Ignite Creation Date:
2024-06-16 @ 11:50 AM
Last Modification Date:
2024-10-26 @ 3:31 PM
Study NCT ID:
NCT06446245
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-06-06
First Post:
2024-05-28
Brief Title:
Adjunctive Doxycycline for Central Nervous System Tuberculosis
Sponsor:
National University Hospital Singapore
Organization:
National University Hospital Singapore
Study Overview
Official Title:
DIRECT Doxycycline Adjunctive Therapy to Reduce Excess Mortality and Complications From Central Nervous System Tuberculosis - Phase II Randomized Clinical Trial
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
DIRECT
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
Detailed Description:
The investigators hypothesize that in patients with CNS-TB the addition of doxycycline to SOC improves clinical outcomes
The specific aims are to determine
1 Whether the primary outcome of mortality rates or severe neurological deficits in CNS-TB patients in the doxycycline arm improves at 8 weeks Neurological deficits will be defined using a modified Rankin scale score of 3 or higher to measure the degree of disability or dependence in the daily activities of people who have suffered from neurological disability
2 Whether MMPs and inflammatory gene transcriptomics in the doxycycline arm are reduced Plasma and cerebrospinal fluid CSF MMPs and TIMPs will be measured by luminex bead array technology The functional activity of CSF MMPs will be assessed using Dye-quenched DQ Gelatin degradation Inflammatory gene transcripts will be measured using whole-blood bulk RNA sequencing and single-cell RNA sequencing CSF will also be profiled using single-cell RNA sequencing
3 Whether concurrent SOC treatment and doxycycline for CNS-TB are safe The investigators will monitor patients for side effects including liver function tests to evaluate any significant change in the safety profile of the patients after administration of adjunctive doxycycline in comparison to the placebo arm Standard measures such as grade 3 or 4 adverse events or serious adverse events will be determined
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 13 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 100000 people which translates to under 3000 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 413 placebo vs 318 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 US 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 individuals 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
1 Whether the primary outcome of mortality rates or severe neurological deficits in CNS-TB patients in the doxycycline arm improves at 8 weeks Neurological deficits will be defined using a modified Rankin scale score of 3 or higher to measure the degree of disability or dependence in the daily activities of people who have suffered from neurological disability
2 Whether MMPs and inflammatory gene transcriptomics in the doxycycline arm are reduced Plasma and cerebrospinal fluid CSF MMPs and TIMPs will be measured by luminex bead array technology The functional activity of CSF MMPs will be assessed using Dye-quenched DQ Gelatin degradation Inflammatory gene transcripts will be measured using whole-blood bulk RNA sequencing and single-cell RNA sequencing CSF will also be profiled using single-cell RNA sequencing
3 Whether concurrent SOC treatment and doxycycline for CNS-TB are safe The investigators will monitor patients for side effects including liver function tests to evaluate any significant change in the safety profile of the patients after administration of adjunctive doxycycline in comparison to the placebo arm Standard measures such as grade 3 or 4 adverse events or serious adverse events will be determined
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
The specific aims are to determine
1 Whether the primary outcome of mortality rates or severe neurological deficits in CNS-TB patients in the doxycycline arm improves at 8 weeks Neurological deficits will be defined using a modified Rankin scale score of 3 or higher to measure the degree of disability or dependence in the daily activities of people who have suffered from neurological disability
2 Whether MMPs and inflammatory gene transcriptomics in the doxycycline arm are reduced Plasma and cerebrospinal fluid CSF MMPs and TIMPs will be measured by luminex bead array technology The functional activity of CSF MMPs will be assessed using Dye-quenched DQ Gelatin degradation Inflammatory gene transcripts will be measured using whole-blood bulk RNA sequencing and single-cell RNA sequencing CSF will also be profiled using single-cell RNA sequencing
3 Whether concurrent SOC treatment and doxycycline for CNS-TB are safe The investigators will monitor patients for side effects including liver function tests to evaluate any significant change in the safety profile of the patients after administration of adjunctive doxycycline in comparison to the placebo arm Standard measures such as grade 3 or 4 adverse events or serious adverse events will be determined
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 13 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 100000 people which translates to under 3000 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 413 placebo vs 318 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 US 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 individuals 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
1 Whether the primary outcome of mortality rates or severe neurological deficits in CNS-TB patients in the doxycycline arm improves at 8 weeks Neurological deficits will be defined using a modified Rankin scale score of 3 or higher to measure the degree of disability or dependence in the daily activities of people who have suffered from neurological disability
2 Whether MMPs and inflammatory gene transcriptomics in the doxycycline arm are reduced Plasma and cerebrospinal fluid CSF MMPs and TIMPs will be measured by luminex bead array technology The functional activity of CSF MMPs will be assessed using Dye-quenched DQ Gelatin degradation Inflammatory gene transcripts will be measured using whole-blood bulk RNA sequencing and single-cell RNA sequencing CSF will also be profiled using single-cell RNA sequencing
3 Whether concurrent SOC treatment and doxycycline for CNS-TB are safe The investigators will monitor patients for side effects including liver function tests to evaluate any significant change in the safety profile of the patients after administration of adjunctive doxycycline in comparison to the placebo arm Standard measures such as grade 3 or 4 adverse events or serious adverse events will be determined
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None