MAIN STUDY: Switching Relapsing Multiple Sclerosis Patients Treated With Natalizumab at Risk for Progressive Multifocal Leukoencephalopathy to Teriflunomide: Is This Safe and Effective? SUB-STUDY: Analysis of JCV Antibody Index in MS Patients Treated With Teriflunomide
Phase: PHASE4
Conditions: Multiple Sclerosis
Sponsor: Providence Health & Services

 
 
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Study Title:   
Analysis of John Cunningham virus (JCV) antibody index in MS patients treated with 
teriflunomide (SWITCH-JCV) 
 
This is an addendum to add JCV antibody index test for patients who had participated in the 
previously approved study: SWITCH (Switching Relapsing Multiple Sclerosis Patients Treated with 
Natalizumab at Risk for Progressive Multifocal Leukoencephalopathy to Teriflunomide: Is this 
safe and effective?) 
 
Investigators & Site information:  
 
Stanley Cohan, MD, PhD (Principal) 
Providence Multiple Sclerosis Center, Providence Brain & Spine Institute (Coordinating center and 
regulatory sponsor for this sub-study)  
9135 SW Barnes Rd, Ste. 461, Portland, OR 97225 
503-216-1150 (Phone) 
503-216-1039 (Fax) 
 
 
Keith Edwards, MD 
 
Multiple Sclerosis Center of Northeastern New York 
 
1182 Troy Schenectady Rd, Ste. 203, Latham, NY 12110 
 
518-785-1000 (phone) 
 
518-785-5000 (Fax) 
  
Funder: 
 
Sanofi Genzyme 
 
 
  
Protocol Addendum:  
05FEB2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Background rationale for the proposed addendum: 
1. John Cunningham virus (JCV) is the responsible organism for the development of progressive 
multifocal encephalopathy (PML). Multiple sclerosis (MS) patients treated with natalizumab 
(NTZ), who have evidence of exposure to JCV have a significantly elevated risk, as high as 12/1000 
patients, of developing PML, necessitating the elective transition of patients off NTZ. 
2. JCV is a member of the polyoma virus family, and closely related to BK virus. BK virus has been 
found to be a significant threat to destroy transplanted kidneys and there is growing evidence 
that treatment with leflunomide, the pro-drug of teriflunomide (TFM) clears BKV from the kidney. 
3. Our previously approved SWITCH protocol assessed the clinical efficacy of TFM in MS patients 
transitioned off NTZ solely because they have evidence of exposure to JCV, as determined by the 
presence of serum anti-JCV IgG. Previous work by other investigators has demonstrated a close 
correlation between positive anti-JCV antibody titers and the presence of active JCV infection. 
4. Because there is evidence that JCV is closely related to its fellow polyoma virus BKV, and that BKV 
is cleared by treatment with the TFM pro-drug leflunomide, we propose to determine if treatment 
of the JCV antibody positive patients currently enrolled in the approved protocol results in 
reduction in, or reversion to negative, of the anti-JCV antibody titer as measured by the JCV 
antibody Index, a commercially available assay which is used internationally as the standard for 
evidence of JCV exposure in NTZ-treated patients. 
 
Study Hypothesis: 
TFM will inhibit JCV proliferation and there will be a reduction, or conversion to negative of the 
anti-JCV antibody Index in patients enrolled in this study being treated with TFM. 
 
Study Objective:  
To study the number of patients experiencing a reduction in the anti-JCV antibody Index value in 
patients who had received at least one dose of TFM during participation in the SWITCH protocol.  
 
Study Population: 
The 55 patients, who were taken off NTZ because of a positive anti-JCV ab titer and received at 
least one dose of daily 14 mg TFN as part of the SWITCH study, will be contacted to obtain 
written informed consent for a blood draw to collect a follow-up serum sample for the anti-JCV 
Index test. 
 
Methods: 
We propose, after signed informed consent, to draw a follow-up serum sample within 30 days of 
consent to determine if there has been a change in the anti-JCV ab Index value. Patients who 
consent to participate in this sub-study will have the blood draw at a local, contracted Quest 
Diagnostic Lab.  The study coordinator will perform a chart review and use prior collected 
information from the SWITCH study to collect duration of TFM therapy and use of other DMT(s) 
if patient is no longer being treated with TMF. Each patient will be contacted via phone 5 ± 2 
days after their blood draw to collect and assess adverse events. Analysis will include the 
number and percentage of patients reverting to negative titers, and the relationship between 
the total number of TFM doses received and/or duration of TFM therapy, and subsequent anti-
JCV ab Index.  
 

 
 
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Statistical Analysis: 
For patients who received at least one dose of TFM in the SWITCH protocol and consented to 
additional anti-JCV Index testing in the sub-study protocol, we will examine: 
1. The number and percentage of patients reverting to negative anti-JCV antibody status 
2. The number and percentage of patients having a reduced anti-JCV antibody  index but still 
positive anti-JCV antibody status 
3. The relationship between dosing of TFM and a) change in anti-JCV antibody index, and b) change 
in anti-JCV antibody status using correlation and regression analyses 
4. AEs and SAEs will be summarized 
 
Study Population:  
 
Eligibility Criteria:  
1. Must have been enrolled in the SWITCH protocol and received at least 1 dose of 
14mg TFM during the study period.  
2.  Must be willing to sign written informed consent for this JCV sub-study and follow 
the protocol requirements. 
 
Adverse Events:  
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution. Pre-existing conditions which worsen during the study period are to be 
reported as AEs. The patient should be followed and treated by the investigator until the abnormal 
parameter or symptom has resolved or stabilized.  
 
The study period during which all AEs and SAEs must be reported begins after informed consent is 
obtained and ends 5 ± 2 days following the blood draw or study discontinuation/termination, 
whichever is earlier. 
 
Serious Adverse Events: 
A serious Adverse Event (SAE) means any adverse event fitting the description above but also 
containing at least one of the following: 
 
Death 
 
Life threatening experience which places the patient at immediate risk of death from the 
event as it occurred.  
 
Full Inpatient hospitalization or prolongation of hospitalization 
 
Persistent or significant disability/incapacity 
 
Congenital anomaly or birth defect 
 
Other significant medical event, per investigator judgment  
 
AE and SAE Reporting: 
Any occurrence of a SAE during the conduct of the study will be reported on a MedWatch Form FDA 
3500 to the Providence Regional Research Regulatory Office via email or fax 503-215-6547 within 24 
hours of the investigator learning of the event.  The site will also report the SAE to the IRB of record per 
its policy, if the SAE meets the IRB reporting requirements.  As the regulatory sponsor, the Providence 
Regulatory Manager will be responsible for submitting the MedWatch Form FDA 3500 to the funder.