A Phase 2 interventional study of Doxycycline and Placebo in Tuberculosis, Meningeal, Tuberculosis; Meningitis (Etiology) and Tuberculosis, Central Nervous System, sponsored by National University Hospital, Singapore. Recruiting at 6 sites in 3 countries. Open to participants aged 21 Years and older. Per ClinicalTrials.gov, last updated 2026-06-01.
Sponsored by National University Hospital, Singapore · Phase 2, Interventional, and Treatment
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 investigators hypothesize that in patients with CNS-TB, the addition of doxycycline to SOC improves clinical outcomes.
The specific aims are to determine:
These specific aims will determine if doxycycline will improve clinical outcomes in the management of CNS-TB, reduce long-term neurological deficits whilst demonstrating a comparable safety profile. These aims are critical to form the basis of a large-scale Phase 3 randomised-controlled trial of CNS-TB which will positively impact clinical practice and international guidelines.
Background and Clinical Significance
The global burden of tuberculosis and TB sequelae
Despite being declared an emergency by the World Health Organisation (WHO) in 1993, tuberculosis (TB) remains a global health epidemic. A significant proportion of the global population is infected with TB, particularly in lower- to middle-income countries in resource-limited settings. Despite strategies directed towards infection control and TB management, worldwide annual TB deaths are estimated to be 1.3 million. Furthermore, the coronavirus disease 2019 (COVID-19) pandemic has also impacted TB, and TB incidence is expected to rise substantially. In Singapore, TB incidence has stagnated after some significant improvements with an annual incidence of approximately 39 TB infections per 100,000 people, which translates to under 3,000 TB patients per year. Additionally, there are rising multi-drug-resistant (MDR) and extensively drug-resistant (XDR) TB regionally and in the world, which pose clinical challenges. MDR and XDR TB often require prolonged treatment courses with medications that are often unavailable in resource-limited settings. Singapore is not exempted from the scourge of MDR and XDR TB cases, which have been described in prisons, gaming arcades and even housing estates. Global and local epidemiology indicates that TB remains an infectious disease threat.
One of the most severe forms of TB is CNS-TB which can lead to significant morbidity and mortality. In CNS-TB, tissue destruction can result in long-term neurological sequelae with permanent neurological deficits. Even with appropriate treatment for CNS-TB and microbiological cure, mortality rates for CNS-TB remain high at up to 30-50%; CNS-TB may still leave behind residual neurological deficits. Patients can become bed-bound and dependent on activities of daily living. Even with good standard-of-care, there still is cognitive impairment in up to 55% of patients and motor deficits in up to 40% of patients, with significant residual neurological deficits. Adjunctive steroids significantly reduce mortality (41.3% placebo vs 31.8% in the steroid arm), but death rates remain unacceptably high. Critically, steroids did not show a significant improvement in severe disability from neurological deficits. TB sequelae cause substantial morbidity long after TB itself is treated, as currently there is no treatment to prevent severe neurological disability.
Host immunopathology and TB tissue destruction
Prior published work has shown that the cause of tissue destruction in TB resulting in sequelae is excessive host inflammatory and adaptive immune response. Although the immunopathology in TB is not fully understood, it has been shown that pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α) may play a key role. Proteases result in tissue destruction in TB patients, with MMPs having a unique ability to collectively degrade all extracellular matrix fibrils at a neutral power of hydrogen (pH), of which the secretion of MMPs in TB is excessive. MMP activity is dysregulated in TB, which is the key in the pathophysiology. The secretion of multiple MMPs are up-regulated, arising from human macrophages, epithelial cells and neutrophils which we showed. The upregulation of MMPs with tissue destruction has been shown in several TB animal models, which provides further evidence on the role of pathogenic MMPs in vivo.
Doxycycline is the only MMP inhibitor licensed by the U.S. Food and Drug Administration which has both anti-bacterial and immunomodulatory properties. It is an antibiotic that is used for decades for a range of clinical indications, including periodontal disease (gum disease), acting on periodontal clefts by reducing the concentration of collagenases. Doxycycline has also been shown to be bacteriostatic to Mycobacterium tuberculosis (Mtb). It has an excellent safety profile, even when given for prolonged durations. It may also be administered by nasogastric tube for individuals with swallowing disability. Furthermore, it is a drug that is widely available and cheap, making it highly accessible even in resource-limited settings. The addition of doxycycline adjunctive therapy to corticosteroids and standard TB therapy may decrease host MMP expression and inflammatory gene responses in human CNS-TB, hence improving clinical outcomes and neurological sequelae.
