Conditions: Multiple Sclerosis (MS)
Keywords: Radiologically Isolated Syndrome (RIS)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 87
Healthy volunteers: no

Brief summary:
The purpose of this investigation is to systematically study the efficacy of Tecfidera in those individuals who possess incidental white matter anomalies within the brain following a MRI study that is performed for a reason other than for the evaluation of MS (multiple sclerosis).

Detailed description:
This is a multi-center, randomized, double-blinded study in which approximately 90 RIS (radiologically isolated syndrome) subjects will be treated with either Tecfidera or placebo for 2 years (1:1 randomization). Study participants, along with the treating and examining physicians, will be blinded to treatment assignment. Central Clinical and Imaging Units will screen all potential study subjects for inclusion/exclusion criteria. We expect to enroll all RIS subjects within the U.S.

Following informed consent and verification of entry criteria by the core units, study participants will be randomized 1:1 to either Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily) or placebo. Clinical follow-up by the treating physician will occur at weeks 0, 48, 96, 144 and/or End of Study and during or immediately following clinical exacerbations. During clinical visits, comprehensive medical history data will be obtained by the treating physician. All reported acute or progressive clinical events will be adjudicated by the Central Clinical Unit. Clinical visits due to suspected exacerbations associated with CNS (central nervous system) demyelination, and associated diagnostic studies and treatments, will be covered under the medical standard of care by third party payers. A recommendation to re-evaluate the patient within 3 months following the clinical event to assess for extent of recovery will be made. In addition to the face-to-face visits described above, study participants will be contacted over the telephone at weeks 4, 8, 36, 60, 84, 108, and 132 to assess for medical or treatment difficulties and for study medication compliance. Standardized MRI studies of the brain will be performed at weeks 0, 96, 144 or End of Study. Clinical imaging studies of the brain and/or spinal cord performed during or immediately following the onset of a clinical exacerbation will be performed at the discretion of the site PI with scan costs covered under the medical standard of care. An end of study clinical MRI of the cervical spinal cord with and without contrast will be recommended to study participants at week 96 as medical standard of care.

Arms:
arm 1: Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily) arm 2: Placebo by mouth twice daily.

Interventions: intervention 1: Tecfidera intervention 2: Placebo
Intervention descriptions: intervention 1: Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs. intervention 2: Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs.

Protocol document:
ICF_002.pdf: 
Official title: Multi-center, randomized, double-blinded assessment of 
Tecfidera® in extending the time to a first attack in radiologically isolated 
syndrome (RIS) (ARISE) 
 
 
NCT number: NCT02739542 
IRB Approved date: 12/05/2018 


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The University of Texas Southwestern Medical Center  
Parkland Health & Hospital System 
Children’s Medical Center 
Retina Foundation of the Southwest 
Texas Scottish Rite Hospital for Children 
Texas Health Presbyterian Hospital Dallas 
 
CONSENT TO PARTICIPATE IN RESEARCH 
 
Title of Research: 
Multi-center, randomized, double-blinded assessment of 
Tecfidera in extending the time to a first attack in 
radiologically isolated syndrome (RIS) (ARISE) 
 
Sponsor: 
The University of Texas Southwestern Medical Center  
 
Funding Agency: 
Biogen  
 
Study Doctors: 
Darin Okuda, MD 
 
 
You may call the study doctor or research personnel during regular office hours and at 
other times at 214-645-8800.   
 
Instructions: 
Please read this consent form carefully and take your time making a decision about 
whether to participate.  As the researchers discuss this consent form with you, please 
ask him/her to explain any words or information that you do not clearly understand.  The 
purpose of the study, risks, inconveniences, discomforts, and other important 
information about the study are listed below.  If you decide to participate, you will be 
given a copy of this form to keep. 
 
Why is this study being done? 
This study is being done to find out whether an FDA-approved drug for relapsing forms 
of multiple sclerosis (MS) called Tecfidera (dimethyl fumarate) can treat your condition 
better or more safely than no medication.  
 
Why is this considered research?  
This is a research study because, currently, there is no FDA-approved medication for 
Radiologically Isolated Syndrome (RIS). 
 
The following definitions may help you understand this study:  
 Double-blind means neither you nor the researchers will know which study drug 
you are receiving.  
 Placebo-controlled means that some participants will get a placebo. A placebo 
looks like the investigational drug but it includes no active ingredients.  
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 Randomization means you will be placed by chance (like a flip of a coin) in one of 
the study groups.   
 Standard medical care means the regular care you would receive from your 
personal doctor if you choose not to participate in this research. 
 Researchers means the study doctor and research personnel at the University of 
Texas Southwestern Medical Center at Dallas and its affiliated hospitals. 
 
Why am I being asked to take part in this research study? 
You are being asked to take part in this study because you have Radiologically Isolated 
Syndrome (RIS).   
 
Do I have to take part in this research study?” 
No. You have the right to choose whether you want to take part in this research study.  
If you decide to participate and later change your mind, you are free to stop participation 
at any time. 
 
If you decide not to take part in this research study it will not change your legal rights or 
the quality of health care that you receive at this center. 
 
How many people will take part in this study? 
About 50 people will take part in this study at UT Southwestern Medical Center. This 
study also is taking place at a number of other medical facilities around the country.  
There will be a total of 90 people participating in this research study throughout the 
United States and/or other countries. 
 
What is involved in the study? 
If you volunteer to take part in this research study, you will be asked to sign this consent 
form and will have the following tests and procedures.  Some of the procedures may be 
part of your standard medical care, but others are being done solely for the purpose of 
this study. 
 
Screening Procedures 
To help decide if you qualify to be in this study, the researchers will ask you 
questions about your health, including medications you take and any surgical 
procedures you have had. 
 
You may also have to fill out certain forms or have the following exams, tests or 
procedures: 
 
Procedures and Evaluations during the Research 
 
Screening (approximately 2 hours): 
• 
Review of inclusion and exclusion criteria 
• 
Evaluation of clinical and radiological data  
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• 
Consent and Discussion of Study Expectations  
 
Week 0, +/- 2 weeks (approximately 2.5 hours) 
• 
Record Demographics, and Medical and Clinical History  
• 
Physical examination including vital signs 
• 
Visual System tests (Low Vision Contrast charts, Ocular Coherence Tomography 
(OCT) (to be performed at UT Southwestern ONLY) 
• 
Pregnancy test – urine 
• 
Cognitive/Functional Assessments (Appendix 1) 
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw (½ tablespoon): Lab tests – CBC & CMP 
• 
Biological mechanistic samples for future use (including DNA and RNA) 
o Serum 
o Spinal fluid (CSF) (optional) 
• 
Standardized brain MRI at 1.5 or 3.0 Tesla Recommendation for MRI of the 
cervical spine with and without contrast (per medical standard of care) 
• 
Obtain randomization number  
• 
Administer Study Medication  
• 
Review any adverse events and concomitant medications 
 
Week 4, +/- 2 weeks (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications 
 
Week 8, +/- 2 weeks (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications 
 
Week 12, +/- 2 weeks: (approximately 20 minutes) 
• 
Blood draw (½ tablespoon): Lab tests – CBC & CMP 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications 
• 
Dispense Study Medication 
 
Week 24, +/- 2 weeks: (approximately 20 minutes)  
• 
Blood draw (½ tablespoon): Lab tests – CBC & CMP 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications 
• 
Dispense Study Medication 
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Week 36, +/- 2 weeks: (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications 
• 
Dispense study medication (via mail or patient pick up) 
 
Week 48, +/- 2 weeks (approximately 1 hour): 
• 
Review of Interval Medical History  
• 
Physician examination (including vital signs) 
• 
Visual System tests (Low Vision Contrast charts, Ocular Coherence Tomography (OCT) 
(to be performed at UT Southwestern ONLY) 
• 
Cognitive/Functional Assessments (Appendix 1) 
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
  ○ Spinal fluid (CSF) (optional) 
• 
Standardized brain MRI at 1.5 or 3.0 Tesla (to be performed at UT Southwestern ONLY 
• 
Dispense Study Medication  
• 
Review any adverse events and concomitant medications 
 
Week 60, +/- 2 weeks: (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications  
• 
Dispense study medication (via mail or patient pick up) 
 
Week 72, +/- 2 weeks, (approximately 20 minutes): 
• 
Blood draw: (½ tablespoon): Lab tests – CBC & CMP 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Dispense Study Medication  
• 
Review any adverse events and changes in medications 
 
Week 84, +/- 2 weeks: (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Dispense study medication (via mail or patient pick up) 
• 
Review any adverse events and changes in medications 
 
Week 96, +/- 2 weeks (approximately 2 hours): 
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• 
Review of Interval Medical History 
• 
Physician examination (including vital signs) 
• 
Visual System tests (Low Vision Contrast charts, Ocular Coherence Tomography (OCT) 
(to be performed at UT Southwestern ONLY) 
• 
Cognitive/Functional Assessments (Appendix 1) 
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
  ○ Spinal fluid (CSF) (optional) 
• 
Standardized brain MRI at 1.5 or 3.0 Tesla 
• 
Recommendation for MRI of the cervical spine with and without contrast (per medical 
standard of care) 
 
Week 108, +/- 2 weeks: (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Review any adverse events and changes in medications 
• 
Dispense Study Medication (via mail or patient pick up) 
 
Week 120, +/- 2 weeks, (approximately 20 minutes): 
• 
Blood draw (½ tablespoon): Lab tests – CBC & CMP 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Dispense Study Medication  
• 
Review any adverse events and changes in medications 
 
 
Week 132, +/- 2 weeks: (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Review any adverse events and changes in medications 
• 
Dispense Study Medication (via mail or patient pick up) 
 
 
Week 144, +/- 2 weeks (approximately 2 hours): 
• 
Review of Interval Medical History 
• 
Review of AEs and Concomitant Medications 
• 
Physician examination (including vital signs) 
• 
Visual System tests (Low Vision Contrast charts, Ocular Coherence Tomography (OCT) 
(to be performed at UT Southwestern ONLY) 
• 
Cognitive/Functional Assessments (Appendix 1) 
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
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 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
  ○ Spinal fluid (CSF) (optional) 
• 
Standardized brain MRI at 1.5 or 3.0 Tesla 
• 
Recommendation for MRI of the cervical spine with and without contrast (per medical 
standard of care) 
• 
Collect all remaining study medication 
 
Relapse Visit (approximately 2 hours): 
• 
Review of Interval Medical History 
• 
Review any adverse events and changes in medications 
• 
Physician examination (including vital signs) 
• 
Cognitive/Functional Assessments (Appendix 1) 
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
• 
Recommendation for Standardized brain MRI at 1.5 or 3.0 Tesla at the discretion of the 
treating neurologist (per medical standard of care) 
 
Unscheduled Visit (approximately 2 hours): 
• 
Review of Interval Medical History 
• 
Review any adverse events and changes in medications 
• 
Physician examination (including vital signs) 
• 
Cognitive/Functional Assessments (Appendix 1)  
• 
Patient Reported Surveys (Appendix 2) 
• 
If standard of care brain CBC, CMP obtained at this visit, data should be recorded. 
• 
If standard of care brain and/or cervical spine MRI completed at this visit, data should be 
recorded. 
 
Early Withdrawal/Discontinuation or End of Study (approximately 2 hours): 
• 
Review of Interval Medical History 
• 
Review any adverse events and changes in medications 
• 
Physician examination (including vital signs) 
• 
Visual System tests (Low Vision Contrast charts, Ocular Coherence Tomography (OCT) 
(to be performed at UT Southwestern ONLY) 
• 
Cognitive/Functional Assessments (Appendix 1)  
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
  ○ Spinal fluid (CSF) (optional) 
• 
Standardized brain MRI at 1.5 or 3.0 Tesla 
• 
Recommendation for MRI of the cervical spine with and without contrast (per medical 
standard of care) 
• 
Collect all remaining study medication 
 
Group Assignment 
Study ID: STU 102014-019   Date Approved: 12/5/2018


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If the researchers believe you can take part in this study, you will be assigned 
randomly (like a flip of a coin) to receive either Tecfidera (dimethyl fumarate) or 
placebo (inactive substance). You have a 1 in 2 chance of receiving Tecfidera 
(dimethyl fumarate) or placebo. 
 
The group you will be in is decided by a computer-generated program established 
before the research begins. Neither you nor the researchers will be allowed to 
choose which group you are assigned to. 
 
Study Medication/Intervention 
If you decide to participate in this study you will take either: 
 Tecfidera (dimethyl fumarate), 1 capsule (120 milligrams) twice a day for 7 
days and then increase to 2 capsules (240 milligrams) twice per day 
thereafter 
OR 
 1 tablet of placebo (inactive substance) twice a day for 7 days and then 
increase to 2 capsules twice a day 
 
If you cannot tolerate the study medication by mouth, you may be offered to switch 
to another study medication called pegylated interferon (Plegridy). 
 
Magnetic Resonance Imaging 
You will have magnetic resonance imaging (MRI) of your head.  For this procedure, 
you will lie quietly inside a large, doughnut-shaped magnet for about 45-60 minutes. 
Your head will rest in a special helmet-like holder to help you keep your head still.  
 
How long can I expect to be in this study? 
The study will take place over 144 weeks (approximately three years), or until End of 
Study (EOS) which is March 31, 2021 
 
You can choose to stop participating for any reason at any time. However, if you decide 
to stop participating in the study, we encourage you to tell the researchers. You may be 
asked if you are willing to complete some study termination tests. 
 
What are the risks of the study? 
Study Procedure/Intervention 
Because of your participation in this study, you are at risk for the following side effects. 
You should discuss these with the researchers and your regular health care provider.  
 
Tecfidera (dimethyl fumarate) may cause some, all or none of the side-effects listed 
below.  
 
Frequent (>15%) 
 Headache 
Occasionally (>5%) 
 Abdominal pain 
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 Flushing (redness of the skin 
that may be accompanied by 
feeling warm, burning, 
sweating, or other symptoms)  
 Diarrhea 
 Nausea/Vomiting  
 Elevated liver enzymes 
 
Rare (<1%) 
 Liver or kidney damage 
 
Serious but Rare 
 Death 
 Irregular Heart Beat 
 *PML (Progressive multifocal 
leukoencephalopathy) a rare 
brain infection that usually leads 
to death or severe disability  
 
 
*Progressive multifocal leukoencephalopathy (PML). Some patients receiving Tecfidera 
(dimethyl fumarate) have developed a very rare but severe viral infection of the brain. 
There have been no documented cases of PML in patients with RIS. Some patients who 
were being treated for other indications other than MS developed PML. PML causes 
brain damage and is usually fatal or leads to severe disability. It occurs almost 
exclusively in people with severe immune deficiency, such as transplant patients on 
immunosuppressive medications or patients receiving certain kinds of chemotherapy 
(drugs to treat cancer).   
 
