)
• Sarawak General Hospital — Kuching, Sarawak, Malaysia (NOT_YET_RECRUITING)
• National University Hospital — Singapore, Singapore (RECRUITING)
• Tan Tock Seng Hospital — Singapore, Singapore (RECRUITING)

Conditions: Tuberculosis, Meningeal, Tuberculosis, Meningitis, Tuberculosis, Central Nervous System, Meningoencephalitis