DIRECT: Doxycycline Adjunctive Therapy to Reduce Excess Mortality and Complications From Central Nervous System Tuberculosis - Phase II Randomized Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 200
- 试验地点
- 11
- 主要终点
- Mortality or severe neurological deficits (modified Rankin scale of 3 or more) at 8 weeks, from time of randomization.
研究概览
简要总结
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.
详细描述
The investigators hypothesize that in patients with CNS-TB, the addition of doxycycline to SOC improves clinical outcomes.
The specific aims are to determine:
- 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.
- 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.
- 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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blinded
入排标准
- 年龄范围
- 21 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Doxycycline + standard anti-tuberculous treatment + corticosteroid therapy
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.
干预措施: Anti Tuberculosis Drug (Drug)
Doxycycline + standard anti-tuberculous treatment + corticosteroid therapy
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.
干预措施: Adjunctive corticosteroid (Drug)
Placebo + standard anti-tuberculous treatment + corticosteroid therapy
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.
干预措施: Placebo (Drug)
Placebo + standard anti-tuberculous treatment + corticosteroid therapy
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.
干预措施: Anti Tuberculosis Drug (Drug)
Placebo + standard anti-tuberculous treatment + corticosteroid therapy
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.
干预措施: Adjunctive corticosteroid (Drug)
Doxycycline + standard anti-tuberculous treatment + corticosteroid therapy
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.
干预措施: Doxycycline (Drug)
结局指标
主要结局
Mortality or severe neurological deficits (modified Rankin scale of 3 or more) at 8 weeks, from time of randomization.
时间窗: 8 weeks
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.
次要结局
- 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)
- The pattern of change of host CSF MMPs at week 2 from time of randomization(2 weeks)
- Adverse events and serious adverse events(8 weeks)