Symptoms of PML are diverse, progress over days to weeks, and include the following: 
progressive weakness on one side of the body or clumsiness of limbs; disturbance of 
vision; and changes in thinking, memory and orientation, leading to confusion and 
personality changes. The progression of deficits can lead to severe disability or death. 
 
Pegylated Interferon beta-1a (Plegridy):  
 
More common 
 
Blue-green to black skin 
discoloration 
 
chills 
 
cough or sore throat 
 
diarrhea 
 
dizziness 
 
extremely high fever or body 
temperature 
 
fast, shallow breathing 
 
fast, weak heartbeat 
 
fever 
Less common 
 
Dark urine 
 
decreased appetite 
 
general feeling of tiredness or 
 
weakness 
 
itching skin 
 
light-colored stools 
 
stomach or abdominal pain 
 
yellow eyes or skin 
 
 
 
 
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 
general feeling of discomfort or 
illness 
 
joint pain 
 
muscle aches and pains 
 
muscle cramps 
 
pale, clammy skin 
 
runny nose 
 
shivering 
 
sweating 
 
thirst 
 
trouble sleeping 
 
unusual tiredness or weakness 
 
vomiting 
 
Difficulty with moving 
 
itching, rash, redness, soreness, 
swelling, or warmth at the injection 
site 
 
lack or loss of strength 
 
muscle stiffness 
 
pain, redness, or sloughing of skin 
at the injection site 
 
 
 
 
Rare 
 
Difficulty with swallowing 
 
hives or welts 
 
large, hive-like swelling on the face, 
 
puffiness or swelling of the eyelids 
 
or around the eyes, face, lips, or 
 
tongue 
 
redness of the skin 
 
skin rash 
 
tightness in the chest 
 
 
Magnetic Resonance Imaging (MRI).  
There are no known risks from exposure to magnetic fields. You may experience 
nervousness and/or anxiety due to the loud banging made by the machine while  
it is taking pictures and from confinement in a tight space (claustrophobia). If you 
become anxious, you can stop the procedure at any time  
  
You may also experience some discomfort and fatigue from lying still during 
imaging.  
  
If you have any metal clips or plates in your body, you should tell the investigator.   
 
MRI may not be appropriate if you are pregnant or are trying to become  
pregnant. MRI may not be appropriate if you have permanent eyeliner or   
eyebrows or any pieces of metal in your body, such as the following:  
  
 heart pacemaker, heart valve replacement, or aortic clips  
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 metal fragments in your eyes, skin, or elsewhere in your body  
 brain clips or pieces of metal used in aneurysm surgery or 
intercranial  
bypass  
 venous umbrella  
 pieces of metal in the body resulting from work as a sheet-metal  
worker or welder  
 clips placed in an internal organ  
 prosthetic devices, such as middle ear, eye, joint, or penile implants   
 joint replacement.  
 hearing aid that cannot be removed  
 neurostimulator  
 insulin pump  
 intrauterine device (IUD)  
 shunts or stents  
 metal mesh or coil implants  
 metal plate, pin, screws, or wires, or any other metal implants  
  
The contrast agent you will receive is FDA-approved and used routinely for MRI exams. 
It contains a material called Gadolinium (dye solution used to highlight organs or tissues 
during imaging). The injection of Gadolinium may cause discomfort like headache, 
nausea, strange taste, or coldness at site of injection. These symptoms occur in less 
than 1 out of 20 patients receiving Gadolinium and go away quickly. There is a small 
risk of a severe allergic reaction that can cause breathing difficulties and/or low blood 
pressure, and these symptoms are extremely rare (approximately 1 in 10,000 to 1 in 
100,000 administrations). In the unlikely event you experience these symptoms, a 
physician and nursing staff will be available to evaluate and, if necessary, provide 
treatment.  
  
People with severe kidney failure who receive Gadolinium (dye solution used to 
highlight organs or tissues during imaging) are at risk of developing a disorder called 
Nephrogenic Systemic Fibrosis (NSF). This disease can cause wide spread tissue 
scarring or hardening (fibrosis). In rare cases NSF can lead to lung and heart problems 
and cause death. If you have severe kidney failure and receive gadolinium, the risk of 
developing NSF is 1-5%. We may perform a blood test 30 days before your MRI to 
check how well your kidneys are working before you receive the Gadolinium. This test 
may be repeated closer to your MRI appointment if your medical condition has changed. 
If your kidneys are working at levels known to be at risk for NSF, you will not receive 
Gadolinium.  You will not receive Gadolinium for research purposes if you have sickle 
cell  disease (a disease of the blood cells) since it may put you at risk of developing  
hemolysis (breakdown of blood cells).  
   
Psychological Stress 
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Some of the questions we will ask you as part of this study may make you feel 
uncomfortable.  You may refuse to answer any of the questions, take a break or stop 
your participation in this study at any time. 
 
Loss of Confidentiality 
Any time information is collected; there is a potential risk for loss of confidentiality.  
Every effort will be made to keep your information confidential; however, this cannot be 
guaranteed.  
 
Risks to Sperm, Embryo, Fetus or Breast-fed Infant 
Males: Being in this research may damage your sperm, which could cause harm to a 
child that you may father while on this study. If you take part in this study and are 
sexually active, you must agree to use a medically-acceptable form of birth control. 
Medically-acceptable forms of birth control include: 
(1) surgical sterilization (vasectomy), or 
(2) a condom used with a spermicide (a substance that kills sperm). 
 
Females: If you are part of this study while pregnant or breast-feeding an infant, it is 
possible that you may expose the unborn child or infant to risks.  For that reason, 
pregnant and breast-feeding females cannot participate in the study.  If you can become 
pregnant, a urine pregnancy test will be done, and it must be negative before you 
participate in this study. If you take part in this study and you are sexually active, you 
and any person that you have sex with must use medically-acceptable birth control 
(contraceptives) during the study.  Medically-acceptable birth control (contraceptives) 
includes: 
(1) surgical sterilization (such as hysterectomy or “tubes tied”), 
(2) approved hormonal contraceptives (such as birth control pills, patch or ring; 
Depo-Provera, Implanon), 
(3) barrier methods (such as condom or diaphragm) used with a spermicide (a 
substance that kills sperm), or  
(4) an intrauterine device (IUD). 
 
If you do become pregnant during this study, you must tell the researchers 
immediately. 
 
Risks of Blood Drawing 
Risks associated with drawing blood from your arm include minimal discomfort and/or 
bruising.  Infection, excess bleeding, clotting, and/or fainting also are possible, although 
unlikely. 
 
You will have 4 tablespoons of blood collected because you are in this research study. 
 
Placebo 
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If you receive a placebo, you will not receive active medication for your health problem.  
If your problem becomes worse, your participation in the research will stop. If this 
happens, your study doctor can discuss alternative care with you. 
 
Other Risks 
There may possibly be other side effects that are unknown at this time. If you are 
concerned about other, unknown side effects, please discuss this with the researchers. 
 
Please notify the study doctor or study staff immediately if you experience any of 
these or any other side effects during the study. You will be monitored 
throughout the study in order to minimize risks. 
 
How will risks be minimized or prevented?   
Potential risks and discomforts will be minimized to the greatest extent possible by 
using procedures such as: 
 All research personnel will receive appropriate training 
 The study will be monitored on regular basis 
 Evidence of difficulty or side effects may cause the study doctor to withdraw 
you from the study 
 The study doctor may determine that you will need referral for treatment 
 A follow-up visit will be scheduled following the treatment in the study 
 
What will my responsibilities be during the study?   
While you are part of this study, the researchers will follow you closely to determine 
whether there are problems that need medical care.  It is your responsibility to do the 
following: 
 Ask questions about anything you do not understand. 
 Keep your appointments. 
 Follow the researchers’ instructions. 
 Let the researchers know if your telephone number or address changes. 
 Store study materials (capsules or injections) in a secure place at home away 
from anyone who is unable to read and understand labels, especially children. 
 Tell the researchers before you take any new medication, even if it is prescribed 
by another doctor for a different medical problem or something purchased over 
the counter. 
 Tell your regular doctor about your participation in this study. 
 Carry information about Tecfidera or Plegridy in your purse or wallet. 
 Report to the researchers any injury or illnesses while you are on study even if 
you do not think it is related.  
 
If I agree to take part in this research study, will I be told of any new risks that 
may be found during the course of the study? 
Yes. You will be told if any new information becomes available during the study that 
could cause you to change your mind about continuing to participate or that is important 
Study ID: STU 102014-019   Date Approved: 12/5/2018


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to your health or safety. 
 
What should I do if I think I am having problems? 
If you have unusual symptoms, pain, or any other problems while you are in the study, 
you should report them to the researchers right away.  Telephone numbers where they 
can be reached are listed on the first page of this consent form. 
 
If you have a sudden, serious problem, like difficulty breathing or severe pain, go to the 
nearest hospital emergency room, or call 911 (or the correct emergency telephone 
number in your area).  Tell emergency personnel about any medications you are taking, 
including any medications you are taking for this study.   
 
What are the possible benefits of this study? 
If you agree to take part in this study, there may or may not be direct benefits to you.  
The researchers cannot guarantee that you will benefit from participation in this 
research. 
 
We hope the information learned from this study will benefit others with Radiologically 
Isolated Syndrome (RIS) in the future.  Information gained from this research could lead 
to better treatment options, as well as knowledge about the conversion from RIS to a 
definite diagnosis of multiple sclerosis (MS).   
 
What options are available if I decide not to take part in this research study? 
You do not have to participate in this research to receive care for your medical problem. 
Instead of being in this study, you have the following options: to remain untreated for 
your medical condition or to receive standard medical care without research 
participation. 
 
Please talk to the researchers or your personal doctor about these options.  
 
Will I be paid if I take part in this research study? 
Yes.   
 
You will be given the following, if you take part in this research: 
 Parking expenses while on campus for research; and 
 If you return for an additional MRI at One-Year (UTSW patients only) you will be 
paid $50.00 upon completion of the procedure; and 
 The following will be provided for patients living greater than 75 miles from 
UTSW: one night lodging (arrangements made and paid for by UTSW) and 
mileage reimbursement of .54¢ per mile (as calculated by Google Maps)  
 
How will I be paid?  
You will be issued a UT Southwestern Greenphire ClinCard, which can be used as a 
credit or debit card. You will also receive instructions on how use the card.  In order 
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receive study payments, your name, address, date of birth and Social Security Number 
(SSN) will be collected from you by the research staff.  All information will be stored in a 
secure fashion and will be deleted from the UT Southwestern Greenphire ClinCard 
system once the study has been completed.   
 
Important Information about Study Payments 
1. 
Your SSN is needed in order to process your payments. Should you decide not to 
provide your SSN, your study participation payment will decreased at the current 
IRS tax rate. Study payments are considered taxable income and are reportable to 
the IRS. 
2. 
An IRS Form 1099 will be sent to you if your total payments are $600 or more in    
a calendar year.  
3. 
Your information will not be shared with any third parties and will be kept 
completely confidential 
 
This information will remain confidential unless you give your permission to share it with 
others, or if we are required by law to release it. 
 
If you are an employee of UT Southwestern, your payment will be added to your regular 
paycheck and income tax will be deducted. You will not receive a ClinCard.  
 
UT Southwestern, as a State agency, will not be able to make any payments to you for 
your participation in this research if the State Comptroller has issued a “hold” on all 
State payments to you.  Such a “hold” could result from your failure to make child 
support payments or pay student loans, etc.  If this happens, UT Southwestern will be 
able to pay you for your taking part in this research 1) after you have made the 
outstanding payments and 2) the State Comptroller has issued a release of the “hold.” 
 
You will be reimbursed for your parking expenses. In order to receive reimbursement, 
you will need to turn in all your receipts to the research coordinator. 
 
Will my insurance provider or I be charged for the costs of any part of this 
research study? 
No. Neither you, nor your insurance provider, will be charged for anything done only for 
this research study (i.e., the Screening Procedures, Experimental Procedures, or 
Monitoring/Follow-up Procedures described above).   However, the standard medical 
care for your condition (care you would have received whether or not you were in this 
study) is your responsibility (or the responsibility of your insurance provider or 
governmental program).  You will be charged, in the standard manner, for any 
procedures performed for your standard medical care. 
 
What will happen if I am harmed as a result of taking part in this study? 
It is important that you report any illness or injury to the research team listed at the top 
of this form immediately. 
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Compensation for an injury resulting from your participation in this research is not 
available from the University of Texas Southwestern Medical Center at Dallas. 
 
You retain your legal rights during your participation in this research 
 
Can I stop taking part in this research study? 
Yes.  If you decide to participate and later change your mind, you are free to stop taking 
part in the research study at any time. 
 
If you decide to stop taking part in this research study, it will not affect your relationship 
with the UT Southwestern staff or doctors.  Whether you participate or not will have no 
effect on your legal rights or the quality of your health care. 
 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your status 
will not be affected in any way. 
 
Your doctor is a research investigator in this study.  He is interested in both your 
medical care and the conduct of this research study.  At any time, you may discuss your 
care with another doctor who is not part of this research study.  You do not have to take 
part in any research study offered by your doctor. 
 
If I agree to take part in this research study, can I be removed from the study 
without my consent? 
Yes.  The researchers may decide to take you off this study if: 
 Your medical problem remains unchanged or becomes worse. 
 The researchers believe that participation in the research is no longer safe for 
you. 
 The researchers believe that other treatment may be more helpful. 
 The sponsor or the FDA stops the research for the safety of the participants. 
 The sponsor cancels the research. 
 You are unable to keep appointments or to follow the researcher’s instructions. 
 
Will my information be kept confidential? 
Medical information collected during this study and the results of any test or procedure 
that may affect your medical care may be included in your medical record. The 
information included in your medical record will be available to health care providers 
and authorized persons including your insurance company. 
 
You should know that certain organizations that may look at and/or copy your medical 
records for research, quality assurance, and data analysis include: 
 
• Biogen 
• Quintiles, Inc. 
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• Almac 
• Core Clinical Unit 
• Central Imaging Unit 
• Microbiome Laboratory 
• Safety Reviewer 
• Representatives of government agencies, like the U.S. Food and Drug 
Administration (FDA), involved in keeping research safe for people; and 
• The UT Southwestern Institutional Review Board.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time. 
 
In addition to this consent form, you will be asked to sign an "Authorization for Use and 
Disclosure of Protected Health Information."  This authorization will give more details 
about how your information will be used for this research study, and who may see 
and/or get copies of your information. 
 
Are there procedures I should follow after stopping participation in this research? 
Yes.  If you, the researchers, or the sponsor stops your participation in the research, 
you may be asked to do the following: 
 Let the researchers know immediately that you wish to withdraw from the 
research. 
 Return to the research center for tests that may be needed for your safety. 
 Return any unused study materials, including empty containers. 
 Discuss your future medical care, if any, with the researchers and/or your 
personal doctor. 
 
Early Withdrawal/Discontinuation (approximately 2 hours): 
• 
Review of Interval Medical History 
• 
Review any adverse events and changes in medications 
• 
Physician examination (including vital signs) 
• 
Visual System tests (Low Vision Contrast charts, Ocular Coherence Tomography (OCT) 
(to be performed at UT Southwestern ONLY) 
• 
Cognitive/Functional Assessments (Appendix 1)  
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
  ○ Spinal fluid (CSF) (optional) 
• 
Standardized brain MRI at 1.5 or 3.0 Tesla 
• 
Recommendation for MRI of the cervical spine with and without contrast (per medical 
standard of care) 
• 
Collect all remaining study medication 
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Is there anything else I should know before I decide? 
Dr. Okuda and Katy Wright have financial interests in the company funding this study. 
You should feel free to ask questions about this. 
 
Whom do I call if I have questions or problems? 
For questions about the study, contact Darin Okuda, MD at 214-645-8800 during 
regular business hours and also after hours and on weekends and holidays.   
 
For questions about your rights as a research participant, contact the UT Southwestern 
Institutional Review Board (IRB) Office at 214-648-3060. 
 
SIGNATURES: 
 
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP. 
 
 
Your signature below certifies the following: 
 
 You have read (or been read) the information provided above. 
 You have received answers to all of your questions and have been told who to 
call if you have any more questions. 
 You have freely decided to participate in this research. 
 You understand that you are not giving up any of your legal rights. 
 You understand that a copy of this signed consent document, information about 
this study, and the results of any test or procedure that may affect your medical 
care, may be included in your medical record.  Information in your medical 
record will be available to health care providers and authorized persons 
including your insurance company. 
 
 
 
 
____________________________________________ 
 
 
Name of Participant (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Participant 
Date 
Time 
 
 
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____________________________________________ 
 
 
Name of Person Obtaining Consent (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Person Obtaining Consent 
Date 
Time 
 
Study ID: STU 102014-019   Date Approved: 12/5/2018

Prot_000.pdf: 
Official title: Multi-center, randomized, double-blinded assessment of 
Tecfidera® in extending the time to a first attack in radiologically isolated 
syndrome (RIS) (ARISE) 
 
 
NCT number: NCT02739542 
IRB Approved date: 12/05/2018 


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UT Southwestern Medical Center 
Clinical Center for Multiple Sclerosis 
 
 
 
 
 
 
 
 
 
 
Multi-center, randomized, double-blinded assessment of Tecfidera® in 
extending the time to a first attack in radiologically isolated syndrome 
(RIS) (ARISE) 
 
 
 
 
 
 
 
 
 
 
 
Authors:  
Darin T. Okuda, M.D. Christine Lebrun, M.D., Ph.D., Matilde Inglese, M.D., 
Ph.D., Aksel Siva, M.D., Orhun Kantarci, M.D., Daniel Pelletier, M.D. 
 
 
Date:    
 
, November 5, 2018 
 
Version:   
 
8 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
 
 
 
 
 
PAGE 
 
 
Table of contents 
 
 
 
 
 
 
 
2 
 
 
List of abbreviations   
 
 
 
 
 
 
4 
 
 
Protocol synopsis 
 
 
 
 
 
 
 
5-6 
 
 
About this study 
 
 
 
 
 
 
 
6 
 
1.   
Purpose of this manual 
 
 
 
 
 
 
6-7 
 
2. 
Introduction 
 
 
 
 
 
 
 
 
7 
 
2.1  Background 
 
 
 
 
 
 
 
7 
 
2.2  Purpose & rationale 
 
 
 
 
 
 
7 
 
3.   
Study objectives 
 
 
 
 
 
 
 
7 
 
3.1  Primary objective  
 
 
 
 
 
 
7-8 
 
3.2  Secondary objectives 
 
 
 
 
 
 
8 
3.3  Exploratory outcomes 
 
 
 
 
 
 
8 
 
4.   
Organization of the study 
 
 
 
 
 
 
8 
 
4.1  Organizational structure  
 
 
 
 
 
8 
 
4.2  Clinical centers 
 
 
 
 
 
 
 
8 
 
4.3  Principal investigator 
 
 
 
 
 
 
8 
 
4.4  Site personnel 
 
 
 
 
 
 
 
8-9 
 
5.   
Study procedures 
 
 
 
 
 
 
 
9 
 
5.1  Hypothesis 
 
 
 
 
 
 
 
9 
 
5.2  Central clinical and imaging units 
 
 
 
 
9 
 
5.2.1  Core clinical unit 
 
 
 
 
 
 
9 
 
5.2.1  Central imaging unit 
 
 
 
 
 
 
9-10 
 
5.3  Study design 
 
 
 
 
 
 
 
10 
 
5.4  RIS subject numbering  
 
 
 
 
 
11 
 
5.5  Database fields  
 
 
 
 
 
 
11 
 
5.6  Detailed patient schedule of assessments 
 
 
 
11-17 
 
5.7  Clinical exacerbations and radiological progression   
 
 
18 
5.8  Treatment options and safety monitoring  
 
 
18 
 
5.8.1  Treatment options following a confirmed relapse 
 
 
18 
 
5.8.2  Dose reduction options for intolerance 
 
 
 
18-19 
5.8.3 Parameters for low absolute lymphocyte counts 
 
 
19 
5.8.4 Parameters for drug non-compliance  
 
 
19 
 
 
6. 
Selection of study participants 
 
 
 
 
 
19-20 
 
7. 
Study medication 
 
 
 
 
 
 
 
20 
 
8.   
Reporting adverse events and serious adverse events 
 
 
20 
 
8.1  Adverse event reporting  
 
 
 
 
 
20-21 
 
8.2  Association with the study drug  
 
 
 
 
21 


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8.3  Serious adverse events  
 
 
 
 
 
21 
8.4  SAE reporting procedure  
 
 
 
 
 
21 
8.5  Withdrawal of study participants  
 
 
 
 
21 
 
9.   
Data safety monitoring board  
 
 
 
 
 
22 
 
10. 
Informed Consent  
 
 
 
 
 
 
 
22 
 
11. 
Data review and database management 
 
 
 
 
22 
 
12.   
Data analysis  
 
 
 
 
 
 
 
22 
 
12.1  Power calculation 
 
12.1.1 Parameter estimates for the rate of events in the RIS cohort in a Bayesian 
 
framework 
 
 
 
 
 
 
 
 
22-23 
 
12.1.2 Parameters for the prior distribution – Scenario 1 
 
 
23 
 
12.1.3 Parameters for the prior distribution – Scenario 2 
 
 
23 
 
12.1.4 Parameters for the prior distribution – Scenario 3 
 
 
23 
 
12.1.5 Parameters for the prior distribution – Scenario 4 
 
 
24 
12.2Patient demographic and other baseline characteristics 
 
24 
 
12.3  Analysis of other variables 
 
 
 
 
 
24-25 
 
 
13. 
Timeline estimate 
 
 
 
 
 
 
 
25 
 
14.   Biomarker Assessments 
 
 
 
 
 
25-26 
 
15.    References 
 
 
 
 
 
 
 
 
26 
 
Appendix 1: Cognitive/Functional Assessments 
 
 
 
227 
 
 
 
Appendix 2: Patient Reported Surveys 
 
 
 
 
 
27 
 
 
List of Tables 
Table: Recommended data collection schedule 
 
 
 
 
16-17  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
CSF 
 
cerebrospinal fluid 
 
CIU 
 
core imaging unit 
 
CCU 
 
core clinical unit 
 
EDSS  
expanded disability status scale  
 
EOS 
 
end of study 
 
IRB 
 
institutional review board 
 
MRI 
 
magnetic resonance imaging 
 
MS 
 
multiple sclerosis 
 
MSFC  
multiple sclerosis functional composite 
 
PI 
 
principal investigator 
 
PRO 
 
patient reported outcomes 
 
RIS  
 
radiologically isolated syndrome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
 
Title of study:  Multi-center, randomized, double-blinded assessment of Tecfidera® in extending 
the time to a first attack in radiologically isolated syndrome (RIS) (ARISE) 
 
Purpose:  To prospectively study the efficacy of Tecfidera in extending the time to a seminal 
acute or progressive demyelinating event in a cohort of U.S. RIS subjects.    
 
Rationale:  RIS subjects are frequently exposed to disease modifying therapies despite the lack 
of scientific literature supporting the use of such treatments.  Earlier treatment intervention may 
extend the time to the first acute or progressive clinical event resulting from CNS demyelination 
and reduce new radiological activity.  In addition, early treatment may result in more profound 
effects on reducing disability progression long-term. 
 
Primary outcome:  The primary outcome measure for this trial is the time to the first acute or 
progressive neurological event resulting from CNS demyelination from randomization into the 
trial. 
 
Population:  This study will include RIS subjects from the U.S. who fulfill 2009 RIS Criteria1. 
 
Inclusion/Exclusion criteria: 
Inclusion criteria 
1. Males and females 18 years of age and older meeting 2009 RIS criteria1 
2. Identified RIS cases with the initial MRI demonstrating anomalies suggestive of 
demyelinating disease dated > 2009 
3. Incidental anomalies identified on MRI of the brain or spinal cord with the primary reason 
for the acquired MRI resulting from an evaluation unrelated to multiple sclerosis 
4. CNS white matter anomalies meeting the following MRI criteria: 
a. Ovoid, well-circumscribed, and homogeneous foci with or without involvement of 
the corpus callosum 
b. T2-hyperintensities measuring > 3mm2 and fulfilling 3 of 4 Barkhof-Tintoré criteria 
for dissemination in space 
c. CNS anomalies not consistent with a vascular pattern  
d. Qualitative determination that CNS anomalies have a characteristic appearance of 
demyelinating lesions 
5. MRI anomalies do not account for clinically apparent neurological impairments in patients 
 
Exclusion criteria 
1. Women who are pregnant or nursing 
2. Incomplete medical history or radiological data 
3. History of remitting clinical symptoms consistent with multiple sclerosis lasting > 24 hours 
prior to CNS imaging revealing anomalies suggestive of multiple sclerosis 
4. History of paroxysmal symptoms associated with MS (i.e. Lhermitte’s or Uhthoff’s 
phenomena) 
5. CNS MRI anomalies are better accounted for by another disease process 
6. The subject is unwilling or unable to comply with the requirements of the study protocol 


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7. Exposure to a disease modifying therapy for multiple sclerosis/RIS within the past 3 
months 
8. Exposure to high-dose glucocorticosteroid treatment within the past 30 days 
9. Participation in other clinical trials involving treatment with a disease-modifying agent 
 
 
Study design:  Prospective, randomized, double-blinded, multi-center 
 
Key data collection: 
1. Clinical data 
2. Radiologic data 
3. Cognitive/Functional Assessments (EDSS, MSFC-expanded) 
4. Patient reported surveys 
5. Biological samples (CSF, serum DNA and RNA) for future mechanistic studies 
 
Data analysis:  
Primary analysis: 
- We will evaluate the time from randomization to the first demyelinating event (acute or 
development of an initial symptom resulting in a progressive clinical course) utilizing 
Kaplan-Meier survival analyses.  Log-rank tests will be used to compare survival data 
between groups at univariate analysis.   
 
Secondary analyses: 
- Multivariate Bayesian Cox regression models will be created to assess the independent 
predictive value of demographic characteristics (i.e. sex, ethnicity, age at the time of RIS 
diagnosis), clinical data (i.e. MS family history, occult neurological examination findings, 
environmental exposure data, cognitive performance, PRO, CSF profiles, etc.), and 
imaging data (i.e. number of brain MRI lesions, the presence of gadolinium enhancing 
lesions, geographical distribution of lesions, involvement of the spinal cord, brain atrophy, 
etc.) on the time to the first symptomatic event.   
 
- The association of each covariate with time to the first clinical symptom will be 
quantified by hazard ratios (HR) along with their 95% confidence intervals (CI).  
Assessments to determine differences between centers will also be performed with 
statistical adjustments planned for subsequent analyses depending upon the obtained 
results. 
 
- MRI outcomes (proportion of subjects with gadolinium enhancement and new radiologic 
activity). 
 
ABOUT THIS STUDY 
A strategic research alliance was formed between the Radiologically Isolated Syndrome 
Consortium (RISC) and Biogen to explore this important initiative of investigating the impact of 
early treatment intervention in subjects who possess the first visible manifestation of multiple 
sclerosis.  This collaboration enabled the development and effective execution of an innovative 
approach in demyelinating disease more quickly and strategically.  The current home of RISC, 
the University of Texas Southwestern Medical Center at Dallas (Texas, U.S.A.) is proud to serve 
as the study sponsor for this novel research study.   
 
1.  PURPOSE OF THIS MANUAL 
This operations manual is a guide for participation in this clinical trial.  All members of the study 
are responsible for following the procedures stipulated in this operations manual.  Detailed 


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specifications and study procedures are provided for consistency in protocol adherence amongst 
participating clinics. 
 
 
2.  INTRODUCTION 
2.1 Background 
Multiple sclerosis (MS) is a common cause of severe neurological disability in young adults, 
resulting from an autoimmune interruption of both myelin and axons within the central nervous 
system (CNS). The diagnosis is made by fulfilling both spatial criteria, by meeting the requisite 
number of lesions within the brain or spinal cord, along with criteria for time, by demonstrating a 
history of at least a second clinical attack or the development of a new MS lesion on MRI after 
the seminal neurological event2, 3.  Similar to many other chronic diseases, signs of impending 
disease may be observed in the months to years preceding the formal diagnosis.  In the case of 
MS, healthy individuals who do not exhibit signs of neurological dysfunction commonly have 
brain MRI studies performed for a reason other than an evaluation for MS that reveal unexpected 
anomalies highly suggestive of demyelinating plaques given their size, location, and 
morphology1, 4, 5.  These healthy subjects lack symptomatology suggestive of MS and fulfill formal 
criteria for radiologically isolated syndrome (RIS), a recently described MS subtype that expands 
upon the phenotype of at-risk individuals for future demyelinating events.  A formal description of 
RIS was first introduced in 20091, to define this relevant cohort of individuals routinely 
encountered in clinical practice.  The discovery of such anomalies creates intersecting neuro-
ethical, legal, social, and practical medical management quandaries and is, therefore, of both 
immediate and long-term clinical significance.  Despite advancements in the characterization of 
RIS subjects6-9, and in our understanding of risk factors for initial symptom development10, 11, the 
effect of treatment on such cases remain unclear.  In addition, disease-modifying therapies are 
currently being recommended and prescribed outside of controlled clinical trial settings, placing 
subjects at risk for unnecessary exposure to both expensive and potentially harmful treatments. 
 
2.2 Purpose & rationale 
The purpose of this investigation is to systematically study the efficacy of Tecfidera in those 
individuals who possess incidental white matter anomalies within the brain following a MRI study 
that is performed for a reason other than for the evaluation of MS.  A recent multi-national effort, 
involving RIS subjects from 5 countries, revealed that in 16% (73/451) of cases, regardless of the 
presence or absence of an asymptomatic spinal cord focus, a disease modifying therapy was 
prescribed prior to the development of a first clinical event12.  Despite the intention by clinicians 
to prevent disease progression and the biological plausibility of altering the demyelinating 
course, there are no scientific data supporting the use of such treatments in RIS.  The rationale 
for the proposed research is that earlier treatment intervention may extend the time to the first 
acute or progressive clinical event resulting from CNS demyelination and reduce new radiologic 
activity.  In addition, exposure to earlier treatment compared to traditional treatment patterns in 
symptomatic groups may result in more profound effects on reducing disability progression long-
term. 
 
3.  STUDY OBJECTIVES 
3.1 Primary objective 
The primary objective of this study is to assess the time from randomization to the first acute or 
initial neurological symptom resulting in a progressive clinical course related to CNS 
demyelination in those treated and untreated with Tecfidera. 
 
Definitions: 


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Acute neurological event:  The development of an acute neurological episode localized to the 
optic nerve, brainstem, cerebellum, spinal cord, or long sensory or motor tracts, lasting > 24 
hours followed by a period of symptom improvement. 
 
Progressive event:  The onset of a clinical symptom (e.g. leg weakness) with the temporal profile 
revealing at least a 12-month progression of neurological deficits. 
 
3.2 Secondary objectives 
The secondary objectives of this study include the change in the number of new or enlarging T2 
lesions, contrast enhancing lesions, T2-lesion volumes, and brain atrophy at End of Study.    
 
3.3 Exploratory outcomes 
Exploratory outcomes will include differences in cognitive performance and PRO between active 
treatment and placebo groups. 
  
4.  ORGANIZATION OF THE STUDY 
4.1 Organizational Structure 
The organizational structure of the clinical trial will consist of 15-20 clinical sites throughout the 
United States. 
 
4.2 Clinical Centers 
Each clinical center will be responsible for recruitment, treatment, evaluation of participants, and 
collection of study data according to the protocol.  The Principal Investigator will direct each 
clinical center and each site will designate a study coordinator, manager, or regulatory specialist, 
where applicable.  The roles and responsibilities of the study staff are described below.  In 
addition, each center will consist of appropriate support personnel trained in human subject 
protection and HIPAA guidelines for research. 
 
4.3 Principal Investigator (PI) 
The Principal Investigator will be responsible for the overall conduct of research activities at the 
site, including: 
• 
Conduct the study in accordance with the current protocol.  
• 
Supervise the described investigation(s).  
• 
Ensure that the requirements relating to obtaining informed consent and institutional 
review board (IRB) review and approval are met.  
• 
Submit all adverse experiences that occur in the course of the investigation via electronic 
data capture (EDC) for submission by the sponsor.  
• 
Ensure that all associates, colleagues, and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments.  
• 
Maintain adequate and accurate records and to make those records available for 
inspection.  
• 
Promptly report to the IRB all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others.  
• 
Make no changes in the research without IRB approval except where necessary to 
eliminate apparent immediate hazards to human subjects.  
 
4.4  Site Personnel: Clinical Research Project Manager, Regulatory & Contracts Specialist, 
& Study Nurse/Coordinator  
A well-implemented protocol is often attributable to an organized, responsible study coordinator. 
The PI may delegate some or all of the following tasks to the study coordinator, regulatory 
specialist, and/or project manager. Under the PI’s guidance, this person(s) may:  


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• 
Prepare regulatory documentation.  
• 
Ensure the study is conducted in compliance with protocol requirements.  
• 
Maintain IRB correspondence and regulatory documentation.  
• 
Recruit potentially eligible subjects and evaluate them for protocol eligibility.  
• 
Ensure that informed consent has been obtained from the participants before initiating 
any research-related activity.  
• 
Schedule tests and appointments for participants within timeframes required by protocol.  
• 
Complete Case Report Forms (CRFs) accurately.  
• 
Collect data in accordance with the protocol.  
• 
Maintain source documentation for each study participant in accordance with the 
protocol.  
• 
Instruct and educate participants regarding study intervention modalities and anticipated 
side effects and their management.  
• 
Monitor participant compliance.  
• 
Identify and document adverse events and serious adverse events.  
• 
Initiate Serious Adverse Event Reports (SAEs) and obtain the PI’s signature within 24 
hours, complete proper documentation notify proper individuals and fax report 
according to protocol.  
• 
Identify and document protocol deviations.  
• 
Respond to data queries in a timely manner.  
 
5.  STUDY PROCEDURES 
5.1  Hypothesis 
We hypothesize that treatment with Tecfidera will i) extend the time to the first acute or 
progressive demyelinating event by reducing CNS autoimmune inflammation and ii) reduce the 
development of new MRI lesions within the CNS compared to subjects randomized to placebo. 
 
5.2  Central Clinical and Imaging Units 
To accurately identify subjects with RIS, formal units will be created to review data prior to study 
entry. 
 
5.2.1 Core Clinical Unit: 
A Core Clinical Data Unit, led by Dr. Okuda, will be formed and comprised of a prominent 
international collaborator and trained MS specialist.  This group will evaluate clinical information 
from both existing and new cases within partnering centers, including results from para-clinical 
studies (i.e. blood work, CSF, electrophysiological studies, etc.) to ensure that subjects 
accurately fulfill criteria for study entry.  In addition, this group will be responsible for adjudicating 
all neurological events and post-attack clinical data during the study period.  If a discrepancy 
exists between reviewers following the independent review of submitted cases, Dr. Okuda will 
provide a decision on the final classification. The Core Clinical Unit will unify all screening data 
(including conclusions from the Central Imaging Unit (below)) and will notify participating site PIs 
when entry criteria are met for potential study participants. 
 
5.2.2 Central Imaging Unit: 
A Central Imaging Unit will be formed and will be comprised of a board certified neuro-
radiologist and MS specialist with neuro-imaging expertise. The MS specialist will confirm 
screened cases for study entry. MRI scans from subjects will be independently reviewed by the 
MS specialist and neuro-radiologist and determinations made if subjects fulfill MRI criteria for 
RIS.  If a discrepancy exists between the two reviewers following the independent review of a 
case the MS specialist with neuro-imaging expertise will provide a decision on the final 
classification.  The MS specialist with neuro-imaging expertise will also be responsible for 


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ensuring that a uniform protocol (“Dummy scans”) is implemented at specified sites for the 
collection of uniform, multi-center data for post processing.  In addition, this group will evaluate 
all MRI studies of the CNS for interval change (i.e. new and enlarging T2 lesion(s), gadolinium 
enhancement) during follow-up imaging studies and imaging studies acquired during clinical 
events.  At End of Study, changes in T2-lesion volumes, and brain atrophy (SIENA) will be 
determined.  
 
5.3 Study Design 
This is a multi-center, randomized, double-blinded study in which approximately 90 RIS subjects 
(refer to section 12 for sample size justification) will be treated with either Tecfidera or placebo 
(1:1 randomization) for 3 years or until End of Study (EOS) which is March 31, 2021.  The 
primary outcome measure is the time to the first acute or progressive neurological event resulting 
from CNS demyelination.  The secondary outcome measures include the number of new or 
enlarging T2 lesions, and the change in the number of contrast enhancing lesions, and T2-lesion 
and brain volumes.  Study participants, along with the treating and examining physicians, will be 
blinded to treatment assignment.  Central Clinical and Imaging Units will screen all potential 
study subjects for inclusion/exclusion criteria. We expect to enroll all RIS subjects within the U.S.   
 
Following informed consent and verification of entry criteria by the core units, study participants 
will be randomized 1:1 to either Tecfidera (120mg by mouth twice daily for 7 days with dose 
escalation to 240mg by mouth twice daily) or placebo.  Clinical follow-up by the treating 
physician, as defined within this protocol, will occur at weeks 0, 48, 96, 144 and/or EOS  and 
during or immediately following clinical exacerbations.  (please refer to Study Schematic).  
During clinical visits comprehensive medical history data, safety labs, and optional biological 
samples will be obtained by the treating physician.   
 
 
Patients will be scheduled for safety screenings (CBC & CMP) at weeks 12, 24, 72, 120; at which 
time they will be seen by research coordinator or research nurse.  
 
In addition to the face-to-face visits described above, study participants will be contacted over 
the telephone at weeks 4, 8, 36, 60, 84, 108, and 132 to assess for medical or treatment 
difficulties in addition to study medication compliance.   
 
Standardized MRI studies of the brain will be performed at weeks 0 ,96, 144 or EOS; an 
additional MRI will be obtained at week 46 for those patients enrolled at the UTSW site only. 
Clinical imaging studies of the brain and/or spinal cord performed during or immediately following 
the onset of a clinical exacerbation will be performed at the discretion of the site PI with scan 
costs covered under the medical standard of care.  A clinical MRI of the cervical spinal cord with 
and without contrast will be recommended to study participants at week 0 and week 144 as 
medical standard of care.  
 
Participants who cannot receive contrast due to allergic reaction or abnormal blood counts will 
not be excluded from the study. Their imaging studies without contrast will be accepted. 
 
All reported acute or progressive clinical events will be adjudicated by the Central Clinical Unit.  
Clinical visits due to suspected exacerbations associated with CNS demyelination, and 
associated diagnostic studies and treatments, will be covered under the medical standard of care 
by third party payers.  A recommendation to re-evaluate the patient within 3 months following the 
clinical event to assess for extent of recovery will be made.  
 


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5.4  RIS subject numbering 
Each RIS subject will be uniquely identified by a combination of the originating center and study 
subject number.  Upon signing the informed consent, the subject will be given a unique 
participant number by the participating center PI.  For example, the first RIS participant at UT 
Southwestern Medical Center (Dallas, Texas, U.S.A.) would be assigned the following 
identification number: UTSW-001.    
 
5.5 Database fields 
The following data will be captured in this study via electronic data capture (EDC).  
 
Clinical Data:  Comprehensive demographic data (i.e. date of birth, sex, race and ethnicity, etc.) 
and clinical data (i.e. date of first clinical visit, reason for the initial MRI scan, findings from the 
patient’s clinical examination (to include vital signs), Visual Systems Tests (low vision contrast 
charts, ocular coherence tomography (OCT)) CMP and CBC results, cerebrospinal fluid test 
results, new onset clinical attacks, extent of recovery, etc. will be obtained from face-to-face 
clinical visits and existing medical records.  Cognitive/Functional assessments (EDSS, expanded 
MSFC (Timed 25-FT Walk (T25-FW), 9-Hole Peg Test (9-HPT), Paced Auditory Serial Addition 
Test (PASAT-3 (3-second interval pause)), Symbol Digit Modalities Test (SDMT), will also be 
performed. Please refer to Appendix 1 – Cognitive/Functional Assessments 
 
Patient Reported Surveys:  Surveys containing questions related to Demographics, Family 
History, Lifestyle, Environment, and Environmental Exposure and the Neuro Quality of Life 
Questionnaire (Neuro-QOL data), will be completed by each study participant ; included will be 
inquiries into previous illnesses, the use of over-the-counter supplements, diet, occupational 
histories, exposure to vaccinations, etc.  Please refer to Appendix 2 – Patient Reported Surveys. 
 
Adverse events as well as concomitant medications will be collected and reported. All data 
collected for clinical assessments will be submitted via EDC and shared with Biogen. At the time 
of any patient withdrawing from the trial, an attempt will be made to determine the reason for 
discontinuation. 
 
Radiological Data:  Comprehensive radiological data will be collected from RIS subjects.  Data to 
be incorporated into the study database include the date of the first MRI scan demonstrating 
anomalies within the brain that are suggestive of MS, number of lesions, lesion location, the 
presence of contrast enhancing lesions, the number of contrast enhancing lesions, changes 
observed between MRI studies, etc.  In addition, data from the clinical MRI study of the cervical 
spine obtained at screening or Month 0 and at EOS will be incorporated if completed. 
 
5.6 Detailed Patient Schedule of Assessments 
Screening: 
• 
Review of inclusion and exclusion criteria 
• 
Evaluation of clinical and radiological data by the Core Clinical and Central Imaging Units 
• 
Consent and Discussion of Study Expectations following approval for participation by the 
Centralized Units. 
 
Week 0, +/- 2 weeks (approximately 2.5 hours) 
• 
Record Demographics, and Medical and Clinical History  
• 
Physical examination (including vital signs)  
• 
Visual System tests (Low Vision Contrast charts, Ocular Coherence Tomography (OCT) 
(to be performed at UT Southwestern ONLY) 
• 
Pregnancy test (urine) 


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• 
Cognitive/Functional Assessments (Appendix 1) 
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
• 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
  ○ Spinal fluid (CSF) (optional) 
• 
Standardized brain MRI at 1.5 or 3.0 Tesla 
• 
Recommendation for MRI of the cervical spine with and without contrast (per medical 
standard of care) 
• 
Obtain randomization number (1:1 Randomization of Tecfidera and Placebo) 
• 
Administer Study Medication (including titration dosing) 
• 
Review any adverse events and concomitant medications 
 
Week 4, +/- 2 weeks (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications 
 
Week 8, +/- 2 weeks (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications 
 
Week 12, +/- 2 weeks: (approximately 20 minutes) 
• 
Blood draw: CBC, CMP  
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications 
• 
Dispense Study Medication 
 
Week 24, +/- 2 weeks: (approximately 20 minutes)  
• 
Blood draw: CBC, CMP 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications 
• 
Dispense Study Medication 
 
Week 36, +/- 2 weeks: (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications 
• 
Dispense Study Medication (via mail or patient pick up) 
 
Week 48, +/- 2 weeks (approximately 1 hour): 
• 
Review of Interval Medical History  
• 
Physician examination (including vital signs) 
• 
Visual System tests (Low Vision Contrast charts, Ocular Coherence Tomography (OCT) 
(to be performed at UT Southwestern ONLY) 


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• 
Cognitive/Functional Assessments (Appendix 1) 
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
• 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
  ○ Spinal fluid (CSF) (optional) 
• 
Standardized brain MRI at 1.5 or 3.0 Tesla (to be performed at UT Southwestern ONLY 
• 
Dispense Study Medication  
• 
Review any adverse events and concomitant medications 
 
Week 60, +/- 2 weeks: (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Assessment of adverse events and changes in medications 
• 
Dispense Study Medication (via mail or patient pick up) 
 
Week 72, +/- 2 weeks, (approximately 20 minutes): 
• 
Blood draw: CBC, CMP 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Dispense Study Medication  
• 
Review any adverse events and changes in medications 
 
Week 84, +/- 2 weeks: (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Dispense Study Medication (via mail or patient pick up) 
• 
Review any adverse events and changes in medications 
 
Week 96, +/- 2 weeks (approximately 2 hours): 
• 
Review of Interval Medical History 
• 
Physician examination (including vital signs) 
• 
Visual System tests (Low Vision Contrast charts, Ocular Coherence Tomography (OCT) 
(to be performed at UT Southwestern ONLY) 
• 
Cognitive/Functional Assessments (Appendix 1) 
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
• 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
  ○ Spinal fluid (CSF) (optional) 
• 
Standardized brain MRI at 1.5 or 3.0 Tesla 
• 
Recommendation for MRI of the cervical spine with and without contrast (per medical 
standard of care) 
 
• 
Dispense Study Medication  
• 
Review any adverse events and concomitant medications 
 
Week 108, +/- 2 weeks: (approximately 20 minutes) 
• 
Telephone conversation 


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• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Review any adverse events and changes in medications 
• 
Dispense Study Medication (via mail or patient pick up) 
 
Week 120, +/- 2 weeks, (approximately 20 minutes): 
• 
Blood draw: CBC, CMP 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Dispense Study Medication  
• 
Review any adverse events and changes in medications 
 
Week 132, +/- 2 weeks: (approximately 20 minutes) 
• 
Telephone conversation 
• 
Assessment for medical or medication difficulties 
• 
Assessment of medication compliance 
• 
Review any adverse events and changes in medications 
• 
Dispense Study Medication (via mail or patient pick up) 
 
Week 144, +/- 2 weeks (approximately 2 hours): 
• 
Review of Interval Medical History 
• 
Review of AEs and Concomitant Medications 
• 
Physician examination (including vital signs) 
• 
Visual System tests (Low Vision Contrast charts, Ocular Coherence Tomography (OCT) 
(to be performed at UT Southwestern ONLY) 
• 
Cognitive/Functional Assessments (Appendix 1) 
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
• 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
  ○ Spinal fluid (CSF) (optional) 
• 
Standardized brain MRI at 1.5 or 3.0 Tesla 
• 
Recommendation for MRI of the cervical spine with and without contrast (per medical 
standard of care) 
• 
Collect all remaining study medication 
 
Relapse Visit (approximately 2 hours): 
• 
Review of Interval Medical History 
• 
Review any adverse events and changes in medications 
• 
Physician examination (including vital signs) 
• 
Cognitive/Functional Assessments (Appendix 1) 
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
• 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
• 
Recommendation for Standardized brain MRI at 1.5 or 3.0 Tesla at the discretion of the 
treating neurologist (per medical standard of care) 
 
Unscheduled Visit (approximately 2 hours): 
• 
Review of Interval Medical History 
• 
Review any adverse events and changes in medications 


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• 
Physician examination (including vital signs) 
• 
Cognitive/Functional Assessments (Appendix 1)  
• 
Patient Reported Surveys (Appendix 2) 
• 
If standard of care brain CBC, CMP obtained at this visit, data should be recorded. 
• 
If standard of care brain and/or cervical spine MRI completed at this visit, data should be 
recorded. 
 
Early Withdrawal/Discontinuation or End of Study (approximately 2 hours): 
• 
Review of Interval Medical History 
• 
Review any adverse events and changes in medications 
• 
Physician examination (including vital signs) 
• 
Visual System tests (Low Vision Contrast charts, Ocular Coherence Tomography (OCT) 
(to be performed at UT Southwestern ONLY) 
• 
Cognitive/Functional Assessments (Appendix 1)  
• 
Patient Reported Surveys (Appendix 2) 
• 
Blood draw: CBC, CMP 
• 
Biological mechanistic samples for future use (including DNA/RNA),  
  ○ Serum 
  ○ Spinal fluid (CSF) (optional) 
• 
Standardized brain MRI at 1.5 or 3.0 Tesla 
• 
Recommendation for MRI of the cervical spine with and without contrast (per medical 
standard of care) 
• 
Collect all remaining study medication 
 
 
Table. Summary of study related events by visit. 
 
 


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• 
SOC:  If standard of care MRI completed at this visit, data should be recorded 
• 
CBC & CMP (safety labs): To be processed on-site for PI review and NOT shipped to UTSW 
• 
Medication Assessment & Administration INCLUDES completion of ‘Drug Accountability 
Record’ 
• 
If subjects who were consented for 96 weeks choose not to extend their participation through 
week 114/or EOS, their week 96 should be recorded as ‘early withdrawal’ visit. 
 
 
 
 
 
 
 
 
 
Assessment 
Screening 
Week 0 
Week 
4 
Week 
8 
Week 
12 
Week 
24 
Week 
36 
Week 48 
Week 
60 
Week 
72 
Week 
84 
Week 96 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
Review of Eligibility 
X 
  
  
  
  
  
  
  
  
  
  
  
Evaluation by Clinical 
Core and Central Imaging 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Record History and 
Demographics 
X 
  
  
  
  
  
X 
  
  
  
X 
Visual Systems tests 
 
UTSW 
only 
 
 
 
 
 
UTSW 
only 
 
 
 
UTSW 
only 
Patient Reported Surveys 
  
X 
  
  
  
  
  
X 
  
  
  
X 
Physical Exam (including 
vital signs) 
  
X 
  
  
  
  
  
X 
  
  
  
X 
Cognitive/Functional 
Assessments 
  
X 
  
  
  
  
  
X 
  
  
  
X 
Pregnancy Test (urine) 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood draw : 
CBC/CMP for safety 
screening 
(local lab for PI review) 
  
X 
  
  
X  
 X 
  
X 
  
 X 
  
X 
Biological sample for 
DNA/RNA: 
SERUM 
 
X 
 
 
 
 
 
X 
 
 
 
X 
CSF Samples 
(optional) 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Medication Assessment 
& Dispense rx  via pt pick 
up or mail 
  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Brain MRI 
X 
  
  
  
  
  
UTSW 
only  
  
  
  
X 
Cervical Spine MRI 
(optional – standard of 
care)  
 
SOC 
 
 
 
 
 
 
 
 
 
SOC 
Telephone conversation 
  
  
X 
X 
X 
  
X 
X 
  
Patient Compensation 
  
X 
  
  
  
  
  
X 
  
  
X 
Review adverse events & 
changes in medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect remaining study 
medication 
 
 
 
 
 
 
 
 
 
 
 
 


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Assessment 
Week 
108 
Week 
120 
Week 
132 
Week 
144 
Relapse 
Early Withdrawal 
Unscheduled 
Informed Consent 
 
 
 
 
 
 
 
Review of Eligibility 
 
 
 
 
 
 
 
Evaluation by Clinical Core 
and Central Imaging 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
Record History and 
Demographics 
 
 
 
X 
X 
X 
X 
Visual Systems tests 
 
 
 
UTSW 
only 
 
UTSW only 
 
Patient Reported Surveys 
 
 
 
X 
X 
X 
X 
Physical Exam (including vital 
signs) 
 
 
 
X 
X 
X 
X 
Cognitive/Functional 
Assessments 
 
 
 
X 
X 
X 
X 
Pregnancy Test (urine) 
 
 
 
 
 
 
 
Blood draw : 
CBC/CMP for safety 
screening 
(local lab for PI review) 
 
X 
 
X 
X 
X 
SOC 
Biological sample for 
DNA/RNA: 
SERUM 
 
 
 
X 
X 
X 
 
CSF Samples 
(optional) 
 
 
 
X 
 
X 
 
Medication Assessment & 
Dispense rx  via pt pick up or 
mail 
X 
X 
X 
X 
 
 
 
Brain MRI 
 
 
 
X 
SOC 
X 
SOC 
Cervical Spine MRI 
(optional – standard of care)  
 
 
 
SOC 
 
SOC 
SOC 
Telephone conversation 
X 
 
X 
 
 
 
 
Patient Compensation 
 
 
 
X 
 
 
 
Review adverse events & 
changes in medication 
 
 
 
 
X 
X 
X 
Collect remaining study 
medication 
 
 
 
X 
 
X 
 
 
 
 


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5.7  Clinical exacerbations and radiological progression 
All participating subjects will be advised to contact the lead site investigators if a clinical 
symptom is suspected or experienced in a RIS subject.  Site PIs will be responsible for 
confirming clinical events and will perform the EDSS examination.  Data will be entered via 
electronic data capture (EDC) for review by the Central Clinical Unit where the clinical 
exacerbation will be adjudicated.  In the event of a suspected seminal acute or progressive 
demyelinating event, attempts will be made to evaluate the subject on an urgent basis within 48-
72 hours from symptom onset by the site investigators (medical standard of care).  Repeat 
imaging of the brain and spinal cord will be ordered at the discretion of the treating physician 
based on symptom localization and will be performed as per medical standard of care.  Acute 
interventions (i.e. high-dose glucocorticosteroid treatment, etc.) will be prescribed and managed 
at the discretion of the treating physician at participating sites.   The study visit will be labeled as 
either an “unscheduled visit” or a “relapse visit”. Study participant may be asked to provide 
additional biological specimens (serum) for future investigations.  Sites will be encouraged to re-
evaluate the patient within 3 months (medical standard of care) following the clinical event to 
assess the extent of recovery.  All subjects who experience a seminal neurological event related 
to CNS demyelination, or those who are found to be intolerant to the study medication, will be 
provided with options highlighted in section 5.8.  
 
RIS subjects will be made aware of any radiological progression identified on longitudinal 
imaging of the brain and spinal cord.  As there is no FDA approved acute or long-term treatment 
for RIS, subjects will be extensively counseled by the PI as to their medical options. 
 
5.8  Treatment options and safety monitoring following a confirmed relapse, intolerance to 
the study medication, or low absolute lymphocyte counts 
 
5.8.1  When eligible, subjects on blinded study treatment who experience a confirmed clinical 
relapse by the Core Clinical Unit during the study will be offered the following options: 
 
1. Remain on study treatment, with assignment remaining blinded 
2. Prematurely discontinue blinded study treatment, begin treatment with Tecfidera (covered 
by Biogen up to 3-years from study enrollment date or until EOS) or subcutaneous 
peginterferon beta 1-a (Plegridy) if the study subject was randomized to Tecfidera, and 
remain in the study to complete a modified schedule of follow-up 
 
Modified Schedule of Follow-Up: 
 
- Re-evaluate patient within 3 mos of clinical event / relapse. 
 
- Patient then presents every 12 weeks for post-relapse (PR) follow up; Week 48 
PR, Week 96 PR etc, until original EOS date. 
 
  
 
3. Prematurely discontinue blinded study treatment, decline open-label treatment with 
Tecfidera or Plegridy, and remain in the study to complete the schedule of follow-up 
evaluations. Original treatment assignment remained blinded 
 
5.8.2  Dose reduction treatment option for intolerable flushing and/or gastrointestinal 
disturbances related to study medication: 
 
Patient-reported complaints of persistent, intolerable flushing and/or gastrointestinal 
disturbance to blinded study medication will be asked to reduce the blinded study medication 
administration to one capsule twice daily for one month. Following the one-month reduction in 


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dose, patients will be asked to resume taking two capsules twice daily. If the patient is still unable 
to tolerate the blinded study treatment, the patient will be required to discontinue study treatment.  
 
Any patient continuing to experience intolerance to study medication following the one-
month reduction in dose will be offered a switch to Plegridy as an alternative therapy. The patient 
will be unblinded to the study medication at this time.  Plegridy will be administered per FDA-
dosing and titration instructions for relapsing forms of multiple sclerosis.   
 
Any patient continuing to experience intolerance to study medication following the one-
month reduction in dose, refusing a switch in therapy to Plegridy, and prematurely discontinuing 
dosing with blinded study treatment due to intolerance will be asked to consider remaining in the 
study and encouraged to continue participation in the trial on a modified schedule of 
assessments. Patient treatment will remain blinded. 
Modified Schedule of Follow-Up: 
 
- Re-evaluate patient within 3 mos of clinical event / relapse. 
 
 
- Patient then presents every 12 weeks for post-relapse (PR) follow up; Week 48 
PR, Week 96 PR etc, until original EOS date. 
 
  
       5.8.3  Parameters for low lymphocyte counts: 
 
 
In the event that the absolute lymphocyte count is observed to be <500 cells/L during any 
time within the study, a repeat blood draw will be performed 3 months later.  If a sustained 
reduction of the absolute lymphocyte count is observed (<500 cells/L), the study subject will be 
unblinded to the study medication and removed from the randomized portion of the trial.  Repeat 
assessments will be performed monthly until the absolute lymphocyte count is >500 cells/L.  
Once the absolute lymphocyte count is found to be >500 cells/L, study subjects randomized to 
Tecfidera will be given the opportunity to receive Plegridy (covered by Biogen until study 
conclusion). 
 
The rationale for providing these options to subjects was 2-fold: to conduct this placebo-
controlled study ethically and to make every effort to continue to follow the subjects (for efficacy 
and safety evaluations), even after they discontinued the study treatment. 
 
5.8.4 Parameters for drug non-compliance 
 
Patients who are non-compliant with medication dosing, or who discontinue taking their 
medication, may remain in the study in observation. They will remain on their original 
follow-up schedule but will no longer be dispensed medication. It should be noted in 
WebEz that medication has stopped. 
 
6.  SELECTION OF STUDY PARTICIPANTS 
Inclusion criteria 
1. Males and females 18 years of age and older meeting 2009 RIS criteria1 
2. Identified RIS cases with the initial MRI demonstrating anomalies suggestive of 
 
demyelinating disease dated > 2009 
3. Incidental anomalies identified on MRI of the brain or spinal cord with the primary reason 
 
for the acquired MRI resulting from an evaluation of a process other than MS 
4. CNS white matter anomalies meeting the following MRI criteria: 
a. Ovoid, well-circumscribed, and homogeneous foci with or without involvement of 
the corpus callosum 


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b. T2-hyperintensities measuring > 3mm2 and fulfilling 3 of 4 Barkhof-Tintoré criteria 
for dissemination in space 
c. CNS anomalies not consistent with a vascular pattern  
d. Qualitative determination that CNS anomalies have a characteristic appearance of 
demyelinating lesions 
5. MRI anomalies do not account for clinically apparent neurological impairments in  patients 
 
 
Exclusion criteria 
1. Women who are pregnant or nursing 
2. Incomplete medical history or radiological data 
3. History of remitting clinical symptoms consistent with multiple sclerosis lasting > 24 hours 
prior to CNS imaging revealing anomalies suggestive of MS 
4. History of paroxysmal symptoms associated with MS (i.e. Lhermitte’s or Uhthoff’s 
phenomena) 
5. CNS MRI anomalies are better accounted for by another disease process 
6. The subject is unwilling or unable to comply with the requirements of the study protocol 
7. Exposure to a disease modifying therapy for MS/RIS within the past 3 months 
8. Exposure to high-dose glucocorticosteroid treatment within the past 30 days 
9. Participation in other clinical trials involving treatment with a disease-modifying agent 
 
7.  STUDY MEDICATION 
Study drug defined as Tecfidera or placebo will be provided at no cost to study participants.  
Study drug will be provided to the study sites by a study drug management vendor as triggered 
through an enrollment/randomization system. If patients are eligible to switch to Plegridy (due to 
study medication intolerance), this treatment will also be provided at no cost to the study 
participants for the duration of three 48ars from the date of randomization into the trial. 
 
Any patient that becomes pregnant during the trial will discontinue study medication and 
complete the early withdrawal assessments according to the schedule of assessments table 
(page 14). 
 
8.  REPORTING ADVERSE EVENTS (AEs) AND SERIOUS ADVERSE EVENTS (SAEs) 
8.1 Adverse Event Reporting 
An adverse event is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that occurs after first dose of study treatment through 
week 144 or EOS visit or early withdrawal/discontinuation visit, whether or not considered related 
to study treatment. Signs and symptoms existing prior to first dose and documented on the 
baseline Medical History form or Physical Examination Form are not considered AEs. Only 
baseline signs and symptoms that worsen while the subject is on the study drug are considered 
adverse events. 
 
At every visit, participant will be questioned regarding the occurrence and nature of any adverse 
experiences. If any signs, symptoms or the results of the laboratory tests indicate an adverse 
effect, the study physician should determine the severity (grade) of the AE and judge the 
relationship to the study treatment according to the current version of the U.S. Department of 
Health and Human Services Common Terminology Criteria for Adverse Events (CTCAE). In 
addition, if an adverse event necessitates medical care, appropriate care will be provided. 
Adverse events should be documented on the Adverse Event Report form, regardless of 
relationship to the study drugs. Notably, AEs thought to be due to treatment with the study drug 
are still reported as AEs in this study. The following information will be collected for all Adverse 


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Events: 
 
• 
Start and stop dates  
• 
Severity (See the Severity Grading section below) 
• 
CTCAE score  
• 
Relationship to study drugs (See the Association with the Study Drug below )  
• 
Action taken with study drugs  
• 
Treatment for the AE and outcomes  
 
Severity Grading 
For evaluation and reporting purposes, events will be graded by a numerical score according to 
their impact on the subject’s ability to perform daily activities as follows:  
  
1 - Mild (causing no limitation of usual activities) 
  
2 - Moderate (causing some limitation of usual activities)  
  
3 - Severe (causing inability to carry out usual activities)  
 
8.2 Association with the Study Drug  
Association with the use of the study drug means that there is a reasonable possibility that the 
adverse event may have been caused by the drug under investigation. All adverse events are 
graded with regard to their association with the use of the study drug. The classifications used 
include Not Related or Related.  
 
8.3 Serious Adverse Event (SAE) 
A serious adverse event means any adverse drug experience occurring at any dose that results 
in any of the following outcomes: death, a life-threatening adverse drug experience, requires 
participant hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. An important medical event that may 
not result in death, be life-threatening, or require hospitalization may be considered a SAE, 
when, based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical / surgical intervention to prevent one of the outcomes listed above. Notably, any 
hospitalization, regardless of its nature, severity or etiology will be reported as an SAE.  SAEs 
are collected from signing of Informed Consent through week 144 /or EOS visit or early 
withdrawal/discontinuation visit. 
 
8.4  SAE Reporting Procedure  
In the interest of subject safety and to fulfill regulatory requirements, all Serious Adverse Events, 
regardless of whether or not it is related to the study drug, should be reported to Quintiles 
Lifecycle Safety within 24 hours of event identification. Biogen or designee will forward a CIOMS 
form to the Sponsor-Principal Investigator to immediately onward submit to the FDA and all 
participating investigators in the study.  All PIs are responsible for ensuring that all SAEs are 
recorded on the CRF and are reported to respective IRBs.  
 
8.5 Withdrawal of Study Participants: 
The researchers may decide to withdraw the patient from the study if: 
•      The medical problem becomes worse 
•  
The researchers believe that participation in the research is no longer safe for the patient 
•  
The researchers believe that other treatment may be more helpful 
•  
The sponsor, IRB or the FDA stops the research for the safety of the participants 
•  
The sponsor cancels the research 
•  
The patient is unable to keep appointments or to follow the researcher’s instructions 
 


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9.  DATA SAFETY MONITORING BOARD (DSMB) 
As Tecfidera is an approved FDA treatment for relapsing forms of multiple sclerosis, we do not 
anticipate any impediments to patient enrollment or significant adverse or serious adverse 
events.  As a result, no data safety advisory board is required during the study. 
 
10.  INFORMED CONSENT 
The informed consent form must be reviewed and approved by IRB. All revisions of the protocol 
must be reflected in the consent form and reviewed by the IRB. Obtaining informed consent is 
more than obtaining a signature on a form. It is a process designed to: 
• 
Provide the participant with current and ongoing information about the study 
• 
Ensure the participant understands the information that has been presented and has an 
opportunity to ask questions  
• 
Discuss the participant’s rights as outlined in the consent form  
• 
Allow the participant the opportunity to agree or disagree to take part in the study, and  
• 
Allow the participant the opportunity to freely withdraw from the study in the future. The 
investigator or coordinator should discuss in detail with the potentially eligible subjects 
about the nature, aims, duration, potential hazards of the study, and procedures to be 
performed during the study. The investigator or coordinator will explain all aspects of the 
study in lay language and answer all of the candidate's questions regarding the study. 
The investigator must also explain that the participants are completely free to refuse to 
enter the study or to withdraw from it at any time. The written informed consent form 
should be signed and personally dated and timed by the participant. Participants receive 
a copy of the informed consent form. The original copy of the signed and dated consent 
form should be kept in the participant’s source document file and a copy should be 
scanned into the patient’s medical record. Subjects who refuse to participate should be 
treated without prejudice.  
• 
Should be obtained prior to any study-related procedures 
 
11.  DATA REVIEW AND DATABASE MANAGEMENT Clinical and radiographic information will 
be transmitted to Core Clinical Unit via secure FTP – MOVEit DMZ. 
Quintiles will provide for support related to data management, safety management, and project 
management. Data should be entered into eCRF (Oracle Inform) within 7 days of the visit, 
except: Day 1 data, which should be entered within 24 hours. 
 Automatic validation programs will be implemented by the external vendor to assess for data 
discrepancies.  At the end of the study, each participating PI will certify that the data entered are 
complete and accurate prior to database lock.   
 
12.  DATA ANALYSIS 
The purpose of this study is to assess the risk for a first clinical neurological event related to CNS 
demyelination in a cohort of RIS subjects from the U.S.   
12.1 Power calculation 
 
A Bayesian approach has been used to calculate the sample size. The Bayesian approach is 
based on combining a prior distribution for the treatment effect with the result of the trial (which 
represents here the likelihood). The prior distribution for the effect of Tecfidera vs. placebo was 
built using the data from DEFINE and CONFIRM trials in RRMS. 
 
12.1.1 Parameter estimates for the rate of events in the RIS cohort in a Bayesian framework 
 


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The parameters for the expected treatment effect of a 50% reduction in the risk of the first clinical 
event are HR=0.50 (i.e. logHR=-0.69). A SD for logHR is set to 2.2 to get a power of 80% to detect 
a 50% reduction in the hazard of events with 80 patients per arm (original design). This base 
scenario is set in order to use the same assumptions done as for the original calculations. 
 
Several scenarios were considered to allow a sensitivity analysis for the power calculations. 
 
12.1.2 Parameters for the prior distribution – Scenario 1 
 
The 2 arms treated with Tecfidera are pooled together (i.e. same efficacy) 
Patients from DEFINE and CONFIRM are classified as “early RRMS” if they had: 
 
- No previous treatment 
 
- Less than 5 years from disease onset 
 
- EDSS≤1.5 
 
Total 
Placebo 
Tecfidera 
RRMS 
703 
1372 
2075 
Early 
68 
157 
225 
Total 
771 
1529 
2300 
 
 
225 patients are classified as Early in the 2 trials merged. 
 
Treatment effect in the “Early” group (HR=0.24, risk reduction=76%) logHR=-1.45; SE=0.31. 
Treatment effect in the rest of RRMS (HR=0.59, risk reduction 41%) 
 
The parameters of the prior distribution, according to the Tecfidera effect in early RRMS in the 
DEFINE+CONFIRM studies, are: mean=-1.45, SD=0.31.  
 
12.1.3 Parameters for the prior distribution – Scenario 2 
 
The 2 arms treated with Tecfidera are pooled together (i.e. same efficacy) 
We take the Tecfidera effect form the merged trials: HR=0.58, risk reduction=42%; logHR=-
0.548; SE=0.073. 
 
The parameters of the prior distribution, according to the Tecfidera effect all the patients included 
in the DEFINE+CONFIRM studies, are:  mean=-0.548, SD=0.073.  
 
 


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12.1.4 Parameters for the prior distribution – Scenario 3 
 
The 2 arms treated with Tecfidera are pooled together (i.e. same efficacy) 
We take the Tecfidera effect form the merged trials: HR=0.58, risk reduction=42% 
We assume the treatment effect on the RIS cohort to be reduced by 20% since there is a portion 
of RIS that are not subclinical MS.  
 
HR=0.58*1.20 =0.70 
logHR=-0.36  
mean=-0.36, SD=0.073.  
 
12.1.5 Parameters for the prior distribution – Scenario 4 
 
The 2 arms treated with Tecfidera are pooled together (i.e. same efficacy) 
We take the Tecfidera effect form the merged trials: HR=0.58, risk reduction=42%; SE=0.073 
 
We assume the treatment effect on the RIS cohort to be reduced by 30% since there is a portion 
of RIS that are not subclinical MS.  
  
HR=0.58*1.30 =0.75; logHR=-0.282; mean=-0.282, SD=0.073 
 
 
 


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We report here the different power estimates for a sample size of 80 RIS patients (40 per 
arm) according to the 4 scenarios and 4 different assumptions on SD (representing those 
observed multiplied by 2, 3, 4 and 5).   
 
  
  
  
SD 
  
Prior HR 
Parameters for the 
prior 
x2 
x3 
x4 
x5 
  
 
 
 
 
 
  
Scenario 1 (early RRMS, 
subgroup of the trials) 
HR=0.235 
Prior mu=-1.45, 
SD=0.31 
86% 
70% 
63% 
9% 
  
 
 
 
 
 
  
Scenario 2 (all RRMS in the 
trials) 
HR=0.58 
Prior mu= -0.548, 
SD=0.07 
100% 
99.60% 
91.30% 
80% 
  
 
 
 
 
 
  
Scenario 3 (all RRMS with 
an effect diluted by 20%) 
HR=0.70 
Prior mu= -0.362, 
SD=0.07 
99% 
86% 
70% 
61% 
  
 
 
 
 
 
  
Scenario 4 (all RRMS with 
an effect diluted by 30%) 
HR=0.75 
Prior mu= -0.282, 
SD=0.07 
96% 
67% 
56% 
49% 
 
 
Overall, the power analysis shows that the projected sample size of 80 patients should result in 
adequate power for the majority of scenarios considered. 
 
 
12.2.  Patient demographic and other baseline characteristics 
Patient demographic and baseline characteristic data will be described by means of absolute and 
relative frequencies for categorical variables and mean, standard deviation minimum and 
maximum, for continuous variables.  Categorical variables will include sex, race, ethnicity, 
country, date of birth, age at RIS, etc.   
 