Doxycycline modulates TB tissue destruction
The first doxycycline pulmonary TB trial worldwide was conducted by us. In a Phase 2 double-blind randomised-controlled trial of 30 pulmonary TB patients, investigating doxycycline host-directed therapy funded by the National Medical Research Council, the investigators showed that 2 weeks of doxycycline improved pulmonary cavity resolution as indicated by the patients exhibiting significantly smaller cavities. In addition, there was also a beneficial host immunological effect that persisted 6 weeks post-discontinuation of the doxycycline, accelerating a return to healthy gene expression of the host transcriptome. MMPs were also down-regulated with suppression of plasma MMP-1 and further reduction of collagenase and gelatinase MMPs in the sputum. However, the effects of doxycycline on mortality or neurological outcomes in CNS-TB are unknown. This Phase 2 randomised-controlled-trial determines if adjunctive doxycycline treatment can be extended to CNS-TB to improve clinical outcomes and neurological sequelae. Reducing neurological disability would alleviate burden on healthcare facilities and maximise an individual's economically productive life. If positive, these findings will provide preliminary data for a Phase 3 RCT. Findings will be rapidly conveyed to the WHO with whom the investigators closely collaborate, to impact international guidelines and clinical practice.
Specific Aims and Hypothesis
The investigators hypothesize that in patients with CNS-TB, the addition of doxycycline to SOC improves clinical outcomes.
The specific aims are to determine:
These specific aims will determine if doxycycline will improve clinical outcomes in the management of CNS-TB, reduce long-term neurological deficits whilst demonstrating a comparable safety profile. These aims are critical to form the basis of a large-scale Phase 3 randomised-controlled trial of CNS-TB which will positively impact clinical practice and international guidelines.
31 studies on the registry are indexed under Tuberculosis, Meningeal; 9 are open to participants now.
This study's planned enrollment of 200 is above the median of 125 across 24 interventional studies indexed under Tuberculosis, Meningeal.
Browse Tuberculosis, Meningeal studies →National University Hospital, Singapore is the lead sponsor of 454 studies on the registry; 99 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Patients with clinical evidence of TB meningitis, as per established diagnostic criteria, defined as either definite, probable or possible CNS-TB:
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Autoimmune disease
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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 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
adjunctive doxycycline to standard anti-tuberculous treatment and corticosteroid therapy
Placebo
Standard anti-tuberculous therapy
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
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.
Time frame: 8 weeks
Mortality at 8 weeks, from time of randomization
Mortality at 8 weeks, from time of randomization
Time frame: 8 weeks
Persistent neurological disability at 8 weeks, from time of randomization
Persistent neurological disability at 8 weeks, from time of randomization
Time frame: 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
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
Time frame: 8 weeks
The pattern of change of host transcriptome at week 8 from time of randomization
Whole blood will be collected in Tempus tubes and processed in a biosafety level-3 laboratory. Library preparation and bulk RNA sequencing will be performed as previously described. In addition, in the subset of patients recruited from Singapore, single-cell RNA sequencing (scRNAseq) will be performed from the doxycycline and placebo arm, analysing 10,000 cells per sample. In this subset of patients, blood for bulk RNAseq will also be stored as a backup. Single-cell RNAsequencing from the CSF will also be performed. Bioinformatic analyses will be performed to evaluate the pattern of change of host transcriptome at week 8, in established pipelines.
Time frame: 8 weeks
The pattern of change of host plasma MMPs at week 8 from time of randomization
Whole blood will be spun down, plasma collected and sterile filtered in a biosafety level-3 laboratory before transferring to a biosafety level-2 laboratory. MMP Luminex bead array will be performed which has been established in Dr Catherine Ong's laboratory. The pattern of change of host plasma MMPs at week 8.
Time frame: 8 weeks
The pattern of change of host CSF MMPs at week 2 from time of randomization
CSF will be collected and sterile filtered in a biosafety level-3 laboratory before transferring to a biosafety level-2 laboratory. MMP Luminex bead array will be performed which has been established in Dr Catherine Ong's laboratory. The host CSF MMPs at week 2 shall be evaluated.
Time frame: 2 weeks
Adverse events and serious adverse events
These will be recorded using the Division of AIDS table for Grading the Severity of Adult and Paediatric adverse events (December 2004)
Time frame: 8 weeks
Plan to share: Undecided — Data may be made available on reasonable request
Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.
No contact was published for this record. The registry link below has the sponsor’s details.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Studies of the drug tested here: Doxycycline
National University Hospital, Singapore →