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CTRI Number  CTRI/2020/11/029276 [Registered on: 20/11/2020] Trial Registered Prospectively
Last Modified On: 13/09/2023
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Placebo Controlled Trial 
Public Title of Study   Cyclophosphamide to treat CNS TB related proliferative arachnoiditis not responding to usual medications In our Department, we tried cyclophosphamide in four patients after consent, and found remarkable improvement in all of them. In order to test this, a randomized controlled trial is needed. 
Scientific Title of Study   Efficacy and safety of Cyclophosphamide in the treatment of refractory proliferative arachnoiditis in Central nervous system Tuberculosis - A Randomized double blinded placebo controlled Trial  
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
NCT04620772  ClinicalTrials.gov 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Arunmozhimaran Elavarasi 
Designation  Assistant Professor 
Affiliation  All India Institute of Medical Sciences, New Delhi 
Address  Department of Neurology, AIIMS, New Delhi

South West
DELHI
110029
India 
Phone  9013844274  
Fax    
Email  arun_ela@yahoo.com  
 
Details of Contact Person
Scientific Query  
Name  Arunmozhimaran Elavarasi 
Designation  Assistant Professor 
Affiliation  All India Institute of Medical Sciences, New Delhi 
Address  Department of Neurology, AIIMS, New Delhi

South West
DELHI
110029
India 
Phone  9013844274  
Fax    
Email  arun_ela@yahoo.com  
 
Details of Contact Person
Public Query  
Name  Arunmozhimaran Elavarasi 
Designation  Assistant Professor 
Affiliation  All India Institute of Medical Sciences, New Delhi 
Address  Department of Neurology, AIIMS, New Delhi

South West
DELHI
110029
India 
Phone  9013844274  
Fax    
Email  arun_ela@yahoo.com  
 
Source of Monetary or Material Support  
All India Institute of Medical Sciences, Intramural research grant 
 
Primary Sponsor  
Name  All India Institute of Medical Sciences New Delhi 
Address  AIIMS New Delhi 
Type of Sponsor  Research institution and hospital 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Arunmozhimaran Elavarasi  All India Institute of Medical Sciences, New Delhi  Room no 706, Department of Neurology, Ansari Nagar, New Delhi
South West
DELHI 		 9013844274

arun_ela@yahoo.com 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
Institute Ethics Committee AIIMS  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: G031||Chronic meningitis, (2) ICD-10 Condition: G01||Meningitis in bacterial diseases classified elsewhere,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Cyclophosphamide  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 mesna 50% administered prior to infusion and 50% after the infusion of cyclophosphamide 
Comparator Agent  Placebo-normal saline  Participants randomized to the placebo group will be given similar quantity of normal saline and mesna as described above 
 
Inclusion Criteria  
Age From  14.00 Year(s)
Age To  60.00 Year(s)
Gender  Both 
Details  1.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
2.Atleast 14 years of age of all sexes
3.Not more than 60 years of age at time of enrolment
4.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
5.Developed paraparesis/quadriparesis/sphincter dysfunction due to spinal radiculomyelitis OR vision loss due to due to optico-chiasmatic arachnoiditis with imaging evidence of arachnoiditis
6.Has received standard ATT for atleast 3 months with adequate dose and compliance
7.Received corticosteroids for treatment of arachnoiditis and deemed to be refractory to corticosteroids by the primary physician treating the patient
8.MRI brain and spine are suggestive of Arachnoiditis
9.CSF GeneXpert/Line Probe assay/cultures are not suggestive of drug resistant tuberculosis
10.Reasonable clinical certainty OR allied investigations such as CECT chest/abdomen/PET CT ruling out drug resistant tuberculosis
11.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.
12.Willing to undergo periodic assessment clinically and with MRI.
13.Ready to provide consent for cyclophosphamide therapy
14.Willing to adhere to protocol and comply with follow up visits 
 
ExclusionCriteria 
Details  1.Not willing to provide consent
2.Not willing to adhere to protocol
3.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
4.Drug resistant tubeculosis
5.Men and Women of childbearing potential who are not using adequate contraception or women who are pregnant and lactating
6.Patients who are on immunosuppressants such as cyclophosphamide/ azathioprine/ methotrexate/MMF/ calcineurin inhibitors for autoimmune conditions/post transplantation or chemotherapy for any systemic malignancy
7.HBsAg, HIV serology and anti HCV positive
8.Having life threatening infections such as pneumonia/urosepsis
9.Patients who have developed large artery strokes with significant brain parenchymal damage
10.Patients with expected life expectancy less than 1 year due to primary disease or comorbidity based on clinical prediction scores for specific disease
11.Patients with systemic malignancy within the last 5 years
12.Known allergy to cyclophosphamide or its preservatives/excipients
13.Receiving cyclophosphamide for any indication in the last 12 weeks
14.Gross hematuria prior to enrolment to the study/USG features of hemorrhagic cystitis
15.Cytopenias Hct <25%, TLC<4000/mm3 or Platelet count <1,20,000/mm3 at the time of enrolment
16.Alanine amino transferase (ALT) > 3 upper limit of normal at time of enrolment 
 
Method of Generating Random Sequence   Stratified block randomization 
Method of Concealment   Sequentially numbered, sealed, opaque envelopes 
Blinding/Masking   Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded 
Primary Outcome  
Outcome  TimePoints 
To compare the proportion of patients who attain functional independence (mRS 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 Outcome  
Outcome  TimePoints 
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.  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.  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  6 months 
To compare the proportion of patients improving from mRS ≥3 to mRS ≤2 six months post cyclophosphamide therapy  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 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  6 months 
Shift analysis pre-and 6 months post therapy in terms of change in mRS  6 months 
Comparing Global patient well being as assessed by SF-36 pre and 6 months post cyclophosphamide therapy  6 months 
Occurrence of life threatening infections necessitating cessation of therapy upto 3 months post cyclophosphamide therapy  3 months 
Occurrence of infections needing hospitalization or intravenous antibiotic/antiviral/anti-fungal therapy upto 3 months post cyclophosphamide therapy  3 months 
Flare up of underlying tuberculosis upto 3 months post cyclophosphamide therapy  3 months 
Occurrence of Grade III cytopenias defined as per common terminology criteria for adverse events v 5.0 upto 6 weeks post cyclophosphamide therapy  6 weeks 
Grade III transaminitis as per CTCAE v 5.0 upto 6 weeks post cyclophosphamide therapy  6 weeks 
Occurrence of hemorrhagic cystitis upto 2 weeks post cyclophosphamide therapy  2 weeks 
Any other significant adverse effect  12 weeks 
 
Target Sample Size   Total Sample Size="40"
Sample Size from India="40" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 2/ Phase 3 
Date of First Enrollment (India)   30/11/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="2"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   nil 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - NO
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

In our Department, 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.  
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