12.3.  Analysis of other variables 
To validate the association between incidentally identified anomalies within the CNS that are 
highly suggestive of MS and seminal demyelinating events, systematically acquired 
environmental exposure, clinical, and radiological, data will be assimilated in an effort to identify 
significant risk factors.  We will evaluate the time from the initial MRI revealing incidental 
anomalies to the first demyelinating event (acute or initial symptom resulting in a progressive 
clinical course) or new MRI focus utilizing Kaplan-Meier survival analyses.  Log-rank tests will be 
used to compare survival data between groups at univariate analysis.  Multivariate Bayesian Cox 
regression models will be created to assess the independent predictive value of demographic 
characteristics (i.e. sex, ethnicity, age at the time of RIS diagnosis), clinical data (i.e. MS family 
history, occult neurological examination findings, environmental exposure data, CSF profiles, 
cognitive performance, etc.), and imaging data (i.e. number of brain MRI lesions, the presence of 
gadolinium enhancing lesions, geographical distribution of lesions, involvement of the spinal 


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cord, brain atrophy, etc.) on the time to the first symptomatic event.  The association of each 
covariate with time to the first clinical symptom will be quantified by hazard ratios (HR) along with 
their 95% confidence intervals (CI).  Assessments to determine differences between centers will 
also be performed with statistical adjustments planned for subsequent analyses depending upon 
the obtained results.  Corrections to co-variables will be made when necessary if baseline 
differences are detected. 
 
13.  TIMELINE ESTIMATE 
• 
Contracting completion to IRB approval:  7 months 
• 
Last patient in: September 30, 2019 
• 
Last patient out: March 31, 2021 
• 
Study completion and submission of final manuscript for publication:  September 1, 2021  
 
14.  BIOMARKER ASSESSMENTS 
Whole blood samples and cerebrospinal fluid (CSF) for biomarker analysis may be collected 
from all subjects and transferred to UT Southwestern biorepository. A portion of the biosamples 
will be stored at -80oC prior to being shipped on dry ice to Biogen in batches every quarter where 
they will be centrally analyzed. 
 
• 
Whole blood may be collected at week 0, week 48, week 96, week 144/or EOS,, Early 
Withdrawal and at relapse. 
• 
CSF may be collected at week 0, week 48, week 96, and week 144/or EOS.  
 
A total of approximately 400mL (25-27-30 tablespoons) of whole blood may be collected for the 
scheduled visits. Approximately 71 mL (5 tablespoons) of whole blood may be collected at each 
relapse or early withdrawal. 
 
Those subjects who are unable or unwilling to contribute CSF samples will still be included in the 
study.  Failure to acquire CSF will not be considered a protocol deviation.   
 
The samples collected may be utilized to identify or verify putative prognostic and predictive 
markers associated with disease and markers of therapeutic response to DMF treatment. 
Baseline and dynamic (on-study) clinical disease characteristics and associated biomarker data 
may be utilized to predict subsequent disease worsening (severity), identify high-risk patient 
subgroups, and identify predictors of response to DMF treatment. 
 
Specifically, whole blood, collected in EDTA coated and PAXgene tubes, and CSF, collected in 
PAXgene tubes, will be collected for future analysis of DNA, RNA, and protein biomarkers, as 
follows: 
• 
Deoxyribonucleic acid (DNA) from whole blood collected at Baseline may be used for an 
exploratory pharmacogenomics analysis. Experience with treatment in MS shows that 
there is heterogeneity in clinical response, and some of the heterogeneity may be 
associated with genetic variants in patients. Genome-wide studies have identified 
approximately 50 single-nucleotide polymorphisms (SNPs) as MS-associated loci. DNA 
may be used for genome-wide or candidate gene SNP analysis. Allelic variants at SNP 
loci will be tested for association with efficacy and treatment response. 
• 
Ribonucleic acid (RNA) from whole blood and CSF cell pellet may be used for analysis of 
gene expression. RNA may be used for genome-wide or candidate gene expression 
studies. The transcriptional profile will be used to understand the heterogeneity and to 
define the sub-structure of the MS patient population. Additionally, potential predictive 


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markers at Baseline through identification of transcript pattern that may predict 
disease/treatment outcome may be assessed. 
• 
Serum and CSF samples may be used to determine the levels of markers of 
inflammation, pro- and anti-inflammatory cytokines related to T helper 1 (Th1)/Th2 and 
Th17 pathways, chemokines, and other proteins known to play a role in the 
transmigration of leukocytes and neurodegeneration. This targeted protein list is not all 
encompassing and may be expanded to include markers related to disease, efficacy or 
mechanism of action of DMF as more knowledge becomes available. 
• 
In addition, serum and CSF samples will be stored for future exploratory analyses at UT 
Southwestern.  
 
15.  REFERENCES 
1. 
Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI anomalies suggestive of 
multiple sclerosis: the radiologically isolated syndrome. Neurology 2009; 72(9): 800-5. 
2. 
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 
revisions to the McDonald criteria. Annals of neurology 2011; 69(2): 292-302. 
3. 
Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 
revisions to the "McDonald Criteria". Annals of neurology 2005; 58(6): 840-6. 
4. 
Lebrun C, Bensa C, Debouverie M, et al. Unexpected multiple sclerosis: follow-up of 30 
patients with magnetic resonance imaging and clinical conversion profile. Journal of neurology, 
neurosurgery, and psychiatry 2008; 79(2): 195-8. 
5. 
Siva A, Saip S, Altintas A, Jacob A, Keegan BM, Kantarci OH. Multiple sclerosis risk in 
radiologically uncovered asymptomatic possible inflammatory-demyelinating disease. Multiple 
sclerosis 2009; 15(8): 918-27. 
6. 
Lebrun C, Blanc F, Brassat D, Zephir H, de Seze J, Cfsep. Cognitive function in 
radiologically isolated syndrome. Multiple sclerosis 2010; 16(8): 919-25. 
7. 
De Stefano N, Stromillo ML, Rossi F, et al. Improving the characterization of radiologically 
isolated syndrome suggestive of multiple sclerosis. PloS one 2011; 6(4): e19452. 
8. 
Gabelic T, Radmilovic M, Posavec V, et al. Differences in oligoclonal bands and visual 
evoked potentials in patients with radiologically and clinically isolated syndrome. Acta 
neurologica Belgica 2012. 
9. 
Giorgio A, Stromillo ML, Rossi F, et al. Cortical lesions in radiologically isolated 
syndrome. Neurology 2011; 77(21): 1896-9. 
10. 
Lebrun C, Le Page E, Kantarci O, et al. Impact of pregnancy on conversion to clinically 
isolated syndrome in a radiologically isolated syndrome cohort. Multiple sclerosis 2012; 18(9): 
1297-302. 
11. 
Okuda DT, Mowry EM, Cree BA, et al. Asymptomatic spinal cord lesions predict disease 
progression in radiologically isolated syndrome. Neurology 2011; 76(8): 686-92. 
12. 
Okuda DT, Siva, A., Kantarci, O., et al.  . Radiologically Isolated Syndrome: 5-year risk 
for an initial clinical event from a multi-national cohort. Contemporary Clinical Issues Plenary 
Session  65th American Academy of Neurology Meeting 2013; San Diego, CA. 
 
 
 


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APPENDIX 1:  Cognitive/Functional Assessments 
 
EDSS, expanded MSFC (Timed 25-FT Walk (T25-FW), 9-Hole Peg Test (9-HPT), Paced 
Auditory Serial Addition Test (PASAT-3 (3-second interval pause)), Symbol Digit Modalities Test 
(SDMT) 
 
• 
See attached 
 
 
APPENDIX 2: Patient Reported Surveys 
 
Surveys containing questions related to Demographics, Family History, Lifestyle, Environment, 
and Environmental Exposure and the Neuro Quality of Life Questionnaire (Neuro-QOL data), will 
be completed by each study participant ; included will be inquiries into previous illnesses,. 
 
• 
See attached 
 
 
 

SAP_001.pdf: 
Official title: Multi-center, randomized, double-blinded assessment of 
Tecfidera® in extending the time to a first attack in radiologically isolated 
syndrome (RIS) (ARISE) 
 
 
NCT number: NCT02739542 
Document date: 07/09/2021 


 
________________________________________________________________________________ 
 
 
 
 
 
 
Title of the study: Multi-center, randomized, double-blinded 
assessment of Tecfidera® in extending the time to a first attack in 
radiologically isolated syndrome (RIS)  
 
Protocol Code: ARISE 
 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
 
 
 
 
 
 
 
 
 
Authors 
 
 
 
Version and date 
Version 01 – 09 July 2021 


 
________________________________________________________________________________ 
 
1 
ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
SUMMARY 
LIST OF ABBREVIATIONS ..................................................................................................................2 
1. 
INTRODUCTION .....................................................................................................................3 
2. 
STUDY DOCUMENTS, DATA SOURCE AND SOFTWARE ...........................................................4 
2.1. 
Study documents ..................................................................................................................4 
2.2. 
Data source ...........................................................................................................................4 
2.3. 
Software for statistical analysis .............................................................................................5 
3. 
STUDY DESIGN AND FLOW ....................................................................................................6 
3.1. 
Study design .........................................................................................................................6 
3.2. 
Study flow .............................................................................................................................7 
4. 
STUDY POPULATION AND ANALYSIS SET ...............................................................................8 
5. 
OBJECTIVES ...........................................................................................................................9 
5.1. 
Primary objective ..................................................................................................................9 
5.2. 
Secondary objectives ............................................................................................................9 
6. 
SEQUENCE OF PLANNED ANALYSES.....................................................................................10 
6.1. 
Interim analyses ..................................................................................................................10 
6.2. 
Final analyses and reporting................................................................................................10 
7. 
VARIABLES / ENDPOINTS AND PLANNED ANALYSIS .............................................................11 
7.1. 
Subject characteristics at study entry ..................................................................................11 
7.2. 
Primary endpoint ................................................................................................................11 
7.2.1. Primary analysis ..................................................................................................................11 
7.2.2. Secondary analysis ..............................................................................................................11 
7.3. 
Secondary endpoints ..........................................................................................................12 
8. 
STUDY DEFINITIONS AND CONVENTIONS ............................................................................14 
8.1. 
Data handling ......................................................................................................................14 
8.2. 
Missing data........................................................................................................................14 
LIST OF SUMMARY TABLES (T) AND FIGURES (F) ............................................................................15 
 
 
 
 
 
 
 


 
________________________________________________________________________________ 
 
2 
ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
LIST OF ABBREVIATIONS 
9-HPT 
9-Hole Peg Test 
CNS 
Central Nervous System 
EDC 
Electronic Data Capture 
EOS 
End of Study 
EDSS 
Expanded Disability Status Score 
ITT 
Intent-To-Treat 
ICH 
International Council for Harmonisation  
MS 
Multiple Sclerosis 
Neuro-QOL 
Neuro Quality of Life Questionnaire 
OCT 
Ocular Coherence Tomography 
PASAT 
Paced Auditory Serial Addition Test 
PRO 
Patient Reported Outcome 
PPS 
Per Protocol Set 
RIS 
Radiologically Isolated Syndrome 
RS 
Randomized Set 
SAP 
Statistical Analysis Plan 
SDMT 
Symbol Digit Modalities Test 
T25-FW 
Timed 25-FT Walk 
 
 
 
 
 
 


 
________________________________________________________________________________ 
 
3 
ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
1. INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the relevant sections of the study protocol ARISE, 
Version 8 - November 5, 2018.  
Following International Council for Harmonisation (ICH) Guidelines E3 and E9, its purpose is to 
describe in more detail how the analyses will be performed and presented. All definitions, derivation 
rules and handling of missing data procedure are reported. 
Some relevant statements are directly quoted from the protocol, without however a full description 
of study design. 
This document is finalized before the data is unblinded. 
 


 
________________________________________________________________________________ 
 
4 
ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
2. STUDY DOCUMENTS, DATA SOURCE AND SOFTWARE 
2.1. Study documents 
The following study documents are referred for the preparation of this SAP: 
- 
Study protocol - Multi-center, randomized, double-blinded assessment of Tecfidera® in 
extending the time to a first attack in radiologically isolated syndrome (RIS) (ARISE) 
(Version 8 - November 5, 2018) 
- 
SAS Listing Specifications for UT Southwestern - ARISE_109MS001 (Version: Final V4.0 - 
Version Date: 11Apr2019) 
- 
CRF  (Version e date). 
- 
Sample size calculation document (Version Final, V1.1, Date 06Aug2018) 
 
2.2. Data source 
The following study databases are used in the study: 
- 
SAS database 
- 
MRI database 
- 
Randomization list (PDF file) 
Data will be captured via electronic data capture (EDC).  
- 
Demographic and clinical Data:  Comprehensive demographic data (i.e. date of birth, sex, 
race and ethnicity, etc.) and clinical data (i.e. date of first clinical visit, reason for the initial 
MRI scan, findings from the patient’s clinical examination (to include vital signs), Visual 
Systems Tests (low vision contrast charts, ocular coherence tomography (OCT)) CMP and 
CBC results, cerebrospinal fluid test results, new onset clinical attacks, extent of recovery, 
etc. will be obtained from face-to-face clinical visits and existing medical records.   
- 
Cognitive/Functional assessments (EDSS, expanded MSFC) Timed 25-FT Walk (T25-
FW), 9-Hole Peg Test (9-HPT), Paced Auditory Serial Addition Test (PASAT-3 (3-second 
interval pause)), Symbol Digit Modalities Test (SDMT), will also be performed.   
- 
Patient Reported Surveys:  Surveys containing questions related to demographics, family 
history, lifestyle, environment and environmental exposure, and the Neuro Quality of Life 
Questionnaire (Neuro-QOL data), will be completed by each study participant.   


 
________________________________________________________________________________ 
 
5 
ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
- 
Adverse events, as well as concomitant medications, will be collected and reported. At the 
time of any patient withdrawing from the trial, an attempt will be made to determine the 
reason for discontinuation. 
- 
Radiological Data:  Comprehensive radiological data will be collected from RIS subjects.  
Data to be incorporated into the study database include the date of the first MRI scan 
demonstrating anomalies within the brain that are suggestive of MS, number of lesions, 
lesion location, the presence of contrast enhancing lesions, the number of contrast 
enhancing lesions, changes observed between MRI studies, etc.   
In addition, data from the clinical MRI study of the cervical spine obtained at screening 
or Month 0 and at EOS will be incorporated if completed. 
 
2.3. Software for statistical analysis 
All statistical analyses will be performed with the use of SAS software, version 9.4 (SAS Institute), 
or R, version 3.5.1 and SPSS (IBM) version 24.0. 


 
________________________________________________________________________________ 
 
6 
ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
3. STUDY DESIGN AND FLOW 
3.1. Study design 
This is a multi-center, randomized, double-blinded study in which subjects will be treated with either 
Tecfidera or placebo (1:1 randomization) for 3 years or until End of Study (EOS) date.   
Central Clinical and Imaging Units will screen all potential study subjects for inclusion/exclusion 
criteria.  
Study participants, along with the treating and examining physicians, will be blinded to treatment 
assignment.  Following informed consent and verification of entry criteria, study participants will be 
randomized 1:1 to either Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 
240mg by mouth twice daily) or placebo.   
Clinical follow-up will occur at weeks 0, 48, 96, 144 and/or EOS and during or immediately following 
clinical exacerbations.   
During clinical visits comprehensive medical history data, safety labs, and optional biological 
samples will be obtained by the treating physician.   
Patients will be scheduled for safety screenings at weeks 12, 24, 72, 120.  
In addition, to the face-to-face visits, study participants will be contacted over the telephone at weeks 
4, 8, 36, 60, 84, 108, and 132 to assess for medical or treatment difficulties in addition to study 
medication compliance.   
Standardized MRI studies of the brain will be performed at weeks 0, 96, 144 or EOS; an additional 
MRI will be obtained at week 46 for those patients enrolled at the UTSW site only.  
Clinical imaging studies of the brain and/or spinal cord performed during or immediately following 
the onset of a clinical exacerbation will be performed at the discretion of the Site.   
A clinical MRI of the cervical spinal cord with and without contrast will be recommended to study 
participants at week 0 and week 144 as medical standard of care.  
All reported acute or progressive clinical events will be adjudicated by the Central Clinical Unit.  A 
recommendation to re-evaluate the patient within 3 months following the clinical event to assess for 
extent of recovery will be made.  
 
 
 
 


 
________________________________________________________________________________ 
 
7 
ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
 
3.2. Study flow 
 
SCHEDULE OF ASSESSMENT 
 
 
Screen 
W 0 
W 4 
W 8 
W 12 
W 24 
W 36 
W 48 
W 60 
W 72 
W 84 
W 96 
INFORMED CONSENT 
X 
 
 
 
 
 
 
 
 
 
 
 
REVIEW OF ELIGIBILITY 
X 
 
 
 
 
 
 
 
 
 
 
 
EVALUATION BY CLINICAL CORE AND CENTRAL IMAGING 
X 
 
 
 
 
 
 
 
 
 
 
 
RANDOMIZATION 
 
X 
 
 
 
 
 
 
 
 
 
 
RECORD HISTORY AND DEMOGRAPHICS 
 
X 
 
 
 
 
 
X 
 
 
 
X 
VISUAL SYSTEMS TESTS 
 
UTSW 
 
 
 
 
 
UTSW 
 
 
 
UTSW 
PATIENT REPORTED SURVEYS 
 
X 
 
 
 
 
 
X 
 
 
 
X 
PHYSICAL EXAM (INCLUDING VITAL SIGNS) 
 
X 
 
 
 
 
 
X 
 
 
 
X 
COGNITIVE/FUNCTIONAL ASSESSMENTS 
 
X 
 
 
 
 
 
X 
 
 
 
X 
PREGNANCY TEST (URINE) 
 
X 
 
 
 
 
 
 
 
 
 
 
BLOOD DRAW : 
CBC/CMP FOR SAFETY SCREENING 
(LOCAL LAB FOR PI REVIEW) 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
BIOLOGICAL SAMPLE FOR DNA/RNA: 
SERUM 
 
X 
 
 
 
 
 
X 
 
 
 
X 
CSF SAMPLES 
(OPTIONAL) 
 
X 
 
 
 
 
 
X 
 
 
 
X 
MEDICATION ASSESSMENT & DISPENSE RX VIA PT PICK UP OR MAIL 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
BRAIN MRI 
 
X 
 
 
 
 
 
UTSW 
 
 
 
X 
CERVICAL SPINE MRI 
(OPTIONAL – STANDARD OF CARE)  
 
X 
 
 
 
 
 
 
 
 
 
X 
TELEPHONE CONVERSATION 
 
 
X 
X 
 
 
X 
 
X 
 
X 
 
PATIENT COMPENSATION 
 
X 
 
 
 
 
 
X 
 
 
 
X 
REVIEW ADVERSE EVENTS & CHANGES IN MEDICATION 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COLLECT REMAINING STUDY MEDICATION 
 
 
 
 
 
 
 
 
 
 
 
 
- Medication assessment & administration includes completion of ‘drug accountability record’. 
- For subjects consented for 96 weeks which choose not to extend their participation through week 114/or EOS, week 96 should be recorded as ‘early withdrawal’ visit. 
 
ASSESSMENT 
WEEK 108 
WEEK 
120 
WEEK 132 
WEEK 144 
RELAPSE 
EARLY WITHDRAWAL 
UNSCHEDULED 
INFORMED CONSENT 
 
 
 
 
 
 
 
REVIEW OF ELIGIBILITY 
 
 
 
 
 
 
 
EVALUATION BY CLINICAL CORE AND 
CENTRAL IMAGING 
 
 
 
 
 
 
 
RANDOMIZATION 
 
 
 
 
 
 
 
RECORD HISTORY AND DEMOGRAPHICS 
 
 
 
X 
X 
X 
X 
VISUAL SYSTEMS TESTS 
 
 
 
UTSW only 
 
UTSW only 
 
PATIENT REPORTED SURVEYS 
 
 
 
X 
X 
X 
X 
PHYSICAL EXAM (INCLUDING VITAL 
SIGNS) 
 
 
 
X 
X 
X 
X 
COGNITIVE/FUNCTIONAL ASSESSMENTS 
 
 
 
X 
X 
X 
X 
PREGNANCY TEST (URINE) 
 
 
 
 
 
 
 
BLOOD DRAW : 
CBC/CMP FOR SAFETY SCREENING 
(LOCAL LAB FOR PI REVIEW) 
 
X 
 
X 
X 
X 
SOC 
BIOLOGICAL SAMPLE FOR DNA/RNA: 
SERUM 
 
 
 
X 
X 
X 
 
CSF SAMPLES 
(OPTIONAL) 
 
 
 
X 
 
X 
 
MEDICATION ASSESSMENT & DISPENSE 
RX  VIA PT PICK UP OR MAIL 
X 
X 
X 
X 
 
 
 
BRAIN MRI 
 
 
 
X 
SOC 
X 
SOC 
CERVICAL SPINE MRI 
(OPTIONAL – STANDARD OF CARE)  
 
 
 
SOC 
 
SOC 
SOC 
TELEPHONE CONVERSATION 
X 
 
X 
 
 
 
 
PATIENT COMPENSATION 
 
 
 
X 
 
 
 
REVIEW ADVERSE EVENTS & CHANGES 
IN MEDICATION 
 
 
 
 
X 
X 
X 
COLLECT REMAINING STUDY 
MEDICATION 
 
 
 
X 
 
X 
 
 


 
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8 
ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
4. STUDY POPULATION AND ANALYSIS SET 
Study population: This study will include RIS subjects from the U.S. who fulfill 2009 RIS Criteria. 
Inclusion and exclusion criteria to be met are reported in the study protocol. 
For this analysis all tables will be presented only by referring to the whole randomized sample 
according to the intent-to-treat principle (ITT). Otherwise, the Sponsor will provide a list of patients 
to be included in the primary analysis. 
Per Protocol Set (PPS):  A subject will be part of the PPS if she/he will receive any amount of study 
medication and have no major protocol deviations. This Set will be identified by the Sponsor prior 
unblinding. 
 


 
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9 
ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
5. OBJECTIVES 
5.1. Primary objective 
Assessment of the time from randomization to the first acute or initial neurological symptom resulting 
in a progressive clinical course related to CNS demyelination in those treated and untreated with 
Tecfidera. 
 
Acute neurological event:  The development of an acute neurological episode localized to the optic 
nerve, brainstem, cerebellum, spinal cord, or long sensory or motor tracts, lasting > 24 hours followed 
by a period of symptom improvement. 
Progressive event:  The onset of a clinical symptom (e.g. leg weakness) with the temporal profile 
revealing at least a 12-month progression of neurological deficits. 
 
5.2. Secondary objectives  
Evaluation of the change in the number of new or enlarging T2 lesions, contrast enhancing lesions, 
T2-lesion volumes, and brain atrophy at the End of Study.    
 
 


 
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ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
6. SEQUENCE OF PLANNED ANALYSES 
6.1. Interim analyses 
No interim analysis is planned for this study. 
 
6.2. Final analyses and reporting 
Description of baseline characteristics and analyses of primary endpoint identified in this SAP will 
be performed only after the last patient has completed the study.  
The randomization codes will not be unblinded until this SAP has been approved and database has 
been locked.  
 


 
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ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
7. VARIABLES / ENDPOINTS AND PLANNED ANALYSIS 
7.1. Subject characteristics at study entry 
Demographics and clinical data at baseline (reasons for the initial MRI scan and neurostatus scales) 
will be summarized by presenting frequency distributions and/or basic summary statistics (mean, 
standard deviation, median, and range). 
 
7.2. Primary endpoint 
 
7.2.1. Primary analysis 
To run the primary analysis a Multivariate Bayesian Cox regression model will be created with the 
time from randomization to the first demyelinating event (acute or development of an initial symptom 
resulting in a progressive clinical course) as the primary outcome and  with treatment as a binary 
covariate. The following baseline variables will be used to adjust for their possible confounding 
effect: 
• Sex (F/M) 
• Age at the time of RIS diagnosis (Index MRI Scans) 
• MS family history (Y/N/Ukn) 
• EDSS 
• Number of brain MRI T2 lesions 
• Presence of gadolinium enhancing lesions (Y/N) 
• Presence of spinal cord lesions (Y/N) 
• CSF examination (OCB+/OCB-) 
 
Four different scenarios will be used to create the parameters of the prior distribution to be used in 
the Bayesian analysis. These scenarios are detailed in the Sample size calculation document. 
The association of each covariate with time to the first clinical symptom will be quantified by hazard 
ratios (HR) along with their 95% credible intervals (CI).  
 
7.2.2. Secondary analysis 
As a secondary analysis a classical survival analysis with the time from randomization to the first 
demyelinating event (acute or development of an initial symptom resulting in a progressive clinical 


 
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12 
ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
course) will be run. Kaplan-Meier survival analyses will be used to evaluate the outcome and Log-
rank tests will be used to compare survival data between groups (treated vs non-treated) at univariate 
analysis. A multivariate Cox model adjusting for the above-mentioned covariates will be also run. 
 
7.3. Secondary endpoints  
Analyses of MRI outcomes will include participants who had at least one follow-up MRI.  
 
- In the trial the mean T2 lesion volume derived from T2-weighted MRI over a 144-week period and 
the slope of change from baseline to week 96 and week 144 will be compared between treatment 
arms. Analyses will be based on a linear mixed effect model for repeated measures which will include 
a random intercept to account for the within-participant correlation and with treatment, visit, and 
treatment and visit interaction as fixed effects. T2 lesion volume will be log-transformed for the 
analysis. Adjusted analyses may include, if necessary, the number of enhancing lesions at baseline as 
covariate. 
 
- The mean cumulative number of new enhancing lesions and the mean cumulative combined number 
of unique lesions (include new lesions enhanced on T1-weighted MRI plus new and newly enlarging 
lesions on T2-weighted MRI, without double-counting) over 144 weeks and the change from baseline 
to week 96 and week 144 will be compared between the two study groups. Means, differences, and P 
values will be calculated with the use of negative binomial regression models (with number of lesions 
enhanced on MRI at baseline as the covariate for the cumulative number of new lesions enhanced on 
MRI and the cumulative combined number of unique lesions). 
 
- Whole brain atrophy using percent brain volume change (PBVC) derived from SIENA will be 
compared between treatment arms from baseline to week 96, week 96 to week 144, and baseline to 
week 144. Means, differences, and P values will be calculated with ….. Adjusted analyses may 
include, if necessary, baseline brain volumes, as measured by normalized brain parenchymal volumes 
(nBPV) derived from SIENAX. 
 


 
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ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
For patients missing the 144 weeks MRI visit, the 96-week visit will be used, including an offset 
variable indicating the follow up duration. An additional analysis will be run using a Poisson mixed 
model, which included a random intercept to account for the within-participant correlation.  


 
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ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
8. STUDY DEFINITIONS AND CONVENTIONS 
8.1. Data handling 
Continuous data will be summarized by using a descriptive statistics (n, mean, standard deviation, 
median, maximum, and minimum). Unless otherwise stated, mean and/or median will be displayed 
to one more decimal place than the original data; the standard deviation will be displayed to two 
decimal places more than the original data; minimum and maximum will be displayed to the same 
number of decimal places as the original data.  
Categorical variables will be summarized using counts and percentages (displayed with one decimal 
place).  
All p-values will be rounded to three decimal places, unless the true p-value is less than 0.001, and 
the notation “p < 0.001” will be used or if the true p-value is greater than 0.999, for which “p > 0.999” 
will be used.  
All statistical hypotheses will be tested at the 0.05 significance level, and p-values reported will be 
based upon two-sided testing. 
Confidence intervals, if needed, will be calculated at the 95% level. 
 
8.2. Missing data 
Missing dates will be imputed as follows: 
- 
If only day is missing/unknown, then the 1st of the month will be imputed 
- 
If day and month are missing/unknown, then the1st of January will be imputed 
- 
When the whole date is missing, the date will be considered as missing. 
 
No plan is foreseen for imputing missing data of other variables, therefore only the observed values 
up to study completion (or withdrawal time) will be used in the statistical analyses. Dropouts will be 
not replaced.  
 
 


 
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ARISE – Statistical Analysis Plan (Version 01-28.05.2021) 
LIST OF SUMMARY TABLES (T) AND FIGURES (F) 
 
 
Name 
Description 
Population 
TYPE 
DEMO 
Demographic and 
clinical data at baseline 
ITT 
T 
COX 
Cox regression 
ITT 
T 
KM 
KM curves 
ITT 
F 
MRI 
Linear mixed regression 
and Poisson mixed 
regression 
ITT 
T