Cyclophosphamide in the Treatment of Refractory Proliferative Arachnoiditis in CNS Tuberculosis

Brief Title

Cyclophosphamide in the Treatment of Refractory Proliferative Arachnoiditis in CNS Tuberculosis

Official Title

Efficacy and Safety of Cyclophosphamide in the Treatment of Refractory Proliferative Arachnoiditis in Central Nervous System Tuberculosis- A Randomized Double Blinded Placebo Controlled Trial

Brief Summary

      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.
    

Detailed Description

      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:

      Cyclophosphamide is a potent immunosuppressant agent. It is used in Lupus and other immune
      mediated conditions and has been shown to be effective in randomized controlled trials in
      Lupus nephritis, granulomatous polyangiiitis etc. Though it is widely used off label in
      various inflammatory immune mediated neurologic conditions such as CNS vasculitis, CIDP,
      multiple sclerosis, autoimmune encephalitis, refractory myasthenia gravis etc, the evidence
      for this is basically derived from the rheumatology and nephrology literature. It has to be
      emphasized that all the data for immunosuppression with azathioprine, cyclophosphamide,
      mycophenolate mofetil, methotrexate, calcineurin inhibitors in various immune mediated
      conditions have been derived from renal transplant/solid organ transplant cohorts, lupus
      nephritis cohorts, systemic vasculitis cohorts and inflammatory bowel disease cohorts. The
      various guidelines issued by the professional bodies for these conditions form the principles
      of treatment of rare conditions such as neuroimmunologic diseases. The major adverse effects
      of concern in patients on Cyclophosphamide is the occurrence of life threatening infections
      such as tuberculosis. It has been seen that patients on high dose corticosteroids and
      cyclophosphamide are at higher risk of infection than those on steroids alone or on neither
      drug.Though the risk of TB increases with administration of immunosuppressants, the mainstay
      of management is early diagnosis and starting appropriate therapy and not cessation of
      immunosuppression. In the context of SLE the occurrence of infection is also dependent on
      various other factors such as disease activity, previous exposure to tuberculosis etc. The
      Americal college of rheumatology guidelines do not say anything on the course of action in
      case patients develop infections. There are no professional guidelines for the management of
      infections in patients on cyclophosphamide. There are no RCTs on the most appropriate form of
      ATT regimens or the modification of immunosuppression in these conditions. There are various
      case series and case reports who have been systematically studied infections and their
      management including the large prospective EuroLupus cohort. None of these authors advice
      complete cessation of immunosuppression in patients who develop infections including
      tuberculosis. The guidelines for management of tuberculosis such as British thoracic society
      guidelines for the management of TB in CKD,do not suggest cessation of immunosuppression in
      post renal transplant patients. The guidelines clearly mention that TB in patients with CKD
      have to be treated in same lines of immunocompetent patients, and the anti-tubercular drugs
      may need to be given in renal modified doses. In case of tuberculosis risk, it has been shown
      by various long term follow up studies that a considerable proportion of patients with latent
      TB infections progress to develop active TB post transplantation or after treatment with
      immunosuppressants or biologic agents such as anti TNF therapy. In such circumstances, the
      guidelines suggest not dropping immunosuppression, but treatment of latent TB or active TB.
      The guidelines for the management of active TB in solid organ transplantation suggests early
      diagnosis and treatment of tuberculosis along with increasing the dose of immunosuppressants
      such as corticosteroids, cyclosporine or tacrolimus as the ATT regimen containing rifamycins
      tend to induce the metabolism of these immunosuppression and trough levels of calcineurin
      inhibitors have to be maintained by increasing the dose of cyclosporine or tacrolimus by upto
      4-5 times.

      These recommendations are mainly based on a large multicentre cohort of more than 2000
      patients derived from 187 publications who had received solid organ transplantation and
      developed tuberculosis, where the dose of immunosuppressant drugs had been increased to
      maintain adequate blood levels to avoid rejection of the organ graft. Similar recommendations
      have been made by the TBNET consensus statement for management of Tuberculosis in transplant
      recipients.

      The management of immunosuppression in these cases are mainly based on expert consensus in
      other conditions such as rheumatoid arthritis, spondyloarthropathy etc. The TBNET consensus
      statement also says that in case the organ is not vital or the infection is life threatening,
      it may be considered to reduce the level of immunosuppression. The guidelines for the use of
      anti TNF-α therapy is clearer in this aspect. While the occurrence of active TB during anti
      TNF-α therapy warrants withholding (NOT cessation) of immunosuppression, it may be re started
      2 months after ATT the if patients demonstrate a favorable response to anti-TB therapy and
      require early resumption of anti TNF therapy.The BTS guidelines suggest that if active TB was
      diagnosed prior to starting of "Anti-TNF-α therapy, treatment should not be commenced for at
      least 2 months after antituberculosis treatment with full compliance has begun, supervised by
      a thoracic physician orinfectious disease specialist, and until the drug susceptibility
      profile of the organism in those with positive cultures is known, as a minimum." However, if
      the patient develops TB while on anti TNF therapy the anti-TNF-α treatment can be continued
      if clinically indicated because the patient would otherwise be prevented from receiving the
      continued clinical benefit to their underlying disease and may have a flare up or major
      clinical deterioration. The rationale provided by these guidelines is that HIV positive
      individuals with reduced CD4 counts and clinical TB, who are even more immunosuppressed than
      those on anti-TNF-a treatment, respond just as well to TB treatment as those who are HIV
      negative. Taking that logic forward, it may be reasonable to start therapy with
      cyclophosphamide three months after starting standard Anti tubercular therapy in patients
      with tubercular meningitis who have shown clearcut improvement followed by deterioration due
      to development of arachnoiditis and paradoxical immune responses.
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Functional independece at 6 months

Secondary Outcome

 Independent ambulation

Condition

Tuberculosis

Intervention

Cyclophosphamide injection

Study Arms / Comparison Groups

 Cyclophosphamide arm
Description:  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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

40

Start Date

January 1, 2021

Completion Date

December 31, 2024

Primary Completion Date

December 31, 2023

Eligibility Criteria

        Inclusion Criteria:

          -  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

        Exclusion Criteria:

          -  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
      

Gender

All

Ages

14 Years - 60 Years

Accepts Healthy Volunteers

No

Contacts

, +919013844274, [email protected]



Administrative Informations


NCT ID

NCT04620772

Organization ID

IEC-975/03.10.2020


Responsible Party

Principal Investigator

Study Sponsor

All India Institute of Medical Sciences, New Delhi


Study Sponsor

, , 


Verification Date

December 2020