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Cyclophosphamide in the Treatment of Refractory Proliferative Arachnoiditis in CNS Tuberculosis

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ClinicalTrials.gov Identifier: NCT04620772
Recruitment Status : Not yet recruiting
First Posted : November 9, 2020
Last Update Posted : December 30, 2020
Sponsor:
Information provided by (Responsible Party):
Arunmozhimaran Elavarasi, All India Institute of Medical Sciences, New Delhi

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.


Condition or disease Intervention/treatment Phase
Tuberculosis Tubercular Meningitis Arachnoiditis; Tuberculous (Etiology) Drug: Cyclophosphamide injection Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Participant, investigator, assessor and the statistician will be blinded to the treatment allocation
Primary Purpose: Treatment
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
Estimated Study Start Date : January 1, 2021
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024


Arm Intervention/treatment
Experimental: 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
Drug: Cyclophosphamide injection
Cyclophosphamide vs placebo

Placebo arm
Participants randomized to the placebo group will be given similar quantity of normal saline and mesna as described above
Drug: Cyclophosphamide injection
Cyclophosphamide vs placebo




Primary Outcome Measures :
  1. Functional independece at 6 months [ Time Frame: 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.


Secondary Outcome Measures :
  1. Independent ambulation [ Time Frame: 6 months ]
    To compare the proportion of patients who attain independent ambulation 6 months after cyclophosphamide therapy for proliferative arachnoiditis refractory to corticosteroids and standard Anti-tubercular therapy in CNS tuberculosis to those who receive placebo.

  2. Improvement in modified Rankin scale [ Time Frame: 6 months ]
    To compare the proportion of patients improving from mRS ≥3 to mRS ≤2 six months post cyclophosphamide therapy

  3. Improvement in visual acuity (1) [ Time Frame: 6 months ]
    To compare the proportion of patients who attain atleast 2 points improvement on Snellen's chart in visual acuity 6 months after cyclophosphamide therapy for proliferative arachnoiditis refractory to corticosteroids and standard Anti-tubercular therapy in CNS tuberculosis to those who receive placebo.

  4. Improvement in visual acuity (2) [ Time Frame: 6 months ]
    To compare proportion of patients who attain atleast two point improvement on a semiquantitative visual acuity measurement in those who have visual acuity less than 1/60 on snellen's chart (finger counting at 1 m, hand movements at 1 m, perception of light, no perception of light considered as discrete points below 1/60 vision on standard Snellen's chart) 6 months after cyclophosphamide therapy

  5. Improvement in visual acuity (3) [ Time Frame: 6 months ]
    To compare proportion of patients improving from visual acuity of <3/60 in the better eye to 3/60 or more 6 months post cyclophosphamide therapy

  6. Improvement in sphincter function [ Time Frame: 6 months ]
    To compare the proportion of patients who attain improvement in bladder/bowel function 6 months after cyclophosphamide therapy for proliferative arachnoiditis refractory to corticosteroids and standard Anti-tubercular therapy in CNS tuberculosis to those who receive placebo..

  7. Change in mRS [ Time Frame: 6 months ]
    Shift analysis pre-and 6 months post therapy in terms of change in mRS

  8. Patient well being [ Time Frame: 6 months ]
    Comparing Global patient well being as assessed by SF-36 pre and 6 months post cyclophosphamide therapy

  9. Life threatening infections [ Time Frame: 3 months ]
    Occurrence of life threatening infections necessitating cessation of therapy upto 3 months post cyclophosphamide therapy

  10. Infections needing hospitalization [ Time Frame: 3 months ]
    Occurrence of infections needing hospitalization or intravenous antibiotic/antiviral/anti-fungal therapy upto 3 months post cyclophosphamide therapy

  11. Flare up of TB [ Time Frame: 3 months ]
    Flare up of underlying tuberculosis upto 3 months post cyclophosphamide therapy

  12. Cytopenias [ Time Frame: 6 weeks ]
    Occurrence of Grade III cytopenias defined as per common terminology criteria for adverse events v 5.0 upto 6 weeks post cyclophosphamide therapy

  13. Transaminitis [ Time Frame: 6 weeks ]
    Grade III transaminitis as per CTCAE v 5.0 upto 6 weeks post cyclophosphamide therapy

  14. Hemorrhagic cystitis [ Time Frame: 2 weeks ]
    Occurrence of hemorrhagic cystitis upto 2 weeks post cyclophosphamide therapy

  15. Adverse effects [ Time Frame: 3 months ]
    Any other significant adverse effect



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Ages Eligible for Study:   14 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04620772


Contacts
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Contact: Arunmozhimaran Elavarasi, MD DM +919013844274 arun_ela@yahoo.com
Contact: Padma Srivastava MV, MD DM +919868398261 vasanthapadma123@gmail.com

Sponsors and Collaborators
All India Institute of Medical Sciences, New Delhi
Publications:
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Responsible Party: Arunmozhimaran Elavarasi, Dr Arunmozhimaran Elavarasi, All India Institute of Medical Sciences, New Delhi
ClinicalTrials.gov Identifier: NCT04620772    
Other Study ID Numbers: IEC-975/03.10.2020
First Posted: November 9, 2020    Key Record Dates
Last Update Posted: December 30, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Based on Institutional protocol

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Arunmozhimaran Elavarasi, All India Institute of Medical Sciences, New Delhi:
tubercular optico-chiasmatic arachnoiditis
tubercular radiculo-myelitis
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Meningeal
Meningitis
Arachnoiditis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Central Nervous System Diseases
Nervous System Diseases
Meningitis, Bacterial
Central Nervous System Bacterial Infections
Tuberculosis, Central Nervous System
Central Nervous System Infections
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists