Clinical trial NCT01970410
Conditions: Multiple Sclerosis
Keywords: teriflunomide natalizumab relapsing multiple sclerosis
Sponsor: Providence Health & Services
Start date: 2013-10-01; Completion date: 2022-02-14
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
MAIN STUDY: The purpose of this study is to determine if teriflunomide will be safe and effective to prevent relapses in patients with relapsing types of MS when switching from natalizumab to teriflunomide in patients at risk for PML. This is a two center interventional study of patients who have had 12 or more continuous infusions of natalizumab , who are anti-JCV-ab positive, and who had been free of clinical relapses during prior 12 months of natalizumab therapy who will be switching to teriflunomide.

SUB-STUDY: 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 teriflunomide during participation in the SWITCH protocol (main study).

Detailed description:
MAIN STUDY: Teriflunomide (TFM) is the primary metabolite of leflunomide, which is marketed worldwide for the treatment of rheumatoid arthritis. Teriflunomide inhibits dihydroorotate dehydrogenase( DHODH), the forth enzyme in the de novo synthesis pathway of pyrimidines. Activated T-lymphocytes utilize both the de novo pyrimidine and salvage pathways of pyrimidines ribonucleotide synthesis.After mitogen stimulation, teriflunomide inhibits in vitro T cell proliferation, DNA and RNA synthesis and expression of cell surface and nuclear antigens that are directly involved in T-cell activation and proliferation.

Natalizumab (NTZ) is a FDA approved treatment for relapsing-forms of multiple sclerosis (MS) with pivotal studies showing an annualized relapse-rate (ARR) reduction of 68%, a reduction of new Gadolinium "enhancing" (Gd+) lesions by 92% and a reduction of disability of 42% compared to placebo. NTZ is highly effective in controlling MS but the risk of developing progressive multifocal leukoencephalopathy (PML) increases with the duration of the use of natalizumab. It can have a serious and life threatening complication in about 1 in 500 to 1 in 250 patients who have had more that 18 infusions due PML and who have a detected antibody (Ab) for the JC virus. The risk of PML is much greater in patients who have had prior immunosuppressive (IS) treatment. The combination of detected anti-JCV Ab , duration of NTZ treatment of greater than 24 months and prior IS increases the risk of development PML to an incidence of 11 per 1000 treated patients. So there is a need to have an alternative MS disease modifying treatment (DMT) to use for patients at risk to develop PML from NTZ treatment that might be sufficiently effective for MS so as not to have the patients' MS worsen while lowering or eliminating the risk of PML.

SUB-STUDY: 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.

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.

Main study 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 immunoglobulin G (IgG). Previous work by other investigators has demonstrated a close correlation between positive anti-JCV antibody titers and the presence of active JCV infection.

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.

Arms: arm 1: Teriflunomide 14 mg oral teriflunomide daily
Interventions: intervention 1: teriflunomide
Intervention descriptions: intervention 1: 14 mg oral teriflunomide daily

Protocol documents:
Prot_SAP_001.pdf: 
Study Protocol Cover Page  
Official Study Title: Switching relapsing multiple sclerosis patients treated with natalizumab at risk for 
progressive multifocal leukoencephalopathy to teriflunomide: Is this safe and effective? 
NCT#: NCT01970410 
 
Note: IRB approval letter included and the February 25, 2015, date is the date the protocol was printed 
and saved. The document date and approval date is listed as February 24, 2015. 


 
This letter also serves as notification that our Institutional Review Board is organized and operates in compliance with Good Clinical 
Practice Guidelines as defined by the U.S. Food and Drug Administration under the Code of Federal Regulations (21 CFR Parts 50 
and 56) and the Department of Health and Human Services regulations (45 CFR Part 46) pertaining to the protection of human 
subjects in research. 
 
 
 
 
 
 
 
 
 
 
 
MEMORANDUM 
 
 
Date:  February 25, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
To:  
Stanley Cohan, MD, PhD 
C/o:  
Katie Orwoll, Regulatory Associate, Providence Regional Research Office 
From:  Heather Murchison, Administrative Assistant, PH&S Institutional Review Board 
 
Re: FULL-BOARD APPROVAL OF PROTOCOL MODIFICATION FOR: 
(14-011B) Switching relapsing multiple sclerosis patients treated with natalizumab 
(Tysabri ®) at risk for progressive multifocal leukoencephalophy to teriflunomide 
(Aubagio®): Is this safe and effective?  PI: Stanley Cohan, MD, PhD 
 
 
This letter acknowledges the protocol modification notice concerning the following revisions to 
this study: 
 
 
Amended Protocol, tracked and clean versions.   
 
Addition of Drs. Ben Jacobson and Alan Morimoto, Removing Dr. John Roll  
 
This report was approved at the full board meeting held on February 24, 2015. 
 


Page 1 of 14 
 
 
CLINICAL TRIAL PROTOCOL 
 
________________________________________________ 
 
Compound:  Teriflunomide 
 
 
Title of Study:   
 
Switching relapsing multiple sclerosis patients treated with 
natalizumab at risk for progressive multifocal leukoencephalopathy 
to teriflunomide:  Is this safe and effective? 
 
