RECRUITINGPhase 2INTERVENTIONAL

Adjunctive Doxycycline 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

About This 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.

Who May Be Eligible (Plain English)

Who May Qualify: 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 willing to sign a consent form. 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 Who Should NOT Join This Trial: 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 conditions (where your immune system attacks your own body) and/or on systemic immunosuppressants. ...See full criteria on ClinicalTrials.gov Always talk to your doctor about whether this trial is right for you.

Original Eligibility Criteria

View original clinical language

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.

Treatments Being Tested

DRUG

Doxycycline

adjunctive doxycycline to standard anti-tuberculous treatment and corticosteroid therapy

DRUG

Placebo

DRUG

Anti Tuberculosis Drug

Standard anti-tuberculous therapy

DRUG

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

Locations (5)

Adam Malik Hospital

Medan, Indonesia

Universitas Sumatera Utara

Medan, Indonesia

Sarawak General Hospital

Kuching, Sarawak, Malaysia

National University Hospital

Singapore, Singapore

Tan Tock Seng Hospital

Singapore, Singapore