Cyclophosphamide in the Treatment of Refractory Proliferative Arachnoiditis in CNS Tuberculosis

NCT04620772 | Unknown Phase 2 DMC

• 1 other identifier: IEC-975/03.10.2020
• Study Type: interventional
• Target: 40
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Tuberculosis; Tubercular Meningitis; Arachnoiditis; Tuberculous (Etiology)

Keywords

tubercular optico-chiasmatic arachnoiditis; tubercular radiculo-myelitis

Outcome Measures

Primary Outcomes (1)

• Functional independece at 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.

  6 months

Secondary Outcomes (15)

• 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

Study Arms (2)

Cyclophosphamide arm

EXPERIMENTAL

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

Placebo arm

OTHER

Participants randomized to the placebo group will be given similar quantity of normal saline and mesna as described above

Drug: Cyclophosphamide injection

Interventions

Cyclophosphamide injection DRUG

Cyclophosphamide vs placebo

Cyclophosphamide arm; Placebo arm

Eligibility Criteria

• Age: 14 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• All India Institute of Medical Sciences: lead

Related Publications (3)

• Goyal V, Elavarasi A, Abhishek, Shukla G, Behari M. Practice Trends in Treating Central Nervous System Tuberculosis and Outcomes at a Tertiary Care Hospital: A Cohort Study of 244 Cases. Ann Indian Acad Neurol. 2019 Jan-Mar;22(1):37-46. doi: 10.4103/aian.AIAN_70_18.

  PMID: 30692758 BACKGROUND

• Gonzalez-Duarte A, Higuera-Calleja J, Flores F, Davila-Maldonado L, Cantu-Brito C. Cyclophosphamide treatment for unrelenting CNS vasculitis secondary to tuberculous meningitis. Neurology. 2012 Apr 17;78(16):1277-8. doi: 10.1212/WNL.0b013e318250d84a. Epub 2012 Apr 4. No abstract available.

  PMID: 22491870 BACKGROUND

• Celotti A, Vianello F, Sattin A, Malipiero G, Faggin R, Cattelan A. Cyclophosphamide immunomodulation of TB-associated cerebral vasculitis. Infect Dis (Lond). 2018 Oct;50(10):779-782. doi: 10.1080/23744235.2018.1467038. Epub 2018 Apr 28. No abstract available.

  PMID: 29708006 BACKGROUND

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Meningeal; Arachnoiditis; Latent Tuberculosis

Interventions

Cyclophosphamide

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis, Central Nervous System; Tuberculosis, Extrapulmonary; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases; Latent Infection

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Central Study Contacts

Arunmozhimaran Elavarasi, MD DM

CONTACT

+919013844274; arun_ela@yahoo.com

Padma Srivastava MV, MD DM

CONTACT

+919868398261; vasanthapadma123@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participant, investigator, assessor and the statistician will be blinded to the treatment allocation
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr Arunmozhimaran Elavarasi

Study Record Dates

• First Submitted: October 27, 2020
• First Posted: November 9, 2020
• Study Start: January 1, 2021
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2024
• Last Updated: December 30, 2020

Record last verified: 2020-12