 
Investigators Names:  
Keith Edwards, M.D. 
Stanley Cohan, M.D., Ph. D 
                              
 
Locations:   
Multiple Sclerosis Center of Northeastern New York 
1205 Troy-Schenectady Road, Suite 105 
Latham, NY 12110   P: 518-785-1000   F: 518-785-5000 
 
Providence Multiple Sclerosis Center 
9427 SW Barnes Road, Suite 595 
Portland, OR 97225    P: 503-216-1150 
 
 
 
 
 


Page 2 of 14 
 
 
 
1. Introduction and rationale: 
 
Teriflunomide   
 
Teriflunomide is the primary metabolite of leflunomide, 1 which is marketed worldwide for the 
treatment of rheumatoid arthritis.  Teriflunomide inhibits dihydroorotate dehydrogenase                
( DHODH), the forth enzyme in the de novo synthesis pathway of pyrimidines. 2  Activated T-
lymphocytes utilize both the de novo pyrimidine and salvage pathways of pyrimidines 
ribomicleotide synthesis. 3  After mitogen stimulation, teriflunomide inhibits in vitro T cell 
proliferation, DNA and RNA synthesis and expression of cell surface and nuclear antigens that 
are directly involved in T-cell activation and proliferation. 4   
 
Natalizumab (NTZ) is a FDA approved treatment for relapsing-forms of multiple sclerosis (MS) 
with pivotal studies showing an annualized relapse-rate (ARR) reduction of 68%, a reduction of 
new gadolinium (Gd+) lesions by 92% and a reduction of disability of 42% compared to 
placebo.5  NTZ is highly effective in controlling MS but the risk of developing progressive 
multifocal leukoencephalopathy (PML) increases with the duration of the use of natalizumab.   It 
can have a serious and life threatening complication in about 1 in 500 to 1 in 250 patients who 
have had more than 18 infusions and who have a detected antibody (Ab) for the JC virus. 6  The 
risk of PML is much greater in patients who have had prior immunosuppressive (IS) treatment.  
The combination of detected anti-JCV Ab , duration of NTZ  treatment of greater than 24 months 
and prior IS increases the risk of developing PML to an incidence of 11 per 1000 treated patients.  
7 There is a need to have an alternative MS disease modifying treatment (DMT) to use for 
patients at risk of developing PML from NTZ treatment that might be sufficiently effective so as 
not to have the patients’ MS worsen while lowering or eliminating the risk of PML. 
 
Many neurologists treating MS patients have not prescribed natalizumab due to a fear of PML 
developing in their patients.  If an effective treatment alternative could be found for patients who 
have been treated with natalizumab for 12 months or longer and who test positive for the anti-
JCV-Ab, perhaps more neurologists would use natalizumab earlier in the disease state for patients 
with unstable disease.   Conversely, for patients with anti-JCV-Ab detected who have been 
treated with natalizumab for more than 12 months, many are continued on natalizumab due to 
fear that their MS might exacerbate off of the medication. 
 
In a single center report  of NTZ withdrawal in an attempt to lower the risk of PML,  32 patients 
who have received more than 12 months of NTZ were withdrawn from NTZ and  not placed on 
any other disease modifying therapy (DMT).  Eleven of the patients (38%) had at least moderate 
relapse of their MS and 2 had a severe relapse with an immune reconstitution inflammatory 
syndrome (IRIS) with multiple gadolinium enhancing (Gd+) lesions with edema. 8  Two of the 
patients who relapsed during the NTZ withdrawal had relapsed while receiving therapy.   There 
was a higher rate of relapse in patients who were a bit younger (mean of 32.5 versus 40.6).   In 
another reported observation series of NTZ withdrawal, patients who did receive an alternative 
DMT did have a much lower relapse rate and they were no cases of IRIS-like syndrome.9 
 
In two controlled studies of NTZ withdrawal, approximately 1/3 of patients withdrawn from NTZ 
experienced either a clinical or MRI relapse or both regardless of post-NTZ treatment.  Eighty-
eight patients treated with NTZ for 24 months in Italy, who were anti-JCV-Ab positive were 
continued on NTZ, on another DMT or on no DMT.  Those continued on NTZ experienced a 


Page 3 of 14 
 
3.7% exacerbation rate over one year, those on another DMT experienced a 17.8% exacerbation 
rate and those on no DMT had a 16.7% exacerbation rate. 10  Teriflunomide was not one of the 
DMTs used in this study but it did not appear that the use of a DMT affected the exacerbation 
rate, although the initiation of the DMT used varied widely. 
 
Another study followed 175 patients who had been treated with NTZ for 12 months or greater.  
Anti-JCV-Ab status was not considered.  There was a 3 month interval between the last dose of 
NTZ and the initiation of a DMT which may have been IVMP, GA, IFN or placebo.  The 
observed relapses clinically and/or of Gd+ recurrence was between 3 and 4 months and often 
proceeded by an elevation of alpha4-integrin saturation. 11 The focus of the report was that of PK, 
PD and MRI measurements rather than clinical status so that details of clinical status were not 
reported but there were several patients noted who had more than 10 acute Gd+ lesions with acute 
black holes indicating that, at least a few patients, had a hyperacute withdrawal from NTZ that 
was more severe than just a return to baseline MS activity prior to NTZ treatment. 
 
In a treatment trial with IVMP after NTZ withdrawal, IVMP was found not to prevent return of 
MS disease activity or rebound activity. 12  Forty-three patients were given IVMP for 6 months 
after NTZ withdrawal on a monthly basis.  Twenty patients (42%) had radiological or clinical 
disease activity above that seen in the pre-NTZ period and 9 patients (19%) had ‘rebound’ 
activity or 5 or more Gd+ lesions.   
 
