Adjunctive Doxycycline for Central Nervous System Tuberculosis

NCT06446245 | Recruiting Phase 2 DMC

• 1 other identifier: 2024/00039
• Study Type: interventional
• Target: 200
• Locations: 3 countries
• Sites: 5

Brief 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.

Conditions

Tuberculosis, Meningeal; Tuberculosis; Meningitis (Etiology); Tuberculosis, Central Nervous System; Tuberculosis; Meningoencephalitis (Etiology)

Outcome Measures

Primary Outcomes (1)

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

  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.

  8 weeks

Secondary Outcomes (7)

• Mortality at 8 weeks, from time of randomization

  8 weeks

• Persistent neurological disability at 8 weeks, from time of randomization

  8 weeks

• Magnetic resonance imaging or Computed tomography brain at 8 weeks, from time of randomization, showing persistent changes associated with CNS-TB at 8 weeks, from time of randomization

  8 weeks

• The pattern of change of host transcriptome at week 8 from time of randomization

  8 weeks

• The pattern of change of host plasma MMPs at week 8 from time of randomization

  8 weeks

Study Arms (2)

Doxycycline + standard anti-tuberculous treatment + corticosteroid therapy

EXPERIMENTAL

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.

Drug: Doxycycline; Drug: Anti Tuberculosis Drug; Drug: Adjunctive corticosteroid

Placebo + standard anti-tuberculous treatment + corticosteroid therapy

PLACEBO COMPARATOR

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.

Drug: Placebo; Drug: Anti Tuberculosis Drug; Drug: Adjunctive corticosteroid

Interventions

Doxycycline DRUG

adjunctive doxycycline to standard anti-tuberculous treatment and corticosteroid therapy

Doxycycline + standard anti-tuberculous treatment + corticosteroid therapy

Placebo DRUG

Placebo

Placebo + standard anti-tuberculous treatment + corticosteroid therapy

Anti Tuberculosis Drug DRUG

Standard anti-tuberculous therapy

Doxycycline + standard anti-tuberculous treatment + corticosteroid therapy; Placebo + standard anti-tuberculous treatment + corticosteroid therapy

Adjunctive corticosteroid DRUG

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

Doxycycline + standard anti-tuberculous treatment + corticosteroid therapy; Placebo + standard anti-tuberculous treatment + corticosteroid therapy

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Active Cancer
• Pregnant or breastfeeding
• Allergies to tetracyclines
• Patients on retinoic acid, neuromuscular blocking agents or pimozide which may increase the risk of drug toxicity.
• Autoimmune disease and/or on systemic immunosuppressants.
• 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.
• Enrolment in any other clinical trial involving a systemic drug or intervention involving the CNS.
• Contraindications to the use of steroids.
• 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.

Sponsors & Collaborators

• National University Hospital, Singapore: lead
• National Medical Research Council (NMRC), Singapore: collaborator

Study Sites (5)

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, 119228, Singapore

RECRUITING

Tan Tock Seng Hospital

Singapore, Singapore

RECRUITING

Related Publications (3)

• Ong CW, Elkington PT, Friedland JS. Tuberculosis, pulmonary cavitation, and matrix metalloproteinases. Am J Respir Crit Care Med. 2014 Jul 1;190(1):9-18. doi: 10.1164/rccm.201311-2106PP.

  PMID: 24713029 BACKGROUND

• Poh XY, Hong JM, Bai C, Miow QH, Thong PM, Wang Y, Rajarethinam R, Ding CSL, Ong CWM. Nos2-/- mice infected with M. tuberculosis develop neurobehavioral changes and immunopathology mimicking human central nervous system tuberculosis. J Neuroinflammation. 2022 Jan 24;19(1):21. doi: 10.1186/s12974-022-02387-0.

  PMID: 35073927 BACKGROUND

• Miow QH, Vallejo AF, Wang Y, Hong JM, Bai C, Teo FS, Wang AD, Loh HR, Tan TZ, Ding Y, She HW, Gan SH, Paton NI, Lum J, Tay A, Chee CB, Tambyah PA, Polak ME, Wang YT, Singhal A, Elkington PT, Friedland JS, Ong CW. Doxycycline host-directed therapy in human pulmonary tuberculosis. J Clin Invest. 2021 Aug 2;131(15):e141895. doi: 10.1172/JCI141895.

  PMID: 34128838 BACKGROUND

MeSH Terms

Conditions

Tuberculosis, Meningeal; Tuberculosis; Meningitis; Tuberculosis, Central Nervous System; Meningoencephalitis

Interventions

Doxycycline; Antitubercular Agents

Condition Hierarchy (Ancestors)

Meningitis, Bacterial; Central Nervous System Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Tuberculosis, Extrapulmonary; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Neuroinflammatory Diseases; Central Nervous System Viral Diseases; Encephalitis; Brain Diseases

Intervention Hierarchy (Ancestors)

Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Anti-Bacterial Agents; Anti-Infective Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blinded
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase II, multi-center randomised controlled trial, parallel design of intervention versus placebo

Study Record Dates

• First Submitted: May 28, 2024
• First Posted: June 6, 2024
• Study Start: August 21, 2025
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: August 27, 2025

Record last verified: 2025-04

Locations

SG (2); ID (2); MY (1)