Efficacy and Safety of Cyclophosphamide in the Treatment of Refractory Proliferative Arachnoiditis in Central Nervous System Tuberculosis- A Randomized Double Blinded Placebo Controlled Trial
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 40
- 主要终点
- Functional independece at 6 months
研究概览
简要总结
Tubercular meningitis occurs in around 10% of those with extrapulmonary tuberculosis and is a major cause of mortality and morbidity. Inspite of effective Anti-tubercular drugs, still around 30% of patients develop complications due to arachnoiditis such as spinal tubercular radiculomyelitis, optico-chiasmatic arachnoiditis, development of new tuberculomas after starting therapy etc. which are probably immune mediated inflammatory responses due to paradoxical reaction to ATT.
The management of arachnoiditis is far from satisfactory. High dose methylprednisolone, intrathecal hyaluronic acid, thalidomide have been tried in small case series and case reports. However, the results have not been satisfactory.
There are two published reports of cyclophosphamide usage in TBM related vasculitis and stroke The investigators tried cyclophosphamide in four patients after consent, and found remarkable improvement in all of them. (Under peer review) In order to test this hypothesis, a randomized controlled trial is needed.
详细描述
Tubercular arachnoiditis occurring as a late complication of TBM is due to immune mediated reactions and is usually treated with high doses of corticosteroids. In the investigators' experience patients have received corticosteroids upto a duration of 20-28 months. In such cases, if the patient is refractory to corticosteroids, it is logical to step up to cyclophosphamide rather than continuing to give high dose steroids only similar to other immune mediated conditions such as CIDP, systemic and CNS vasulitis, Lupus nephritis etc.
Cyclophosphamide has been used most widely in the management of Lupus nephritis and maximum experience with the drug has been in this indication. So the dosage and duration of administration has been adapted from the induction phase dosing schedule of the ACR guidelines for the management of Lupus nephritis. The guidelines recommend 500 to 1000 mg/m2 BSA of cyclophosphamide. So the investigators decided to use 750 mg/m2 of the drug rounded off to the higher 50 mg.
Pathogenesis of tubercular arachnoiditis and Possible mechanism of cyclophosphamide Tubercular arachnoidiitis is a delayed complication in most cases due to inflammation in the optochiasmatic, spinal and other cranial nerves leading to neurologic deficits. In such situations, it is seen that there is an initial improvement in clinical symptoms followed by deterioration due to enlargement of lesions or appearance of new lesions, especially in patients with extrapulmonary tuberculosis. These new lesions are probably due to immune mediated mechanisms-it has been seen that in more than 95% of cases are drug sensitive and corticosteroids are the cornerstone of management of such patients. The complete pathogenesis of immune medicated tissue injury in tuberculosis has not been elucidated. Various studies have shown that there is an excess of pro-inflammatory cytokines and chemokines including TNF-alpha and interleukins that lead to recruitment of inflammatory cells and an exhuberant immune response in patients who develop these complications as compared to those who don't. There have been studies which have shown genetic polymorphisms in the genes encoding pro-inflammatory and anti-inflammatory cytokines-leading to difference in response to corticosteroids like LTA4 (Leukotriene- A4 hydrolase) gene. It is also well known that various immune mediated diseses such as SLE, multiple sclerosis etc are triggered by viruses and other infections. It is routine practice to treat acute bacterial meninigitis and tubercular meningitis with dexamethasone, which is again a steroid and immunosuppressant along with specific antibiotics or anti-tubercular therapy respectively based on evidence from systematic reviews and meta-analysis. Neurocysticercosis is treated with corticosteroids and other immunosuppressant medications such as methotrexate as recommended in guidelines, adalimumab and eternacept used as steroid sparing agents. Various other immune mediated complications of acute and chronic infections such as dengue myocarditis, ADEM etc are also treated with immunosuppression including corticosteroids. Lepra reactions in Leprosy are also treated using steroids, thalidomide, methotrexate, azathioprine, cyclophosphamide, cyclosporine etc.
In recent times, the corticosteroid- Dexamethasone has been shown to have mortality benefit in patients with moderate to severe COVID, proven in a randomized controlled trial. Simliarly, even though there are no RCT data, Tocilizumab, siltuximab and other immunosuppressant medications have been approved for emergency use based on their efficacy shown in large case series in COVID-19.
Justification for the use of cyclophosphamide this study:
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
Participant, investigator, assessor and the statistician will be blinded to the treatment allocation
入排标准
- 年龄范围
- 14 Years 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients attending Neurology/Pulmonary Medicine/Medicine/Geriatric Medicine OPD/admitted in respective wards with proliferative tubercular arachnoiditis refractory to corticosteroids and standard Anti-tubercular drugs for CNS tuberculosis
- •Atleast 14 years of age of all sexes
- •Not more than 60 years of age at time of enrolment
- •Patient was started on ATT for tubercular meningitis and had clearcut clinical improvement with resolution of fever/constitutional symptoms AND improvement in headache, vomiting and sensorium for atleast 10 days following which there is deterioration again due to arachnoiditis
- •Developed paraparesis/quadriparesis/sphincter dysfunction due to spinal radiculomyelitis or vision loss due to due to optico-chiasmatic arachnoiditis with imaging evidence of arachnoiditis
- •Has received standard ATT for atleast 3 months with adequate dose and compliance
- •Received corticosteroids for treatment of arachnoiditis and deemed to be refractory to corticosteroids by the primary physician treating the patient
- •MRI brain and spine are suggestive of Arachnoiditis
- •CSF GeneXpert/Line Probe assay/cultures are not suggestive of drug resistant tuberculosis
- •Reasonable clinical certainty OR allied investigations such as CECT chest/abdomen/PET CT ruling out drug resistant tuberculosis
- •Other relevant investigations like CSF analysis not suggestive of alternative diagnosis such as cysticercal/ cryptococcal/other fungal infections/other causes of chronic meningitis such as brucella/ nocardia/ syphilis/recurrent viral meningitis/ carcinomatous/ lymphomatous meningitis or non infective causes such as sarcoidoisis/sub-arachnoid hemorrhage etc.
- •Willing to undergo periodic assessment clinically and with MRI.
- •Ready to provide consent for cyclophosphamide therapy
- •Willing to adhere to protocol and comply with follow up visits
排除标准
- •Not willing to provide consent
- •Not willing to adhere to protocol
- •Developed significant drug induced liver dysfunction so that patient is not being given Rifampicin, INH or pyrazinamide and is on modified ATT including quinolones, ethambutol and aminoglycosides or second line drugs only in the absence of Rifampicin and INH
- •Drug resistant tubeculosis
- •Men and Women of childbearing potential who are not using adequate contraception or women who are pregnant and lactating
- •Patients who are on immunosuppressants such as cyclophosphamide/ azathioprine/ methotrexate/MMF/ calcineurin inhibitors for autoimmune conditions/post transplantation or chemotherapy for any systemic malignancy
- •HBsAg, HIV serology and anti HCV positive
- •Having life threatening infections such as pneumonia/urosepsis
- •Patients who have developed large artery strokes with significant brain parenchymal damage
- •Patients with expected life expectancy less than 1 year due to primary disease or comorbidity based on clinical prediction scores for specific disease
- •Patients with systemic malignancy within the last 5 years
- •Known allergy to cyclophosphamide or its preservatives/excipients
- •Receiving cyclophosphamide for any indication in the last 12 weeks
- •Gross hematuria prior to enrolment to the study/USG features of hemorrhagic cystitis
- •Cytopenias Hct <25%, TLC<4000/mm3 or Platelet count <1,20,000/mm3 at the time of enrolment
- •Alanine amino transferase (ALT) > 3 upper limit of normal at time of enrolment
研究组 & 干预措施
Cyclophosphamide arm
Participants randomized to the cyclophosphamide arm will be administered 750 mg/m2 body weight (rounded off to the nearest 50 mg above the calculated value) of cyclophosphamide diluted in normal saline every month (Total 6 months) along with equal dose of mesna 50% administered prior to infusion and 50% after the infusion of cyclophosphamide
干预措施: Cyclophosphamide injection (Drug)
Placebo arm
Participants randomized to the placebo group will be given similar quantity of normal saline and mesna as described above
干预措施: Cyclophosphamide injection (Drug)
结局指标
主要结局
Functional independece at 6 months
时间窗: 6 months
To compare the proportion of patients who attain functional independence (mRS-modified Rankin scale 0-2) 6 months after cyclophosphamide therapy for proliferative arachnoiditis refractory to corticosteroids and standard Anti-tubercular therapy in CNS tuberculosis to those who receive placebo.
次要结局
- Independent ambulation(6 months)
- Improvement in modified Rankin scale(6 months)
- Improvement in visual acuity (1)(6 months)
- Improvement in visual acuity (2)(6 months)
- Improvement in visual acuity (3)(6 months)
- Improvement in sphincter function(6 months)
- Change in mRS(6 months)
- Patient well being(6 months)
- Life threatening infections(3 months)
- Infections needing hospitalization(3 months)
- Flare up of TB(3 months)
- Cytopenias(6 weeks)
- Transaminitis(6 weeks)
- Hemorrhagic cystitis(2 weeks)
- Adverse effects(3 months)
研究者
Arunmozhimaran Elavarasi
Dr Arunmozhimaran Elavarasi
All India Institute of Medical Sciences, New Delhi