The use of fingolimod (FTY) to reduce recurrence of disease activity after NTZ discontinuation 
has been successful but it is highly correlated to when FTY is begun in relation to NTZ 
discontinuation. 13  Thirty-nine patients who switched to FTY after 24 weeks on NTZ were 
compared to 9 patients who became treatment free (TF).   Nineteen (49%) patients in the FTY 
group compared to 7 (77%) patients in the TF groups experienced relapses after cessation of NTZ 
within 13 and 16 weeks.   However, if FTY were begun in fewer than 12 weeks after FTY 
cessation, the ARR was reduced from 1.4 to 0.4.  The percentage rate of relapse was not reported 
but it can be estimated, from the data, to be approximately 24% instead of 49% for those begun 
on fingolimod by 12 weeks after NTZ discontinuation.  Earlier treatment initiation of fingolimod 
after NTZ discontinuation was not reported. 
 
Another observation study did not show any benefit from any DMT after NTZ discontinuation.14   
From a total of 119 patients treated with NTZ, 36 stopped NTZ.  At 1 year, the cumulative 
probability of relapse was 46% with the risk of relapse not modified by alternative therapy 
introduced after NTZ.  “Despite the relative small size of our study and the various alternative 
therapies proposed, the association of methlyprednisolone with immunomodulator did not avoid 
the recurrence of the MS inflammatory activity, as attested by MRI Gd+ lesions and the 
occurrence of IRIS, responsible for EDSS increase.”  Teriflunomide was not among the options 
of DMT treatment, but half of the MS patients discontinued from NTZ returned to pre-NTZ 
treatment status or worsened, sometimes with an IRIS-like status similar to that reported by Dr. 
Kinkel. 15   
 
So in a review of the literature, including recent meetings, there is no consensus, and no data 
available to indicate what treatment could change the natural course of events to allow a 
significant relapse rate to occur after withdrawal from NTZ. It appears that early treatment with 
an effective and safe DMT may alter this poor prognosis of treatment withdrawal from NTZ.   
Teriflunomide may be that DMT. 
 
With continued MRI and clinical vigilance, any PML patient should be identified rapidly and 
appropriate intervention begun.   This is to be compared to the return of relapse rate or more 


Page 4 of 14 
 
serious disease in a few months after NTZ discontinuation unless an effective and safe alternative 
can be identified. 
 
Our own experience with transition from NTZ to teriflunomide is limited but so far favorable.  
Since the availability of teriflunomide in September, 2012 we have had a total of 15 patients who 
had been on NTZ over 24 months with anti-JVC-Ab positive status switch from NTZ to 
teriflunomide.. The mean number of days from the last NTZ infusion to the first dose of 
teriflunomide was 39 days.   Of these 15 patients, one discontinued due to diarrhea after 20 days, 
but the other 14 had good tolerance   Four of the patients have been on teriflunomide for fewer 
than 30 days at this time so that no meaningful comment of stability after NTZ withdrawal can 
yet be stated. The remaining 10 patients have been on teriflunomide for a mean of 87 days with 
five of this patients on teriflunomide more than 120 days.  None of the patients experienced any 
recurrent or new MS symptoms and none have had an exacerbation at this time. 
 
 
2. Study and Safety Objectives 
 
A priori concept:  that teriflunomide will be safe and effective to prevent relapses in patients 
with relapsing types of MS when switching from NTZ to teriflunomide in patients at risk for 
PML  provided that the switch to teriflunomide from the last dose of NTZ is carried out in 
fewer than 4 weeks and provided that the patient has been clinically and radiologically stable 
during the NTZ treatment period.  
 
2.1. Primary objective  
 
  Proportion of patients relapse free at 12 months 
 
2.2  Secondary objectives   
 
1) Time to return of radiological evidence of MS activity with new Gd+ lesions on cranial 
MRI. 
2) EDSS sustained progression for 3 months as measured by at least 0.5 increase from     
baseline or 1 in any EDSS set score. 
3) Number of new T2 or enlarging T2 hyperintensities on monthly sentinel brain MRIs    
 
3. Study design 
 
Patients with relapsing forms of MS, ages 21 to 60, male or female, not pregnant and not 
lactating and not planning to become pregnant during the study, who have had 12 or more 
continuous infusions of NTZ , who are anti-JCV-ab positive, and who had been free of 
clinical relapses during prior 12 months of NTZ therapy will be offered participation in this 
study.   There will be limited wash-out period after discontinuation from natalizumab. It will 
be expected that each patient will be able to begin teriflunomide at 4 weeks (+/- 7 days)after 
last  dose of NTZ based on formulary limitation.  After informed consent is obtained 
screening measures will be completed including TB screening either with a PPD skin test or 
quantiferon gold for tuberculosis, a non blinded EDSS, 3T brain MRI,  complete metabolic 
panel and CBC, and if female and potentially fertile, serum HCG will obtained.  
The Becks depression scale will also be completed at this time. 
 


Page 5 of 14 
 
Duration of the first phase of the trial will be six months . Liver function tests (LFTs) will be 
done per FDA guidelines, urine HCG for females of childbearing potential, contrast enhanced 
brain MRI,  physical exam,  neurologic exam and EDSS will be performed.  Adverse Events 
(AE’s)s will be recorded along with any change in concomitant medications.   At subsequent 
clinic visits, Physical, EDSS and AE recordings will be at months 9, 12, 18 and 24. CBC and 
Metabolic panel laboratory evaluations  at months 12,18, and 24, and  MRI will be done at 
months 12 and 24. Symbol Digit (SDMT) will be administered at Baseline, months 6, 12 and 
24.     
 
There will be an interim analysis of data outcome and safety measures at 6 months,  12 
months and 24 months. 
 
After screening measures are completed and results reviewed, patients who qualify for the 
study will begin teriflunomide 14 mg daily within 4 weeks (+/- 7 days) of their last dose of 
NTZ.   The first monthly brain MRI will be carefully reviewed and compared to baseline 
MRI to be sure there is no emergence of PML at that time.    
 
 
3T brain MRI will be performed with standard MS protocol using Gadovist (gadobutrol) at a 
dose of 0.1 mL/kg (0.1 nmol/kg) with post-contrast administration to begin no sooner than 10 
min after administration. 
 
The three main readers who each will back up the other are Joseph Cousins PhD MD, 
Gaetano Pastena MD and James Thomas MD from the Albany (Latham) site using Siemens 
3T Verio, or the GE 3T  and Drs John Roll and Alan Morimoto  from the Portland (OR) site 
using Philips Achieva 3.0T, to be done at Center for Medical Imaging-Tanasbourne. Dr. 
Thomas will be the overall reviewer for all MRIs. All scans will include  the following: 
1. 1mm 3d FLAIR T2 sequence with reformat 3mm sagittal and axial 3mm (Scans will be        
3mm thick only)  
32. Axial t1 pre contrast 3mm thick 
3. Axial DWI  
4. Axial t2 tse 3mm thickness   
5. 3mm thick axial Spin Echo T1 post contrast.  
Contrast agent: gadobutrol weight based single dose. 10 minute delay after injection and post   
contrast scan.  
 
See flow sheet for study specific measures. 
  
Adverse Events that are recorded during the trial and are considered to be study related and 
significant by the investigator,  will be reported to the study sponsor and to Medwatch by the 
sponsor. 
      
 Study medication for this trial will be supplied through the subjects medical insurance.    
This trial does not have placebo element, therefore there will be no method of applying 
subjects to a treatment group. 
 


Page 6 of 14 
 
Statistical Analyses:   
 
In general, continuous variables will be presented with summary statistics (mean, standard 
deviation, median, range), and categorical variables will be presented with frequency 
distributions.  All analyses will be conducted using 2-sided confidence intervals at the 0.05 
significance level, unless otherwise stated. 
 
Primary Analyses: 
 
The proportion of patients relapse-free at Month 12 will be analyzed using Kaplan-Meier 
survival analysis methodology.  
 
Secondary Analyses: 
 
EDSS sustained progression for 3-month as measured by at least 0.5 or 1 (in any functional 
system (FS) score) point increase from baseline will be summarized. Time to return of 
radiological evidence of MS activity and ttime to EDSS sustained progression will be 
analyzed using Kaplan-Meier survival methods. 
 
Number of new T2 or enlarging T2 hyperintensities on MRI will be summarized by visit. 
 
AEs and SAEs will be summarized. Patients who discontinued treatment will be summarized 
as well. 
 
4. Approximate number of patients to be evaluated: 60  completers  with up to 70  to be 
enrolled if needed with an expectation of 80% completion rate.   
 
 
5. Study population 
 
5.1. Inclusion criteria:  
   
1. Male and female patients, age 21 to 60 with relapsing forms of MS, treated with 
natalizumab for 12 consecutive months or longer with anti-JCV Ab positive during 
that time period. 
2. Able to understand and sign Informed Consent Document. 
3. Stable disease during treatment with natalizumab.   No clinical relapses for at least 12 
months. 
4. Stable MRI on follow-up MRI scans for prior 12 months without evidence of new or 
enlarging T-2 hyperintensities or Gd+ lesions. 
5. No evidence of significant cognitive limitation or psychiatric disorder. 
6. EDSS of 1.0 to 6.0 inclusive. 
 
 
 
 
 
5.2. Exclusion criteria 
 


Page 7 of 14 
 
1. Any mental condition of such that patient is unable to understand the nature, scope 
and possible consequences of the study. 
2. Patients that are known HIV positive. 
3. Patients with a known history of hepatitis. 
4. Known history of active tuberculosis not adequately treated, or a positive ppd skin 
test or positive quantiferon gold.  
5. Any persistent or severe infection. 
6. Any malignancy within 5 years, except for Basal or Squamous cell skin lesions, 
which have been surgically excised, with no evidence of metastatis. 
7. Clinically relevant or unstable cardiovascular, neurological (i.e. progressive 
weakness, increasing hypesthesia), endocrine, or other major systemic diseases. 
8. History of drug or alcohol abuse within the past year. 
9. Any significant depression or psychiatric disease (BDI II greater than 25) within the 
past year. 
10. Any significant lab abnormality as deemed by the investigator including but not 
limited to the following: 
a) Hypoproteinemia with serum albumin < 3.0g/dl. 
b) Serum creatinine >133umol/L (or >1.5 mg/dl) 
c) Hematocrit <24% and/or  
d) Absolute white blood cell count < 4,000 cells/mm3 (µl) and/or 
e) Platelet Count <150,000 cells/mm3 (µl) and /or 
f) Absolute neutrophil < 1,500 cells/mm3 (µl) 
g) Liver function impairment or persisting elevations of SGPT/ALT, 
SGOT/AST, or direct bilirubin greater than 1.5 fold the upper limit of 
normal. 
11. Any confounding illness or other diseases of the spine or bone that would impair 
evaluation of the patient or treatment effects. 
12. Any clinical, CSF or MRI evidence for PML, from historical MRI review and results 
of screening MRI 
13. Prior treatment with immunosuppressive drugs except for past use of intravenous 
steroids to treat MS relapses. 
14. Pregnant or breast feeding women. 
15. Women of childbearing potential not protected by effective contraceptive method of 
birth control and/or are unwilling or unable to be tested for pregnancy.  
 
Known history of hypersensitivity to teriflunomide or leflunomide 
16. Known history of hypersensitivity to teriflunomide or leflunomide. 
17. Known history of chronic pancreatic disease or pancreatitis. 
18. Prior use within 4 weeks before randomization of   cholestyramine, or products 
containing St. John’s Wort or concomitant use of  Glatiramer acetate, interferons or 
any other FDA approved DMT due to potential confounding effects on efficacy 
results. 
 
 
 


Page 8 of 14 
 
 
6. Breakthrough disease 
 
1. Definition of relapse:  a new objectively verified neurologic sign not associated with 
fever or infection, lasting at least 24 hours with an increase of one or more grade in two 
or more scales if the EDSS, or an increase of 2 or more grades in one functional scale.  IF 
the patient has a baseline EDSS of 5.5 or 6.0, then an increase of 0.5 or greater in EDSS. 
2. Treatment:  if there is clinically appropriate need for treatment, then a standard dose of 
intravenous methyprednisolone (IVMP), usually 1000 mg for 3 consecutive days. 
 
 
7.  Criteria to reduce reproductive risk 
 
Female subjects must not be breast feeding or pregnant (as confirmed by a serum pregnancy 
test) at the time of study entry and must agree to undergo urine pregnancy testing  
throughout the study.  In addition a pregnancy test should be conducted in case of an 
unexpected delay of menorrhea. 
 
For subjects of childbearing potential/child fathering potential, an adequate contraception 
method is required to prevent pregnancy during the course of the trial and while taking 
teriflunomide. The adequate contraception method is up to the Investigator’s discretion. The 
contraception method must be clearly documented in the source documents. The importance 
of not fathering/bearing a child while using teriflunomide is to be communicated to the 
subject and is the responsibility of the treating Investigator. The subject is to be counseled by 
the Investigator on the importance of reporting to site staff a delayed onset of menses or if 
they have any suspect of pregnancy in themselves or female partner. If the subject is not of 
childbearing potential/child fathering potential or their partner is not of childbearing 
potential/child fathering potential, this must also be documented clearly in the source 
documents. 
 
 
8.  Concomitant Treatments 
 
All treatments being taken by the patients on entry to the study or at any time during the 
study are regarded as concomitant treatments and should be documented.  A history of 
previous treatments for MS should be documented for the prior 2 years,   
 
Medications that are permitted during the study may be used as clinically indicated at the 
physician’s discretion.   However, medication with a low therapeutic index such as digoxin 
should be carefully monitored.  All efforts should be made to adhere to the same dosing 
regimen during the conduct of the trial.  The combined use of teriflunomide and nonsteriodal 
anti-inflammatory drugs (NSAIDS) may be associated with an increased incidence of 
hypertension.  Blood pressure (BP) must be monitored carefully before treatment and at 
regular visits during study medication administration.   
 
The following concomitant treatments or any prior use of these treatments are not permitted 
due to potential effects on the immune system: 
• 
Cladribine or mitoxantrone 
• 
Azathioprine, cyclophosphamide, cyclosporine, methotrexate, or mycophenylate 
• 
Leflunomide and any prior use of teriflunomide. 
 


Page 9 of 14 
 
       The following treatments are not permitted during the study and prior to entry into the study 
       For durations noted, due to potential pharmacokinetic or pharmacodynamic interactions with    
       The study medication: 
 
• 
St. Johns Wort products containing hyperforin in an unknown percentage or greater 
than 1% of the extract. High amounts of hyperformin in St Johns Wort extract has 
been shown to induce CYP3A4 enzymes and potentially increase ethyl estradiol and 
norethindrone clearance. 
• 
Cholestyramine or activated charcoal, which results in the accelerated elimination of 
teriflunomide  
• 
Glatiramer acetate, interferons or any other FDA approved DMT due to potential 
confounding effects on efficacy results. 
 
 
9. Adverse Events 
 
 
Per International Conference of Harmonization (ICH) guidelines, an AE for this trial will be 
any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign, including an 
abnormal laboratory finding, symptom, or disease temporally associated with the use of a 
(investigational) medicinal product, whether or not considered related to the medicinal 
(investigational) product. Pre-existing conditions which worsen during a study are to be 
reported as AEs. All adverse events fitting this description will be captured and recorded on     
the case report forms. 
 
In the event that a subject is withdrawn from the study because of an adverse event, it must 
be recorded on the CRF as such.  The subject should be followed and treated by the 
investigator until the abnormal parameter or symptom has resolved or stabilized.  
 
Serious Adverse Events 
 
A serious Adverse Event (SAE) means any adverse event fitting the description above but 
also containing one of the following: 
 
• 
Death 
• 
Life threatening experience which places the subject 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 
 
Any reports of these events during the conduct of the study will immediately be reported to 
the sponsor,  and  the IRB within 5 days of the investigator learning of it . The sponsor will 
alert the FDA and submit to Medwatch.  The Medwatch FDA Form 3500 should be used 
when submitting an SAE. 
 
Discontinuation of Study Treatment 
 


Page 10 of 14 
 
1. If the patient becomes pregnant (accelerated withdrawal protocol to be used) 
2. at the discretion of the Investigator for medical or ethical reasons. 
3. If the patient withdraws consent 
4. If the patient is unwilling or unable to comply with the protocol 
 
Any patient discontinuing teriflunomide may be treated with an 11day course of 
cholestyramine or activated charcoal according to standard use protocol if indicated. 
 
Data Safety Monitoring Board (DSMB) 
 
A DSMB will be established consisting of 3 respected scientists, not involved with the study 
or with Genzyme, to periodically review developing outcomes and safety data.   The DSMB 
is an independent, paid committee with dual responsibility for the overall safety of the 
participants and integrity of the study. The DSMB can make recommendations to discontinue 
the study permanently or to place the study on hold to determine if the study is safe to 
continue.  The DSMB will provide a written summary of their periodic reviews and 
recommendations’ which will then be forwarded by each investigator to their Investigational 
Review Board (IRB)  
 
There will be an interim analysis of data outcome and safety measures at 6 months to include 
the first 20 patients completing the month 6 visit, and subsequently at 12 months and 24 
months. 
 
 
 
10.    Expanded Disability Status Scale (EDSS) 
 
Based on a standard Neurological Examination, the 7 functional systems  are rated per 
standard format. 16 The EDSS are administered in person by the treating neurologist and is 
not a blinded exam  
 
11. Becks Depression 
The Beck Depression Inventory-II (BDI-II) is a multiple-choice self-report inventory, one of 
the most widely used instruments for measuring the severity of depression. 17 
 
12. Symbol Digit Modality Test (SDMT)   
 
The symbol digit modality test is brief and easy to administer and has demonstrated 
remarkable sensitivity in detecting not only the presence of brain damage but also 
changes in cognitive functioning over time and in response to treatment. 
 


Page 11 of 14 
 
Enrollment, end of study Publication/presentation plans 
 
a) submission of draft proposal, budget and payment schedule to Sanofi by Dr. Edwards and MS 
Center staff by Friday, May 31 2013 
b)  enrollment of first patient begins one month after contract received by MS Center of NE New 
York with 5-10 patient enrolled monthly.    
c) no more than 30 days expected for IRB approval and study start up ready 
d) date of first patient to first 10 patients likely to be 4 weeks after contract received and 
approved. 
e)  end of 30 patient enrollment approx Sep 31, 2014  
 
Submission to a national and/or international meeting as soon as the data have been analyzed, 
most likely ECTRIMS 2014 and possibly CMSC 2014, AAN 2014, ENS 2014.  Submission to a 
peer review journal within 6 months of study analysis completion (Neurology or MSJ). 
 
 
13.  Source Documentation and Case Report Form Completion 
 
Source documents are defined as original documents, data and records.  These may include    
hospital records, clinical and office charts, lab results, cognitive data and information, etc.  
The Case Report Form documents will serve as the source records for this trial.  All forms 
will be completed within 5 business days of the study visit. A CRF will be provided for each 
enrolled study subject. All CRFs will be completed using black ink.  All corrections will be 
made by striking through with a single line and writing correct data above, beside, or below 
the erroneous data, so as not to obscure the original entry.  Each correction will be initialed 
and dated by the person making the correction.  
 
Dr. Edwards’ site will create the CRFs, monitor data and submit data to Dr. Ma for statistical 
analyses.  Dr. Cohan’s site will prepare the ICF.    Dr. Cohan’s site will provide study data to 
Dr. Edwards’s site. (fax:  518-785-5000 or by pdf:   kedwards@tristateneuro.com   and              
cgorman@tristateneuro.com     Study data includes any AE’s. 
 
 
14.  Retention and Availability of Records 
 
The investigator will maintain adequate records for the protocol including signed Informed 
consents, patient information sheets, completed source documents,  CRF’s,  Lab reports, 
Medical records, AE reports and information regarding all subjects who discontinued.   
 
 
15. Ethics 
 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigators Brochure if applicable, informed consent/assent, and all other forms of 
subject information related to the study (including advertisements) be reviewed by the 
IEC/IRB.  IRB approval is mandatory before initiating of any study related activities.  
The study will be conducted per the protocol, in accordance with ICH guidelines, applicable 
regulations, and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.   
 


Page 12 of 14 
 
 
16.  Use of Information/Confidentiality 
 
All information obtained during the conduct of this clinical trial is considered confidential.  This 
information may be disclosed as deemed necessary by t the MS Center of Northeastern New York 
(MSCNENY) or Genzyme to other clinical investigators, the IEC/IRB, the FDA and other 
governmental agencies.  Patient identifiers will include patient assigned number, age, and sex. 
Patient Initials will not be released to the company as this is irrelevant information.  The 
investigator will maintain a confidential subject identification code list of all subjects enrolled in 
the study by name and subject number.  This list will be maintained at the investigative site. 
 
17.  IND Safety Reporting:   Sponsor will provide 3 copies of safety reports to MSCNENY for 
distribution to Dr Cohen’s site and the IRB 
 
18.  References 
 
1. 
Gold R, Wolinsky JS. Pathophysiology of multiple sclerosis and the place of 
teriflunomide. Acta Neurol Scand 2011;124:75-84 
2.  
Fox RI, Herrmann ML, Frangou CG, et al. Mechanism of action for leflunomide in 
rheumatoid arthritis. Clin Immunol 1999;93:198-208 
3. 
Rückemann K, Fairbanks LD, CarreyEA, et al. Leflunomide inhibits pyrimidinede novo 
synthesis in mitogen-stimulated T-lymphocytes from healthy humans.J Biol Chem 
1998;273:21682-91 
4. 
Petty M, Lee L, Ying X, et al. Teriflunomide treatment reduces infiltration of 
macrophages, T cells and B cells, and increases survival of oligodendrocytes in the spinal cord of 
the Dark Agouti rat model of experimental allergic encephalomyelitis. Neurology 
2010;74:Suppl2:A415. abstract 
5. 
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of 
natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910. 
6. 
Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk 
stratification. Ann Neurol 2010; 68:295-303. 
7. Bloomgren G, Richman S, Hoterman C, et al.  Risk of natalizumab-associated PML.  NEJM 
2012; 366:1870-1880 
8. 
Miravalle A, Jensen R, Kinkel RP. Immune reconstitution inflammatory syndrome in 
patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol 2011; 
68:186-91. 
9. 
Stuve O, Cravens PD, Frohman EM, et al. Immunologic, clinical, and radiologic status 14 
months after cessation of natalizumab therapy. Neurology 2009;72:396-401. 
10.   
Clerico M, De Mercanti D, Piazza F et al.  Natalizumab discontinuation after the 24th 
course:  which is the way? The TY-STOP study.  Neurology 2013; 80: P01.197  
11.  
 Cree B, De Seze J, Fox R, et al.  Natalizumab effects during a 6-month dose interruption:  
relationship of PK, PD and MRI measurements.  Neurology 2013; 80: S41.003 
12.   
Vidal-Jordana A, Tintore M, Tur C, et al.  Natalizumab discontinuation and the role of 
corticosteroid treatment.  An observational study. P542.  Multiple Sclerosis Journal 2012; 18: 
(S4) 233 
13.   
Havla J, Tackenberg B, Hellwig K, et al.  Fingolimod reduces the risk of recurrence of 
disease activity during the first 12 months after natalizumab discontinuation in multiple sclerosis.  
P536.  Multiple Sclerosis Journal 2012; 18: (S4) 230 
14.  
 Gueguen A, Bensa C, Deschamps R et al.  Clincal and MRI aspects of immune 
reconstitution after natalizumab interruption.  P972. Multiple Sclerosis Journal 2012; 18: (S4) 48 


Page 13 of 14 
 
15.  
Miravalle A, Jensen R, Kinkel P, et al. Immune reconstitution inflammatory syndrome in 
patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol. 2011; 
68:186-91 
16.       Kurtzke, JF (1983).  Rating neurologic impairment in multiple sclerosis: an expanded 
disability status scale (EDSS)  Neurology 33 (11): 1444-52  
17. Beck AT, Steer RA, Brown GK. BDI-II, manuel. Les Editions du Centre de Psychologie 
Applique´e, Paris, 1996 
     


Page 14 of 14 
 
 
 
 
Schedule of Events 
Procedure/Visit 
  
Screen 
Baseline 
Month 
1 
Month 
2 
Month 
3 
Month 
4 
Month 
5 
Month 
6 
Month 
9 
Month 
12 
Month 
18 
Month 
24/ET 
UNS 
Relapse  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF 
  
x 
  
  
  
  
  
  
  
  
  
  
  
  
Med History 
  
x 
  
  
  
  
  
  
  
  
  
  
  
  
MS History 
  
x 
  
  
  
  
  
  
  
  
  
  
  
  
Inc/exc 
  
x 
x 
  
  
  
  
  
  
  
  
  
  
  
Vitals 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PE 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
EDSS 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Becks 
 
X 
 
 
 
 
 
 
x 
 
x 
 
x 
 
SDMT 
 
 
x 
 
 
 
 
 
x 
 
x 
 
x 
 
 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
Metabolic 
panel 
  
x 
  
  
  
  
  
  
x 
  
x 
  
x 
  
CBC   (a) 
  
x 
  
  
  
  
  
  
x 
  
x 
  
x 
  
LFTs   (b) 
  
  
x 
x 
x 
x 
x 
x 
  
  
  
  
  
  
Serum preg  * 
Urine preg 
  
* 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
PPD or QG 
  
x 
  
  
  
  
  
  
  
  
  
  
  
  
MRI 
  
x 
  
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
Con meds 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Events 
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
(a) 
CBC will include WBC  (Count), RBC (Count), Hemoglobin, 
Hematocrit, Mean Corpuscular Hemoglobin (MCH),  Platelet (Count,  
Neutrophils, Monocytes, Lymphocytes, Eosinophils, Basophils 
 
(b) 
LFT’s will be SGGT, Bilirubin, Total; Bilirubin, Direct; 
Bilirubin, Indirect; Alkaline Phosphatase Transferase, aspartate amino 
(AST) (SGOT); Transferase, alanine amino (ALT) (SGPT). 
 
 
 
 
****Window for Screen to Baseline visit is 21 to 35 days. 
****Window on all other visits is plus or minus 7 days 

ICF_002.pdf: 
14-011B SWITCH JCV Sub-study ICF
Page 1 of 3
ADDENDUM INFORMED CONSENT FORM
Title: Switching relapsing multiple sclerosis patients treated with natalizumab (Tysabri ®) at risk 
for progressive multifocal leukoencephalopathy to teriflunomide (Aubagio®): Is this safe and 
effective?
Analysis of John Cunningham virus (JCV) antibody index in MS patients treated with 
teriflunomide (SWITCH-JCV) (PH&S IRB # 14-011B)
Principal Investigator: Stanley Cohan, MD, PhD
Sponsor: Providence Health & Services
Funder: Sanofi Genzyme
Protocol: SWITCH Protocol Addendum, dated 04 Dec 2018
INTRODUCTION
The purpose of this addendum consent form is to update you about new research questions that 
came up during the course of the main study. Make sure you understand what is written, and 
ask as many questions as needed before you sign this addendum consent form.
All other information in the original consent form you signed is still valid.
Please read the information carefully and feel free to ask questions. It may be helpful for you to 
discuss this information with your family and friends. If you choose not to take part, you will not 
lose the regular care you receive from your doctors.
Please indicate whether or not you would like to participate in this additional blood draw on the 
signature page of this form. You will be given a copy of your signed consent form.
SUB-STUDY BACKGROUND
A drug called leflunomide, which is very similar to teriflunomide, has been found to reduce or 
eliminate BK virus in patients who received kidney transplants. BK virus and JC virus both 
belong to the polyoma virus family and are closely related.
Researchers think it is possible that teriflunomide may reduce or eliminate the amount of JC 
virus in your body, and thereby reduce the risk of developing progressive multifocal 
leukoencephalopathy (PML).
Providence Health and Services (Oregon)
IRB Number: PDX14-011
IRB Approval Date: 10/29/2019
IRB Parent Number: PDX14-011


14-011B SWITCH JCV Sub-study ICF
Page 2 of 3
PROCEDURES
For all patients who enrolled in the SWITCH trial and received teriflunomide, the study team 
would like to collect a blood sample to see if there is an impact on your JC virus status. This will 
be done at a Quest Diagnostic Lab near you. Your study team will discuss the procedure with 
you.
The sample requires 3-5 milliliters (1 teaspoon) of blood to be sent for anti-JCV antibody Index 
test. This blood tests detects antibodies to JC Virus, which indicates exposure to the virus. The 
results will be scanned into your electronic medical record, however your MS treatment will not 
change based on the results of this blood test.
GENERAL INFORMATION
Taking part in this sub-study is voluntary. Refusing to take part will not affect the health care 
benefits you have. If you decide to take part, you are free to stop at any time without any effect 
on your medical care or your relationship with your doctor(s) or Providence Health & Services.
COSTS
You and your health insurance company will be paying for the costs of your routine medical 
care, including any costs of treating your MS while in this sub-study, and medicines to manage 
any side effects.
You or your insurance company will not have to pay for the JC virus test described in this 
consent, or the phone visit with the study coordinator. Providence is responsible for making sure 
these charges are billed to this sub-study and not you or your insurance company.
LIABILITY
If you are injured as a result of taking part in this sub-study, all of the necessary medical 
facilities are available for treatment, as is reasonably possible. You or your insurance will be 
billed for treatment, even for injuries that are a direct result of taking part in the study.
You do not give up any of your legal rights by signing this consent form and taking part in this 
study.
QUESTIONS
You are free to ask questions about this study at any time. Any questions you have about this 
research study or a research-related injury can be answered by:
Study Doctor: 
 at 
Study Coordinator: 
 at 
Any questions you have about your rights as a research subject will be answered by the 
Providence Health & Services Institutional Review Board at (503) 215-6512.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S. Law. This website will not include information that can identify you. At most, the website 
will include a summary of the results. You can search this website at any time.
Providence Health and Services (Oregon)
IRB Number: PDX14-011
IRB Approval Date: 10/29/2019
IRB Parent Number: PDX14-011


14-011B SWITCH JCV Sub-study ICF
Page 3 of 3
CONSENT: I have read this Addendum consent form, and my questions have been answered 
to my satisfaction. Please initial one option below:
______ I agree to provide an additional blood sample
OR
______ I do not agree to provide an additional blood sample
______________________________________
Name of Patient (Please Print)
_____________________________________________________________
Signature of Patient 
Date
________________________________________
Name of Person Obtaining Consent (Please Print)
______________________________________________________________
Signature of Person Obtaining Consent 
Date
Providence Health and Services (Oregon)
IRB Number: PDX14-011
IRB Approval Date: 10/29/2019
IRB Parent Number: PDX14-011

Prot_SAP_000.pdf: 
 
 
Page 1 of 3 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Page 2 of 3 
 
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.  
 


 
 
Page 3 of 3 
 
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.      
 

ICF_003.pdf: