Conditions: Multiple Sclerosis, Relapsing-Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Primary Progressive
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 105
Healthy volunteers: no

Brief summary:
This study will evaluate if giving insulin that is administered in the nostrils (intranasal) is safe and tolerable for people with multiple sclerosis (MS). It is also being done to evaluate if intranasal insulin improves cognitive function in people with MS and to evaluate how it might be working.

Detailed description:
Cognitive impairment is common in and devastating to people with MS. MS is a common, chronic, central nervous system (CNS) disease characterized by inflammation, demyelination, and neurodegeneration. One of the most devastating symptoms of this disease is impaired cognitive function, which is common and present in over 60% of individuals with MS. MS-related cognitive impairment is associated with lowered quality of life and reduced functional capacity, including loss of employment, impaired social relationships, compromised driving safety, and poor adherence to treatment. Impaired cognitive functioning has been observed early in the disease, sometimes even before diagnosis, and cognitive function has been shown to decline longitudinally, both over the short- and long-term. Several cognitive domains are impacted in people with MS, including attention, memory, executive functioning, and especially processing speed.

To date, multiple pharmacologic interventions have been assessed with disappointing results. There was no significant difference between treatment and placebo for cognition in randomized control trials of donepezil, aminopyridines, gingko biloba, and memantine. Psychostimulants demonstrated some efficacy, but only in secondary outcome measures. Behavioral interventions show promise but are understudied. Furthermore, cognitive rehabilitation is often time consuming, costly, and not universally available. Hence, there is an urgent need to identify or develop novel therapies that can help improve cognitive function in MS.

Intranasal insulin is extremely safe and tolerable in other populations, allowing for concentrated delivery to the nervous system. An intranasal delivery system provides a non-invasive way to bypass the blood-brain barrier and allow rapid delivery of a medication to the CNS via the olfactory and trigeminal perivascular channels.The main advantage of the delivery system is reducing systemic side effects via limiting a medication's exposure to peripheral organs and tissues.

Insulin administration has been shown to improve memory and learning in healthy people and in those with neurodegenerative diseases. Intranasal insulin has been shown to have neuroprotective and restorative effects in several human clinical trials. Overall, findings suggest that intranasal insulin not only affects cognitive function acutely, but that over time, there may be associated structural changes that lead to a more permanent treatment benefit. Cognitive dysfunction is very common in MS and can be devastating, therefore a treatment intervention (i.e., intranasal insulin) can help both acutely and longitudinally.

The primary aim of this study is to assess the safety and tolerability of intranasal insulin in people with MS. The secondary aim is to evaluate if intranasal insulin improves learning and memory in people with MS. The third aim is to evaluate the impact of intranasal insulin on measures of oxidative stress, axonal injury, cellular stress, and energy metabolism in MS.

Arms:
arm 1: Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks. arm 2: Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks. arm 3: Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.

Interventions: intervention 1: Insulin intervention 2: Placebo (Sterile diluent)
Intervention descriptions: intervention 1: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study. intervention 2: All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.

Protocol document:
ICF_002.pdf: 
Trial Consent Form for:  
Intranasal Insulin for Improving Cognitive Function in Multiple Sclerosis (NCT02988401) 
Date of Consent Form 7/17/2020 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: July 17, 2020 
Principal Investigator: Ellen M. Mowry, M.D., M.C.R. 
Application No.: IRB00095554 
 
Page 1 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
 
 
 
 
 
 
 
 
 
RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Protocol Title:  
Intranasal insulin for improving cognitive function in multiple 
sclerosis 
 
Application No.: 
IRB00095554 
 
Sponsor: 
 
 
Department of Defense 
 
Principal Investigators: Ellen M. Mowry, M.D., M.C.R. and Scott D. Newsome, D.O. 
Johns Hopkins University 
600 N. Wolfe Street  
Pathology 627  
Baltimore, MD  21287 
Phone: (410) 614-1522   
Fax: (410) 502-6736 
 
1. 
What you should know about this study:   
• You are being asked to join a research study. This consent form explains the research study and your 
part in it. Please read it carefully and take as much time as you need. Ask your study doctor or the 
study team to explain any words or information that you do not understand. 
• You are a volunteer.  If you join the study, you can change your mind later.  There will be no penalty 
or loss of benefits if you decide to quit the study.   
• During the study, we will tell you if we learn any new information that might affect whether you 
wish to continue to participate. 
• If we think your participation in this study may affect your clinical care, information about your 
study participation will be included in your medical record, which is used throughout Johns Hopkins.   
Doctors outside of Johns Hopkins may not have access to this information.  You can ask the research 
team to send this information to any of your doctors. 
• When Johns Hopkins is used in this consent form, it includes The Johns Hopkins University, The 
Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, Howard County General Hospital, 
Johns Hopkins Community Physicians, Suburban Hospital, Sibley Memorial Hospital and All 
Children’s Hospital.  
• Biospecimens will be collected in this study.  Biospecimens may include any of the following: 
blood, tissue, saliva, urine, bone marrow, cells, etc.  Most biospecimens contain DNA, which is the 
genetic code for each person. 
If you are using Epic for this study, fax a copy 
of the signed consent form to 410-367-7382. 
 
 
 
 
 
 
Patient I.D. Plate 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: July 17, 2020 
Principal Investigator: Ellen M. Mowry, M.D., M.C.R. 
Application No.: IRB00095554 
 
Page 2 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
• 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.  
• If you would like to review the information for this study, or a summary of the results, ask the study 
team doctor for the ClinicalTrials.gov study registration number. 
• During this study, you will not have access to certain medical information and test results collected 
for study purposes.  If an emergency occurs while you are in the study, medical information needed 
for your treatment can be made available to your study physician and other physicians who treat you.  
When the study is completed, all the information in your medical record will be available to you. 
 
2. 
Why is this research being done? 
This research is being done to determine if giving insulin that is inhaled (intranasal insulin) is safe and 
tolerable for people with multiple sclerosis (MS). It is also being done to evaluate if intranasal insulin 
improves cognition in people with MS and to evaluate how it might be working. 
 
Intranasal insulin (Novolin R®) has been approved by the Food and Drug Administration (FDA) for the 
treatment of diabetes. Intranasal insulin is not approved by the FDA to improve cognition in people with 
MS and its use in the study is considered investigational. The FDA is allowing for the intranasal insulin 
to be used in the study. The placebo contains inactive ingredients and is also approved for use. 
 
People with MS who are aged 18 to 70 years and have some evidence of cognitive impairment may join. 
 
How many people will be in this study? 
105 people will be enrolled in the study. 
 
3. 
What will happen if you join this study? 
If you agree to be in this study, we will ask you to do the following things: 
 
Study Summary 
If you are able and choose to continue to take part in the study, then you will be randomly assigned (by 
chance, like drawing numbers from a hat) to receive one of three study products for 24 weeks:  
• intranasal insulin 20 international units twice a day,  
• intranasal insulin 10 international units twice a day, or  
• intranasal placebo (an inactive material that does not contain any active study drug) twice a day.  
 
You will then stop the study drug (intranasal insulin or placebo) and come back for follow-up visits for 
another 24 weeks.  
 
About the Study Visits 
You will be asked to come in to see the study team at the beginning of the study and at weeks 6, 12, 24, 
36, and 48. For the first 15 participants, the first visit is expected to take about 4 hours. After enrollment 
of the first 15 participants, the visit is expected to take 2 ½ hours. The weeks 12, 24, and 48 visits are 
expected to be about 3 hours each. The remainder of the visits is expected to be about 1.5 hours each. 
You will be asked to not eat after midnight prior to the first visit but will be provided with breakfast 
after the blood draw. 
 
Study Visits during the COVID-19 pandemic  
During the periods of slowdown or shutdown, study visits at weeks 6, 36, and 48 will take place 
remotely. You will be asked to complete as many study procedures remotely as is possible (see asterisks 
below) for those visits. For the in-person study visits – baseline, week 12, and week 24, we have reduced 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: July 17, 2020 
Principal Investigator: Ellen M. Mowry, M.D., M.C.R. 
Application No.: IRB00095554 
 
Page 3 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
the in-person assessments to the greatest extent possible and have moved the rest to remote assessments. 
If the pandemic resolves, we will go back to an in-person study visit for week 48. If a stay-at-home 
order or severe outbreak recurs, we will also transition all possible study procedures for weeks 12 and 24 
to remote assessments. During the COVID-19 pandemic, you must be willing to comply with state/local 
recommended social distancing and other suggested COVID-19 related safety measures. 
 
About the Study Procedures 
During the visits, you will have the following tests and procedures done as detailed below: 
 
• Teaching and first dose administration and observation of intranasal insulin: At the 
baseline study visit, you will be taught how to prepare and administer the study products. You 
will receive four syringes filled with the study products – two labeled A and two labeled B.  You 
or your caregiver will be instructed on how to fill the intranasal device cartridge using the 
syringes, mix the solutions and prep the device. 
 
• *Update medical record: The study doctor or study coordinator will update your medical 
history and verify the medications you are taking and will ask you about any side effects. 
 
• Vital signs and examination: Pending COVID-19, your vital signs will be taken at baseline, 
week 12 and week 24 study visits. A neurological examination will be conducted by the doctor at 
the first visit. 
 
• *Cognitive tests: You will undergo a series of cognitive tests at all study visits except at weeks 
6 and 36. Some or all of these will be done remotely at a given study visit. 
                                                                                                      
• *Questionnaires: We will ask you to fill out questionnaires about how you are feeling at each 
study visit, as well as about your sleep at some of the visits. 
 
• Blood draw: If COVID-19 restrictions allow in-person visits, you will be asked to give a blood 
sample at the baseline, week 12, and week 24 study visits. You will be asked to give up to 5 
tablespoons of blood at each visit.. 
 
• 
Pregnancy assessment/urine collection: If you are a female and capable of having children, 
you will be asked to collect your own urine so a pregnancy test can be done at all in-person visits 
while taking the study medication. *During the COVID-19 pandemic, if assessments are remote, 
we will ask you to provide the date of your last menstrual period and information about use of 
contraception.  
 
• Dual-Energy X-ray Absorptiometry (DXA) scan: A DXA is one type of x-ray often used to 
measure bone density. X-ray pictures of the body measure how much fat and muscle are present 
in your body. As you lie flat on a table, the machine takes pictures of different parts of the body. 
This test lasts about 15 minutes, and you will have this done at the baseline visit. 
 
• *Daily diary: You will be required to keep a daily electronic diary. The purpose of the daily 
diary is to assess for side effects.  
 
Request to collect and store biospecimens for future research   
As part of this research study, we would like to ask you to let us store your biospecimens and health 
information for future research.  This research could include other diseases and involve research tools 
such as gene sequencing or the creation of cell lines.  


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: July 17, 2020 
Principal Investigator: Ellen M. Mowry, M.D., M.C.R. 
Application No.: IRB00095554 
 
Page 4 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
 
• Gene sequencing of your DNA provides researchers with the code to your genetic material.   
 
• Cell lines are living tissue samples that can be grown in a laboratory.  A cell line can provide 
an unlimited supply of cells in the future without requiring more samples from you.  Each 
cell contains your complete DNA. 
 
The study doctor can provide you with additional information if you have questions. Also, further 
information about our use of your biospecimens can be found in this consent document under the 
heading What happens to Data and Biospecimens that are collected in the study?. 
 
Will you allow us to store the biospecimens we collect for this study for use in future research? 
 
YES     ________________________   
 
 
 
Signature of Participant 
 
 
 
 
 
 
NO     __________________  
 
 
 
Signature of Participant 
 
 
 
 
 
 
How long will you be in the study? 
You will be in this study for 48 weeks.  
 
4. 
What are the risks or discomforts of the study? 
Intranasal insulin 
Intranasal insulin has been shown to be safe and tolerable in other populations and patient groups, but it 
has never been studied in people with MS. The most common side effects related to irritation of the 
nasal passages. Giving insulin through the nose did not result in lower circulating glucose (sugar) levels 
in other studies, but the first 15 people in this study will be monitored for this potential risk by testing a 
fingerstick blood glucose level periodically for 90 minutes after the first dose of intranasal insulin. 
 
Insulin, given by the more traditional subcutaneous (injected under the skin) route, has the following 
potential risks: 
 
Hypoglycemia: Hypoglycemia means low blood sugar. Common symptoms of hypoglycemia include 
sweating, dizziness or lightheadedness, shakiness, hunger, a fast heartbeat, tingling of the hands, feet, 
lips or tongue, trouble concentrating, confusion, blurry vision, slurred speech, anxiety, irritability, or 
mood changes, or headache. Very low blood sugar can cause loss of consciousness (passing out), 
seizures, or temporary or permanent brain problems or death.  You can treat mild low blood sugar 
(hypoglycemia) by drinking or eating something sugary right away (fruit juice, sugar candies, or glucose 
tablets). It is important to treat low blood sugar (hypoglycemia) right away because it could get worse 
and could lead to passing out (loss of consciousness), seizures and death.  
 
Hypokalemia: Hypokalemia means low blood potassium. Hypokalemia can lead to breathing problems, 
low heartbeat, or death. 
 
Allergic reaction: You could have an allergic reaction to insulin. Common symptoms of an allergic 
reaction include a rash all over the body, trouble breathing, a fast heartbeat, sweating, and feeling faint. 
 
Weight gain or swelling of the arms and legs. 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: July 17, 2020 
Principal Investigator: Ellen M. Mowry, M.D., M.C.R. 
Application No.: IRB00095554 
 
Page 5 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
There is no known benefit of intranasal insulin, and thus there is no known risk of being in the placebo 
group. All patients who are already on a medication for MS will be allowed to continue that medication 
during the study. 
 
Blood Draw  
Taking blood may cause discomfort, bleeding or bruising where the needle enters the body. In rare 
cases, it may result in fainting. There is a small risk of infection.  
 
Confidentiality  
Despite the best efforts of the research team, there may still be a risk if information about you were to 
become known to people outside of this study.  
 
Questionnaires  
You may get tired or bored when we are asking you questions or you are completing questionnaires. 
You do not have to answer any question you do not want to answer.  
DXA scan 
DXA testing is painless and involves exposure to radiation. This research study includes exposure to 
radiation from x-rays or gamma rays. This radiation exposure is for research purposes only and is not 
part of your medical care. X-rays and gamma rays can damage cells, but at low doses, the body is 
usually able to repair these cells.  
  
The radiation exposure that you will get in this research study is 0.001 rem (a rem is a unit of absorbed 
radiation). This is less than the 0.3 rem that the average person in the United States gets each year from 
natural sources like the sun, outer space, air, food, and soil. The risk from the radiation exposure in this 
research study is very small.  
  
The radiation exposure described here is what you will get from this research study only. It does not 
include any exposure you may have received or will receive from other medical tests outside of this 
study that are a part of your medical care. Radiation risk builds up with each exposure. You should think 
about your own history of radiation exposure from tests (like x-rays or CT scans) in deciding about the radiation 
in this study. If you have questions about the total amount of radiation you will be receiving, you should 
ask your doctor.  
 
5. 
Are there risks related to pregnancy? 
The risks of intranasal insulin to pregnant women are unknown. If you are pregnant, planning to become 
pregnant, or are breastfeeding a child, you cannot participate in this study. Women who become 
pregnant during the study will stop the study. Radiation from a DXA scan may be harmful to an embryo 
or fetus. 
 
All women capable of having children will be tested for pregnancy at each study visit (except for the last 
2 study visits) by a urine test.  
 
This research may hurt an embryo or fetus in ways we do not currently know.  
 
6. 
Are there benefits to being in the study? 
There may or may not be a direct benefit to you from being in this study. If you take part in this study, 
you may help others in the future. 
 
7. 
What are your options if you do not want to be in the study? 
You do not have to join this study.  If you do not join, your care at Johns Hopkins will not be affected. 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: July 17, 2020 
Principal Investigator: Ellen M. Mowry, M.D., M.C.R. 
Application No.: IRB00095554 
 
Page 6 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
 
8. 
Will it cost you anything to be in this study? 
You will receive a separate Insurance and Research Participant Financial Responsibility Information 
Sheet (Sheet).  
 
This Sheet will give you the following information: 
• The procedures, tests, drugs or devices that are part of this research and that will be paid for by 
the study (no cost to you).   
• The procedures, tests, drugs or devices that will be billed to you and/or your health insurer.  If 
you have health insurance, you will be responsible for any co-pays or deductibles not covered by 
your insurance.  
 
9. 
Will you be paid if you join this study? 
You will receive a parking coupon for all study visits. 
 
You may be required to provide your social security number to be paid for taking part in this study. 
Federal tax law requires that you report your research payments when you file your taxes. If your total 
payments from Johns Hopkins exceed $600 per year, Johns Hopkins will report these payments to the 
Internal Revenue Service and you will receive a 1099-MISC form from us. 
 
10. 
Can you leave the study early? 
• You can agree to be in the study now and change your mind later. 
• If you wish to stop, please tell us right away. 
• Leaving this study early will not stop you from getting regular medical care.  
 
If you leave the study early, Johns Hopkins may use or give out your health information that it has 
already collected if the information is needed for this study or any follow-up activities.  
 
11. 
Why might we take you out of the study early? 
You may be taken out of the study if: 
• Staying in the study would be harmful. 
• You fail to follow instructions. 
• You become pregnant. 
• The study is cancelled. 
• There may be other reasons to take you out of the study that we do not know at this time.  
 
If you are taken out of the study early, Johns Hopkins may use or give out your health information that it 
already has if the information is needed for this study or any follow-up activities. 
 
12. 
How will your privacy be protected?  
We have rules to protect information about you.  Federal and state laws and the federal medical Privacy 
Rule also protect your privacy.  By signing this form you provide your permission, called your 
“authorization,” for the use and disclosure of information protected by the Privacy Rule. 
 
The research team working on the study will collect information about you.  This includes things learned 
from the procedures described in this consent form.  They may also collect other information including 
your name, address, date of birth, and information from your medical records ([which may include 
information about HIV, drug, alcohol or STD treatment, genetic test results, or mental health treatment). 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: July 17, 2020 
Principal Investigator: Ellen M. Mowry, M.D., M.C.R. 
Application No.: IRB00095554 
 
Page 7 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
The research team will know your identity and that you are in the research study.  Other people at Johns 
Hopkins, particularly your doctors, may also see or give out your information. We make this information 
available to your doctors for your safety.    
 
People outside of Johns Hopkins may need to see or receive your information for this study.  Examples 
include government agencies (such as the Food and Drug Administration), safety monitors, other sites in 
the study and companies that sponsor the study.  
 
If you are in a cancer study that receives federal funding, the National Cancer Institute (NCI) now 
requires that we report identifiable information (such as, zip code) about your participation.  You may 
contact the NCI if you have questions about how this information is used.  
 
The Department of Defense (DoD) and the U.S. Army Medical Research and Materiel Command 
(USAMRMC) will have access to records for audit purposes. 
 
We cannot do this study without your authorization to use and give out your information.  You do not 
have to give us this authorization.  If you do not, then you may not join this study. 
 
We will use and disclose your information only as described in this form and in our Notice of Privacy 
Practices; however, people outside Johns Hopkins who receive your information may not be covered by 
this promise or by the federal Privacy Rule.  We try to make sure that everyone who needs to see your 
information keeps it confidential – but we cannot guarantee that your information will not be re-
disclosed. 
 
The use and disclosure of your information has no time limit. You may revoke (cancel) your permission 
to use and disclose your information at any time by notifying the Principal Investigator of this study by 
phone or in writing.  If you contact the Principal Investigator by phone, you must follow-up with a 
written request that includes the study number and your contact information.  The Principal 
Investigator’s name, address, phone and fax information are on page one of this consent form.  
 
If you do cancel your authorization to use and disclose your information, your part in this study will end 
and no further information about you will be collected. Your revocation (cancellation) would not affect 
information already collected in the study, or information we disclosed before you wrote to the Principal 
Investigator to cancel your authorization. 
 
13. 
Will the study require any of your other health care providers to share your health 
information with the researchers of this study?    
As a part of this study, the researchers may ask to see your health care records from your other health 
care providers.   
 
14. 
What treatment costs will be paid if you are injured in this study?  
Johns Hopkins and the federal government do not have programs to pay you if you are hurt or have 
other bad results from being in the study.  However, medical care at Johns Hopkins is open to you as it 
is to all sick or injured people.   
 
The costs for any treatment or hospital care you receive as the result of a study-related injury that are not 
covered by a health insurer will be billed to you. 
 
By signing this form you will not give up any rights you have to seek compensation for injury.  
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: July 17, 2020 
Principal Investigator: Ellen M. Mowry, M.D., M.C.R. 
Application No.: IRB00095554 
 
Page 8 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
15. 
What other things should you know about this research study? 
a. What is the Institutional Review Board (IRB) and how does it protect you?  
The Johns Hopkins Medicine IRB is made up of: 
• Doctors 
• Nurses 
• Ethicists 
• Non-scientists 
• and people from the local community.  
 
The IRB reviews human research studies. It protects the rights and welfare of the people taking part 
in those studies.  You may contact the IRB if you have questions about your rights as a participant or 
if you think you have not been treated fairly.  The IRB office number is 410-955-3008. You may 
also call this number for other questions, concerns or complaints about the research. 
 
When the Johns Hopkins School of Medicine Institutional Review Board (IRB) reviews a study at 
another site, that site (institution) is solely responsible for the safe conduct of the study and for 
following the protocol approved by the Johns Hopkins IRB.   
 
b. What do you do if you have questions about the study?    
Call the principal investigator, Dr. Mowry or Dr. Newsome at 410-614-1522. If you wish, you may 
contact the principal investigator by letter or by fax.  The address and fax number are on page one of 
this consent form. If you cannot reach the principal investigator or wish to talk to someone else, call 
the IRB office at 410-955-3008.   
 
c. What should you do if you are injured or ill as a result of being in this study?  
If you think you are injured or ill because of this study, call Dr. Mowry or Dr. Newsome at 410-614-
1522 during regular office hours.  
 
If you have an urgent medical problem related to your taking part in this study, call Dr. Mowry or 
Dr. Newsome at 410-614-1522 during regular office hours and call the page operator at 410-955-
4331 (http://www.hopkinsmedicine.org/uhs/after_hours.html) and ask to be connected to Dr. Mowry 
or Dr. Newsome after hours and on weekends.  
 
d. What happens to Data and Biospecimens that are collected in the study?  
Johns Hopkins and our research partners work to understand and cure diseases.  The biospecimens 
and/or data you provide are important to this effort. 
 
 
If you join this study, you should understand that you will not own your biospecimens or data, and 
should researchers use them to create a new product or idea, you will not benefit financially.  
 
With appropriate protections for privacy, Johns Hopkins may share your biospecimens and 
information with our research sponsors and partners. 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: July 17, 2020 
Principal Investigator: Ellen M. Mowry, M.D., M.C.R. 
Application No.: IRB00095554 
 
Page 9 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
16. 
What does your signature on this consent form mean?  
Your signature on this form means that: You understand the information given to you in this form; you accept the 
provisions in the form and you agree to join the study. You will not give up any legal rights by signing this 
consent form.  
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                                                           (Print Name)                                                 
 
Date/Time  
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Person Obtaining Consent                                                  (Print Name)                                               
 
Date/Time 
 
 
 
I have received the separate Insurance and Research Participant Financial Responsibility Information Sheet.   
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                 
 
 
 (Print Name)                                                          
Date/Time 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY 
MUST BE GIVEN TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-
7382; IF YOU ARE NOT USING EPIC A COPY MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD (UNLESS NO 
MEDICAL RECORD EXISTS OR WILL BE CREATED).  
 
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN THE CONSENT 
OF RESEARCH PARTICIPANTS. 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: July 17, 2020 
Principal Investigator: Ellen M. Mowry, M.D., M.C.R. 
Application No.: IRB00095554 
 
Page 10 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
 
 
DOCUMENTATION OF PHYSICIAN/MID-LEVEL PROVIDER CONSENT 
 
My signature below indicates that I have discussed the risks, benefits, and alternatives, answered any 
questions, and believe the participant is able to make an informed choice to join the study. 
 
 
________________________________________________________________________________________________________________________ 
Signature of Physician/Mid-Level Provider                     (Print Name)                                                                     
 
Date/Time   
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                                    (Print Name)                                                                    
 
Date/Time     
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY 
MUST BE GIVEN TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-
7382; IF YOU ARE NOT USING EPIC A COPY MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD (UNLESS NO 
MEDICAL RECORD EXISTS OR WILL BE CREATED).  
 
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN THE CONSENT 
OF RESEARCH PARTICIPANTS. 
 

Prot_000.pdf: 
Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
1 
 
 
PROTOCOL TITLE: INTRANASAL INSULIN FOR IMPROVING COGNITIVE FUNCTION IN 
MULTIPLE SCLEROSIS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DATE: November 20, 2020 
 
 
 
 
 
 
 
VERSION: 2.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
2 
 
 
 
 
 
 
SYNOPSIS 
 
This will be a randomized, double-blind, placebo-controlled phase I/II pilot study. Participants will be 
randomized to intranasal insulin 10 international units (IU) twice a day, 20 IU twice a day, or placebo for 24 
weeks. Insulin will be administered intranasally using the novel  ViaNaseTM controlled particle dispersion 
system, allowing for direct delivery of the medication to the nasal epithelium, leading to maximal transport to 
the CNS (Kurve Technology, Lynnwood, WA).34 Cognitive assessments will occur at baseline and throughout 
the 24-week trial, as well as for a period of 24 weeks after discontinuation of the intervention, to evaluate the 
impact of insulin on cognitive performance as well as the longevity of the treatment response. Biomarkers of 
cellular stress, neuronal injury, oxidative stress, inflammation, and energy metabolism will be assessed at 
baseline and at subsequent visits. Stored specimens will be acquired for more detailed future mechanistic 
studies if intranasal insulin does appear to be safe and effective.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
3 
 
 
 
 
 
INTRODUCTION 
 
Cognitive impairment is common in and devastating to people with MS. MS is a common, chronic, central 
nervous system (CNS) disease characterized by inflammation, demyelination, and neurodegeneration. One of 
the most devastating symptoms of this disease is impaired cognitive function, which is common and present in 
over 60% of individuals with MS.1-3 MS-related cognitive impairment is associated with lowered quality of life 
4 and reduced functional capacity, including loss of employment,4-7 impaired social relationships,8 compromised 
driving safety,7 and poor adherence to treatment.9 Impaired cognitive functioning has been observed early in the 
disease, sometimes even before diagnosis,10 and cognitive function has been shown to decline longitudinally, 
both over the short- and long-term.11-13 Several cognitive domains are impacted in people with MS, including 
attention, memory, executive functioning, and especially processing speed.2, 10, 14-18  
To date, multiple pharmacologic interventions have been assessed with disappointing results. There was no 
significant difference between treatment and placebo for cognition in randomized control trials of donepezil,19  
aminopyridines,20 gingko biloba,21 and memantine.22 Psychostimulants demonstrated some efficacy, but only in 
secondary outcome measures.23 Behavioral interventions show promise but are understudied.24 Furthermore, 
cognitive rehabilitation is often time consuming, costly, and not universally available. Hence, there is an 
urgent need to identify or develop novel therapies that can help improve cognitive function in MS.  
 
Insulin is critical for helping with regulation of multiple CNS functions including brain metabolism, 
neurite outgrowth, neurotransmitter channel activity, neuronal survival, and learning and memory.25 ,26 
There are insulin receptors throughout the brain, with robust concentrations located in eloquent areas including 
the olfactory bulb, hippocampus, cerebral cortex, and cerebellum. Insulin is present at high levels in the brain 
and when these levels are decreased, there may be learning and memory impairments.25, 27, 28 The cognitive 
impairment that can ensue in the context of low brain insulin levels may be related to its ability to protect 
neurons from various insults including oxidative stress, ischemia, and glutamate-related excitotoxicity.25 
Moreover, insulin’s anti-inflammatory effects, as detailed below, 
may also impact brain health via suppressing concentrations of 
chemokines, cytokines, and other molecules that may provoke 
ongoing CNS inflammation and damage in disease states.   
 
Insulin has biologically relevant anti-inflammatory and 
neuroprotective CNS effects. At the cellular level, insulin 
regulates various neuronal functions including receptor 
expression, trafficking, and survival pathway activation. 
Insulin signaling in neurons exerts a neuroprotective effect, 
especially under oxidative stress, via the phosphoinositide-3 
kinase (PI3K/AKT) pathway (Figure 1) which, downstream, 
induces the cAMP response element binding protein (CREB). 
CREB regulates the expression of several genes that are crucial 
for learning and memory, including brain derived neurotrophic 
factor (BDNF),29 an important promoter of neuronal survival 
pathways, resulting in regulating learning and memory. This 
neuroprotective effect has been seen in models of Alzheimer’s, 
Parkinson’s, and Huntington’s Diseases.30 Insulin also exerts anti-inflammatory effects on peripheral blood 
Figure 1.  Neuroprotective signaling associated with insulin. 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
4 
 
mononuclear cells (PBMCs) by altering inflammatory markers (e.g. monocyte chemoattractant protein-1, 
chemokine receptor-5) that could ultimately help minimize ongoing nervous system injury.25  
 
Insulin’s ability to regulate energy metabolism could also result in a protective effect on neurons via 
impacting oxidative stress and excessive energy demands. Insulin appears to directly mediate brain glucose 
metabolism maximally within the cortex, and with any disturbance in the communication between insulin and 
neuronal glucose metabolism, there may be impaired adenosine triphosphate (ATP) synthesis followed by 
neuronal apoptosis.31, 32 Moreover, the oxidative stress that results from excessive energy demand leads not only 
to the production of reactive oxygen species (ROS), but also to ceramide production. These signaling pathways 
are connected and may be altered upstream by insulin’s impact on brain glucose metabolism. For example, 
several apoptosis-inducing treatments both activate the sphingomyelin (SM)-ceramide pathway and generate 
oxidative stress.33 Inflammatory cytokines relevant to MS (e.g. tumor necrosis factor [TNF]-α) can also induce 
ceramide formation and ROS. Chemical scavengers prevent elevations in ROS and also SM-ceramide pathway 
activation. Finally, the use of pyrrolidine dithiocarbamate or N-acetyl cysteine, both antioxidants, restricts 
ceramide formation and cell death due to TNF-α in rat astrocytes or human breast carcinoma cells.  
 
The impact of insulin in the nervous system, especially as it relates to cognitive health, deserves more attention, 
as it may be a treatment for disease that cause CNS dysfunction from several pathologies, including MS.  
 
Insulin administration has been shown to improve memory and learning in healthy people and in those 
with neurodegenerative diseases (see Table 1). Intranasal insulin has shown to have neuroprotective and 
restorative effects in several human clinical trials. In a recent randomized, double-blind, placebo-controlled 
study with over 100 people suffering from amnestic mild cognitive impairment or Alzheimer’s Disease, 
intranasal insulin preserved cognitive function in both selective cognitive domains and more globally compared 
to placebo.34 The insulin-treated patients also did not show a decline in measures of brain metabolism, whereas 
the placebo-treated participants did show decreases in fluorodeoxyglucose 18F uptake in various lobes 
(parietotemporal, frontal, precuneus, and cuneus). Further, improvements in episodic memory persisted for 
several weeks after treatment cessation. Overall, these findings suggest that intranasal insulin not only affects 
cognitive function acutely, but that over time, there may be associated structural changes that lead to a more 
permanent treatment benefit. Since cognitive dysfunction is very common in MS and can be devastating, a 
treatment intervention (i.e., intranasal insulin) that can help both acutely and longitudinally is worth pursuing.   
 
Table 1. Summary of past and ongoing human intranasal insulin trials. Adapted from 34-50 
 
REF. 
INTRANASAL 
INSULIN DOSE 
SUBJECTS 
ASSESSMENT 
Benedict 2004 
160 IU (long-term) 
Healthy 
Word list (immediate, delayed recall 
Reger 2006 
20 or 40 IU (acute) 
Probable AD or 
MCI vs. healthy 
Story recall (immediate, delayed recall) 
Word list (immediate, delayed recall) 
Benedict 2007 
20 IU Aspart vs. 20 IU 
Regular (long term) 
Healthy men 
Word list (immediate recall) 
Word list (delayed recall) 
Benedict 2008 
160 IU (acute) 
Healthy, normal 
weight, no meds  
Digit span, object location (immediate recall) 
Mirror tracing (immediate recall) 
Hallschmid 
2008 
160 IU (long-term) 
Obese men 
Word list (delayed recall) 
Word list (immediate recall) 
Reger 2008 
20 IU (long term) 
AD or MCI 
Memory score (immediate/ delayed recall ratio) 
Voice onset time (immediate/delayed recall ratio) 
Reger 2008 
10, 20, 40, 60 IU 
(acute) 
AD or MCI 
vs. healthy 
Story recall (immediate recall or delayed recall) 
Word list learning (immediate & delayed recall) 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
5 
 
Krug 2010 
160 IU (acute) 
Healthy women  Digit span (immediate recall) 
Object location(immediate recall) 
Fan 2012 
I40 IU (acute) 
Schizophrenic 
Hopkins Verbal Learning Test 
Craft 2012 
10 or 20 IU BID 
AD or MCI 
Verbal Memory Composite 
Craft 2012 
20 or 40 IU 
AD or MCI 
Story recall (delayed recall) 
McIntyre 
2012 
40 IU (long term) 
Euthymic with 
bipolar disorder 
California Verbal Learning Test, second edition 
Process Dissociation Task 
Burns 2012 
40 IU (acute) 
Early AD 
Functional MRI activation; cognitive battery 
Novak 2013 
40 IU (long term) 
Diabetic 
Brief Visuo-spatial Memory Test-Revised 
Verbal fluency measures 
Fan 2013 
40 IU (long term) 
Schizophrenic 
Cognitive battery 
Craft 2013 
20 IU BID 
AD or MCI 
Cognitive battery 
Haley 2013 
20 IU 
AD 
Cerebral glutamate levels; cognitive battery 
AD= Alzheimer’s Disease; MCI=mild cognitive impairment; IU=international units; BID=twice daily 
 
Intranasal insulin is extremely safe and tolerable in other populations, allowing for concentrated delivery 
to the nervous system. Intranasal insulin has a long-standing safety track record that spans more than a decade. 
No significant adverse events were reported in the largest intranasal insulin study to date or in any other study 
that has used intranasal insulin (see Table 1). An intranasal delivery system provides a non-invasive way to 
bypass the blood-brain barrier and allow rapid delivery of a medication to the CNS via the olfactory and 
trigeminal perivascular channels.34 The main advantage of the delivery system is reducing systemic side effects 
via limiting a medication’s exposure to peripheral organs and tissues. In addition, first-pass metabolism is 
avoided. Intranasal insulin, as seen in previous human studies, does not adversely affect systemic (blood) 
glucose or insulin, and it increases CSF insulin to biologically protective concentrations within 30-40 minutes.51   
 
Intranasal Insulin for Cognition in MS is an Innovative Treatment Approach-Summary 
Insulin appears to activate biologically relevant pathways within the nervous system for regulating and 
improving learning and memory. The direct and indirect effects of insulin on energy metabolism, oxidative 
stress, and modulation of inflammatory and neuronal pathways, along with the data from clinical trials 
in people with other neurodegenerative disorders, prove the rationale for investigating it in people with 
MS who suffer with cognitive impairment. As noted above, reduced levels of insulin and/or insulin activity 
may contribute to a number of pathological processes that may ultimately lead to long-term disability in 
neurodegenerative diseases. Restoring brain insulin to normal levels and increasing insulin sensitivity in the 
brain may provide therapeutic benefit to people with MS. Herein, we thus propose the first clinical trial in MS 
to determine the safety and tolerability as well as the effectiveness of intranasal insulin as a therapeutic 
intervention for cognitive dysfunction. Our study will investigate associated changes in putative biomarkers (see 
Preliminary Data below) that may corroborate clinical outcomes and provide data regarding the mechanisms by 
which insulin acts. These measures, along with neuropsychological testing, will be incorporated with safety data 
in order to accurately assess the potential utility of intranasal insulin for MS cognitive impairment. 
 
OBJECTIVES/AIMS 
 
Primary Objective: To evaluate the safety and tolerability of intranasal insulin in people with MS 
 
Secondary Objectives: The main secondary objective is to evaluate if intranasal insulin improves cognition in 
people with MS, as assessed by the SDMT. Additional secondary objectives are to determine if intranasal 
insulin is associated with changes in additional components of the Minimal Assessment of Cognitive Function 
in MS (MACFIMS), the Multiple Sclerosis Functional Composite (MSFC) score, health-related quality of life 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
6 
 
(Functional Assessment of Multiple Sclerosis [FAMS]), the Expanded Disability Status Scale (EDSS) score, 
and changes in biomarkers of oxidative stress, neuronal injury, cellular stress, and metabolism. 
 
Aim 1. To evaluate the safety and tolerability of intranasal insulin in people with MS. 
Hypothesis: Intranasal insulin has been shown to be safe in a pilot clinical trial of patients with mild cognitive 
impairment and Alzheimer’s Disease, but its safety and tolerability in MS patients are unknown. We 
hypothesize that intranasal insulin will be safe and tolerable for people with MS. 
 
Aim 2. To evaluate if intranasal insulin improves cognition in people with MS. 
Hypothesis: Intranasal insulin has been shown to improve multiple aspects of cognition in several randomized, 
blinded clinical trials of healthy people and in those with mild cognitive impairment and Alzheimer’s Disease. 
We hypothesize that intranasal insulin will improve cognition in MS patients who are cognitively impaired. 
 
Aim 3. To evaluate the impact of intranasal insulin on measures of oxidative stress, axonal injury, 
cellular stress, and energy metabolism in MS. 
Hypothesis: Although there is not a single biomarker for MS, there are some surrogate measures of interest that 
may well be impacted by treatment with insulin. We will perform an exploratory analysis to evaluate the effect 
that intranasal insulin has on these measures, with the hypothesis that intranasal insulin will improve markers of 
oxidative and cellular stress, neuronal injury, metabolism, and inflammation in people with MS. 
 
 
 
STUDY DESIGN 
 
Design: The design of this phase II, randomized, double-blind, placebo-controlled trial is as follows: 
 
Participants: The eligibility criteria for the trial are provided in the table below: 
Eligibility Criteria 
Rationale 
Meets 2010 criteria for multiple sclerosis 
Study is focused on individuals with MS 
No relapse in past 3 months 
To avoid relapse-induced cognition 
confounding 
Age 18-70 years 
To ensure results generalizable 
At least mild cognitive impairment (1.0 standard deviation 
or greater below the published mean SDMT z-score, or a 
score of <34 on the processing speed test [PST] 
To ensure that we are able to detect 
improvements in cognition if insulin does in 
fact have this effect 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
7 
 
Capacity to learn and self-administer intranasal insulin, or 
presence of a caregiver with such capacity who is willing 
to do it for the duration of the trial 
To ensure that subjects are able to take the 
medication as prescribed 
Untreated/on the same MS therapy for at least 2 months, 
with no anticipated change in the next year 
To avoid change in measures due to change in 
medication 
No current, active major depression 
May impact results of cognitive testing 
If on tricyclic antidepressant or anticonvulsant, on stable 
dose for 6 weeks or more; if on oxybutynin or tolterodine, 
on stable dose for > 6 months without plans for changing 
dose in next year 
May impact results of cognitive testing 
 
If taking selective serotonin (± norepinephrine) reuptake 
inhibitors, pregabalin, gabapentin, sympathomimetic, 
monoamine oxidase inhibitor, antipsychotic, amantadine, 
cholinesterase inhibitor, memantine, modafanil, 
armodafinil, or evening short-acting benzodiazepines, on  
stable dose for 6 weeks or greater 
To minimize impact on cognitive testing 
without  impairing recruitment/limiting 
generalizability (MS patients use these therapies  
commonly) 
Not pregnant or nursing, and willing to prevent pregnancy 
during study if of childbearing potential 
Risks of intervention to developing fetus or 
breastfeeding infant unknown 
No or stable THC use in past 6 weeks; no other illicit drug 
or alcohol abuse in past 3 months* 
To ensure participants can adhere to treatment/ 
avoid impact of substances on cognitive testing 
No known history of diabetes mellitus or insulin resistance  To avoid confounding due to global glucose 
dysregulation or use of systemic insulin 
No active liver disease, stage IV/V kidney disease or 
severe metabolic derangements 
To prevent differential metabolism of insulin 
No CNS disorder other than MS or headache 
To avoid confounding due to insulin effect on 
other disorder 
No issue making participation not in best interest of patient To prevent any undue harm to patient 
During COVID-19 pandemic and related periods of 
slowdown or shutdown, willing to comply with state/local 
recommended social distancing and other suggested 
COVID-19 related safety measures. Additionally, if female 
of childbearing potential, to prevent pregnancy 
To ensure minimization of risks to participants 
 
 
Recruitment: Eligible subjects with MS will be recruited from the Johns Hopkins MS Center, at which over 
3,000 MS patients, who come from diverse racial/ethnic and socioeconomic backgrounds and from a wide 
catchment area, are seen annually. We will also screen potentially eligible subjects using an IRB-approved 
Telephone Screening Script. This will allow us to screen patients who may or may not meet the study’s 
eligibility criteria. If a patient meets the eligibility criteria via telephone screening, we will schedule the patient 
to come in for a baseline visit. The study coordinator will call only patients of physicians on the study team. 
Patients interested in participating will be emailed or mailed the written consent form to review in advance.  
 
Since we began routinely administering the iPAD-based correlate of the SDMT, the Processing Speed Test 
(PST) for all MS Center patients since early 2017 and impaired cognition based on the SDMT is one of the 
main eligibility criteria, we will quickly be able to focus recruitment efforts on those who have evidence of mild 
cognitive impairment, eliminating the need for an extra screening visit.  More than 80 people with MS who are 
currently enrolled in various studies in the center already have SDMT data and thus will also be easily screened 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
8 
 
for eligibility, even if they haven’t had a recent clinic visit. For MS Center patients that have not taken an 
SDMT or PST test, we will use an oral consent process to administer the SDMT test and determine eligibility. 
SDMT or PST test results obtained within 3 months of the baseline visit will be considered as proof of 
eligibility for the study and may be screened in person or by phone. The study coordinator will only approach 
MS Center patients of physicians on the study team or those referred by their treating physician. In addition to 
the above recruitment strategies, we will obtain home-based PST screening test for our MS patients that have 
iPADs (Air, Air 2, and iPAD 2017), as the PST app is now available. This will allow for remotely screening 
potential subjects that have transportation and/or mobility limitations.  If at any time point, enrollment is less 
than 85% of the target, we will interview subjects who have declined to participate to determine the deterrents 
to enrollment; we will then implement alterations in recruitment needed to enhance enrollment. 
 
 
Study Treatment: Intranasal insulin (Novolin R, Novo Nordisk, Princeton, NJ) will be evaluated in two doses 
(10 IU twice a day, 20 IU twice a day) and compared to the sterile diluent (Eli Lilly and Company – 
NDC:00002-0800) (1:1:1 randomization, stratified by relapsing versus progressive MS). The 20 IU dose will 
consist of insulin. The 10 IU dose will be a diluted mixture comprised of normal saline and insulin. The study 
drug, insulin, has a distinct smell. In order to preserve study blinding, we will use the Lilly sterile diluent, which 
has a similar odor as the insulin, to preserve blinding. The study drug and placebo (Lilly diluent) will be 
prepared by the Johns Hopkins Investigational Drug Service and will appear identical to maintain blinding. A 
nasal drug delivery device (Kurve Technology, Lynnwood, WA) will be utilized to ensure optimal exposure of 
the olfactory epithelium. The treatment regimen was chosen to match that of a recent successful pilot study in 
Alzheimer’s Disease.34 Evaluating two doses will allow for the possibility that any benefit of insulin may be 
non-linear. 
 
Treatment Preparation: The study pharmacist will transfer either insulin; sterile diluent (placebo); or normal 
saline into 10cc empty syringes to preserve study blinding. The syringes will be labeled syringe A or syringe B, 
respectively. At the baseline visit, subjects and/or caregivers will be instructed on how to fill the cartridges by 
adding one A and one B syringe to the cartridge; gently mix the contents and be shown how to administer the 
doses using the ViaNase device.  Due to the 28-day shelf life of the insulin/diluent, the subjects need to know 
how to refill their own study products prior to their next study visit.  
 
Methods to Maximize Adherence: Given data from prior studies, it is anticipated that adverse events will not 
reduce adherence. The study coordinator will help each participant set reminder alarms on watches or phones; 
those who do not have access to such devices will be given a medication alarm watch for use during the study. 
Study staff will also identify a patient advocate and to educate that person to help the study participant maintain 
adherence. To maximize visit adherence, patients will receive a reminder in the week prior to the appointment.   
 
Accountability of Medication:  A sufficient amount of medication will be supplied at the baselineand week 12 
visits to ensure the supply will last until the next study visit, otherwise, refills will be mailed to the participants. 
Participants will be asked to return unused medication at each study visit for adherence assessment. The Johns 
Hopkins Investigational Drug Unit will maintain adequate records of the disposition of the study drug and 
accounts of any destroyed study drug.  
 
Study Personnel: All personnel (except the statistician) will be blinded to treatment assignment. The treating 
physician will assess eligibility criteria, obtain informed consent, obtain and maintain the medical history and 
medication record, monitor patients’ safety, conduct the physical examination, and evaluate and report adverse 
events. The examining physician will perform the blinded EDSS. The blinded study neuropsychologist will 
administer the MACFIMS to participants. The blinded study coordinator will be responsible for the study’s 
administrative duties, obtaining vital signs, conducting the MSFC and administering the depression, suicidality, 
and health-related quality of life measures, and drawing and processing blood samples as well as urine 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
9 
 
pregnancy testing, when indicated. The laboratory technician will conduct the biomarker analyses for Aim 3. 
Other personnel include Drs. Haughey and Calabresi, who will interpret biomarker data. A statistician from the 
Johns Hopkins School of Public Health will create the randomization schedule and perform final data analyses. 
 
Study Visits: The visit schedule is detailed below. Visits will take place within ± 5 days of the target date. 
 
Week 0  
Week 6 Week 12 Week 24 
Week 36 
Week 48 
Written consent 
X 
 
 
 
 
 
Verify eligibility 
X 
 
 
 
 
 
Teaching and First dose 
administration and observation 
X 
 
 
 
 
 
Medical history, relapse assessment 
X 
X 
X 
X 
X 
X 
Medication review 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Physical, neurologic (EDSS) exams 
X 
 
X* 
X* 
 
X* 
MS Functional Composite 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
 
X 
X 
X 
X 
X 
Biomarker evaluation 
X 
X 
X 
X 
X 
X 
Stored blood for future studies 
X 
X 
X 
X 
X 
X 
DXA scan 
X 
 
 
 
 
 
A pregnancy test (if woman of 
childbearing potential) 
X 
X 
X 
X 
 
 
MACFIMS battery 
X 
 
X 
X 
X 
X 
Sleep questionnaires 
X 
 
X 
X 
 
X 
Depression and quality of life  
X 
X 
X 
X 
X 
X 
Suicidality evaluation 
X 
X 
X 
X 
X 
X 
 
*EDSS only 
 
Schedule Modification during COVID-19 (will be in effect unless JHU operations have returned to normal, a 
COVID-19 vaccine has been developed, or evidence of substantial likelihood of herd immunity from COVID-
19 due to a high proportion of previously-infected individuals). Additionally, due to COVID-19 and staffing 
shortages during the holiday season, we will allow study visits within ± 10 days of the target date if needed to 
ensure the safety of the participants.   
 
 
Week 0  
Week 
6: 
Virtual 
Week 
12** 
Week 24 
Week 
36: 
Virtual 
Week 48: 
Virtual% 
Written consent& 
X 
 
 
 
 
 
Verify eligibility 
X 
 
 
 
 
 
Teaching and First dose 
administration and observation 
X 
 
 
 
 
 
Medical history, relapse 
assessment 
X 
X 
X 
X 
X 
X 
Medication review 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
 
X 
X 
 
 
Neurologic (EDSS) exam 
X 
 
 
 
 
 
MS Functional Composite 
X 
 
X*** 
X*** 
 
 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
10 
 
Adverse event assessment 
 
X 
X 
X 
X 
X 
Biomarker evaluation 
X 
 
X 
X 
 
 
Stored blood for future studies 
X$ 
 
X$ 
X$ 
 
 
DXA scan 
X 
 
 
 
 
 
Pregnancy assessment* 
X* 
X 
X 
X 
 
 
MACFIMS battery 
X 
 
X 
X 
 
X 
Sleep questionnaires 
X 
 
X 
X 
 
X 
Depression and quality of life  
X 
X 
X 
X 
X 
X 
Suicidality evaluation 
X 
X 
X 
X 
X 
X 
*Pregnancy test at baseline; document last menstrual period/adequate pregnancy prevention plan at virtual 
follow-ups (for women of childbearing potential) 
**will convert to virtual follow-up with activities equal to week 6 if stay-at-home orders recur 
Items that are in bold will be done either virtually or in-person until operations are fully normalized with 
respect to COVID-19 pandemic; in addition, some aspects of the MACFIMS neuropsychological battery can 
(and will) be done virtually as well 
***timed 25-foot walk only 
&Consent will be reviewed at length virtually within the week prior to the day of the visit, with all questions 
asked at that time. At the baseline visit, patients will be given the opportunity to ask any remaining questions 
and can sign during the teleconsent, if capable, or will sign at the time of the baseline visit. 
% if COVID-19 pandemic is lifted, we will still complete this visit in-person; we will accept a study window 
that extends 3 months beyond week 48 if there is indication at that time, even if the pandemic is still affecting 
safety, that it will soon be safe again (e.g. vaccine developed or clear evidence of critical percentage of 
population has already been infected, fully operational at JHU) 
 
If a severe COVID-19 outbreak occurs again such as occurred in the spring of 2020, we will conduct all follow-
up assessments by video or phone until such time as it is safe to pursue the modified schedule, as above, or 
resume the originally-planned schedule. 
 
All study visits will be scheduled for the morning to reduce variability in cognitive function related to the time 
of day. At baseline, fasting laboratory testing will be performed, including a hemoglobin A1c test and insulin 
level.  All subjects will then be given breakfast prior to completing cognitive testing. For follow-up visits, all 
subjects will complete the MACFIMS battery after eating a usual meal (if the participant came without having 
eaten, breakfast will be provided to them) and prior to taking the morning dose of study treatment. Unscheduled 
visits will occur if any safety issue arises. 
 
In order to ensure subjects (or their responsible caregivers) are able to use the medication as instructed, all 
subjects and caregivers (when relevant) will be instructed on the use of the inhaler and will be observed by a 
health care provider when performing their first dose administration at the time of the first visit. 
 
 
Risks 
 
Intranasal insulin 
Intranasal insulin has been shown to be safe and tolerable in other populations and patient groups, but it has 
never been studied in people with MS. The most common side effects related to irritation of the nasal passages. 
Giving insulin through the nose did not result in lower circulating glucose levels in other studies, but the first 15 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
11 
 
people in this study will be monitored for this potential risk by testing a fingerstick blood glucose level 
periodically for 90 minutes after the first dose of intranasal insulin (see Safety section under Outcomes on page 
10). 
Insulin, given by the more traditional subcutaneous route, has the following potential risks: 
Hypoglycemia: Common symptoms of hypoglycemia include sweating, dizziness or lightheadedness, 
shakiness, hunger, a fast heartbeat, tingling of the hands, feet, lips or tongue, trouble concentrating, 
confusion, blurry vision, slurred speech, anxiety, irritability, or mood changes, or headache. Very low 
blood sugar can cause loss of consciousness, seizures, or temporary or permanent brain problems or 
death.  Mild hypoglycemia can be treated by drinking or eating something sugary right away (fruit juice, 
sugar candies, or glucose tablets).  
 
 
Hypokalemia: Hypokalemia can lead to breathing problems, low heartbeat, or death. 
 
 
Allergic reaction: Common symptoms of an allergic reaction include a rash all over the body, trouble 
breathing, a fast heartbeat, sweating, and feeling faint. 
 
 
Weight gain or swelling of the arms and legs. 
 
While these are all risks potentially associated with subcutaneous administration of insulin, none of these risks 
has been demonstrated to be the case in the published trials of intranasal insulin. Thus, by avoiding the 
traditional route of administration, it is anticipated that these risks will be minimized. 
 
Blood Draw  
Taking blood may cause discomfort, bleeding or bruising where the needle enters the body. In rare cases, it may 
result in fainting. There is a small risk of infection. To minimize the risks, blood will be drawn by a trained 
study team member/phlebotomist. 
 
Confidentiality  
Despite the best efforts of the research team, there may still be a risk if information about participants were to 
become known to people outside of this study.  
 
Questionnaires  
Participants may get tired or bored when we are asking questions or they are completing questionnaires. They 
do not have to answer any question they do not want to answer. 
  
DXA scan 
DXA testing is painless and involves exposure to radiation. This research study includes exposure to radiation 
from x-rays or gamma rays. This radiation exposure is for research purposes only and is not part of the 
participant’s medical care. X-rays and gamma rays can damage cells, but at low doses, the body is usually able 
to repair these cells.  
 
The radiation exposure that participants will get in this research study is 0.001 rem. This is less than the 0.3 rem 
that the average person in the United States gets each year from natural sources like the sun, outer space, air, 
food, and soil. The risk from the radiation exposure in this research study is very small. The radiation exposure 
described here is what participants will get from this research study only. It does not include any exposure 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
12 
 
participants may have received or will receive from other medical tests outside of this study that are a part of 
their medical care. 
  
Benefits 
There is no known benefit of intranasal insulin, and thus there is no known risk of being in the placebo group. 
All patients who are already on a medication for MS will be allowed to continue that medication during the 
study. 
Payment and Remuneration 
Participants will receive a parking coupon at each visit.   
 
Costs 
There are no costs to participants for taking part in this study. 
 
 
Outcomes:  
 
Safety Since this medication was extremely well-tolerated in several published studies,34-50 we anticipate the 
same will be true for people with MS. In prior studies, there was no effect of intranasal insulin on serum glucose 
levels. However, we will monitor the first 15 participants for a period of 90 minutes after their first dose of the 
medication to evaluate serial finger stick blood glucose levels. If there is a clinically significant reduction in 
these levels, we will convene a Data Safety Monitoring Board (DSMB) meeting to adjust the protocol. We will 
also record and, when appropriate, report all patient-reported adverse events, as described below. Subjects and 
their caregivers will be required to keep an electronic diary of adverse events, which will be reviewed at each 
study visit. As mandated by the FDA, the Columbia Suicide Severity Rating Scale will be administered at each 
study visit. 
 
Cognitive Assessments  The MACFIMS battery includes the following: The Symbol Digit Modalities Test 
(SDMT) is commonly used in MS to assess processing speed.1, 52-54 The oral version of the test is recommended 
for MS since the written version may be confounded by upper extremity weakness.53, 55, 56 There are three 
alternate versions of this test with strong psychometric properties.37 A 3.5-4 point raw score difference on the 
SDMT has been identified as clinically meaningful.6, 57 The Controlled Oral Word Association Test (COWAT) 
measures phonemic fluency.58 The California Verbal Learning Test, Second Edition (CVLT-II) is a verbal 
learning and memory test.55, 59 The Brief Visuospatial Memory Test – Revised (BVMT-R) is a visual, nonverbal 
test of learning and memory.60 The Rao-version of the Paced Auditory Serial Addition Test (PASAT) evaluates 
processing speed, working memory, and basic addition skills.58 Visual-spatial abilities are assessed with the 
Judgement of Line Orientation Test (JLO).58, 61 The Delis-Kaplan Executive Function System (DKEFS) tests 
executive functioning, concept formation, and cognitive flexibility. 
 
 
  
Exploratory Biomarkers Plasma and/or PBMCs will be collected at baseline, week 12, and week 24 visits 
(except if COVID-19 related shutdown does not permit follow-up blood collection or lab-based processing) and 
will be isolated and cryopreserved for batch analyses in the labs of Dr. Haughey or Calabresi. Inflammatory 
(cytokines, lymphocyte subsets), metabolic (Kreb’s cycle substrate, fatty acids), cellular stress (ceramides, 
sphingomyelin) and neurotrophic (BDNF) measures, as well as markers of oxidative stress (protein carbonyls, 
8-isoprostane, nitrotyrosine, and 4-hydroxynonenal adducts [lysine and histidine]), will be quantified. Since our 
data show oxidative stress biomarkers and elevated ceramides in plasma of MS patients and recent work shows 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
13 
 
the brain has lymphatics, explaining how brain metabolites return to the periphery, blood biomarkers are a 
relevant and convenient way to monitor CNS metabolism.62  
 
Additional Outcomes and Assessment of Covariates In order to identify and, if needed, adjust for comorbid 
depression, the Beck Depression Inventory will be administered at each study visit. Health-related quality of life 
will also be assessed utilizing the FAMS. We will also evaluate how overall sleep quality in people with MS 
impacts health-related quality of life. We will also evaluate for occult insulin resistance or differences in 
metabolism in several ways. We will evaluate dual-energy x-ray absorptiometry (DXA) at baseline, which will 
help determine body composition, in particular bone density. We will also calculate an insulin resistance index, 
the homeostatic model assessment (HOMA-IR),63 using baseline fasting glucose and insulin. Statistical models 
exploring these body composition and insulin resistance parameters as potential confounders or mediators will 
be evaluated. Finally, the MACFIMS, safety, depression, and health-related quality of life outcomes will be 
monitored after discontinuation of the insulin (or placebo) to evaluate for any decline in cognitive function 
associated with medication discontinuation.  
 
Safety/Adverse Event Monitoring  An adverse event (AE) is any occurrence or worsening of an undesirable or 
unintended sign, symptom (or abnormal laboratory test), or disease temporally associated with the use of a 
medicinal product or intervention, whether or not it is considered related to the product/intervention. We will 
use the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0 to report and 
grade all adverse events, whether or not they are related to disease progression or treatment. The relationship 
between an AE and the intervention will be determined by the blinded study physician and recorded on the 
appropriate form. The investigator will record all study adverse events in the chart and will treat participants 
with AEs appropriately, observing them until they resolve or stabilize. AEs will be collected from the start of 
the study until a participant terminates from the study; those that are unresolved at the time of termination will 
be followed until they resolve or up to 30 days. An adverse event is considered unexpected when its nature or 
severity is not consistent with the product information (e.g. protocol or the informed consent form). Serious 
AEs will be collected from informed consent signing until 30 days after study completion or until 30 days after 
a participant withdraws from the study. The following process for reporting a serious AE will ensure 
compliance with the International Conference on Harmonisation guidelines: the Institutional Review Board 
(IRB) and DSMB will be notified in two business days of a serious AE that is medication-related and 
unexpected, and standard reporting (15 calendar days) will occur if the event is serious, expected and 
medication-related, serious, expected and not medication-related, or serious, unexpected and not medication-
related. Life-threatening events will be reported within 7 calendar days. Any pregnancy will be reported to the 
IRB and DSMB, and pregnancies will be followed to their conclusion. Female participants who become 
pregnant will stop the study intervention. The investigator will report pregnancies to the IRB within two 
business days. The study medication will be discontinued if an AE grade 3 or higher occurs and is at least 
possibly related to the medication or if the subject cannot tolerate the medication/ wants to discontinue it. Any 
death that is at least possibly related to the study will put the study on hold until the DSMB evaluates it.  
 
DSMB: The DSMB consists of an independent neurologist, an endocrinologist, and a statistician. It will 
convene any time an adverse event ≥ grade 3 occurs and routinely at 25%, 50%, 75%, and 100% enrollment. 
All serious adverse events will be promptly and simultaneously reported to the IRB, the DSMB and the 
Independent Research Monitor. Only serious adverse events (SAEs) that would also meet the definition of an 
Unanticipated Problem Involving Risks to Subjects or Others (UPIRTSOs) that are related to the protocol will 
be promptly reported to the United States Army Medical Research and Materiel Command Office of Research 
Protections Human Research Protection Office HRPO (USAMRC ORP HRPO). 
 
Independent Research Monitor: The PI, Dr. Mowry, has appointed Dr. Anne Damian, a trained neurologist, as 
the Independent Research Monitor.  Dr. Damian will provide independent safety review and will have the 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
14 
 
authority to stop the research study; remove an individual subject from the research study; and will take any 
steps to protect the safety and well-being of the subjects until the IRB can assess the problem or event. The 
independent research monitor must review all unanticipated problems involving risks to subjects or others 
(UPIRTSO), but not all SAEs.  The monitor will review the SAEs if they also meet the definition of a 
UPIRTSO and will provide an unbiased written report of the event.  The Research Monitor will comment on the 
outcomes of the event or problem and the relationship to participation in the study. Additionally, the research 
monitor will indicate whether she concurs with the details of the report provided by the principal investigator.  
 
 
Analytic Plan 
 
Aim 1. Safety data will be analyzed as they are captured in real time. Assessments will focus on AEs (including 
study treatment tolerability assessments, laboratory evaluations, vital signs, and physical examination). The 
incidence rate of AEs will be recorded by system organ class, severity, and by relationship to the study 
treatment. Tolerability analysis will be based on the number (%) of subjects who failed to complete the study 
due to adverse events. Lab values for each parameter will be summarized by shift tables. For quantitative 
parameters, summary statistics for actual values and change from baseline will be presented. Changes in the 
first 24 weeks will be compared between groups using mixed effects regression analyses to account for the 
longitudinal nature of the data using random subject-specific intercepts and slopes. 
 
Aim 2. Summary statistics (mean ± standard deviation, median and interquartile range, or number and 
percentages) will be used to characterize the outcomes. For each cognitive outcome, to evaluate variability in 
the estimated means across groups, assuming that the within-group means are normally distributed, a one-way 
ANOVA will be conducted at the follow-up visits during the first 24 weeks. If the within-group data are 
strongly non-Gaussian, a Kruskal-Wallis test will be used. A mixed effects longitudinal model will also be used 
to test whether any differences across groups exist at the follow-up visits within the first 24 weeks. Further, 
models accounting for covariates of interest, including the HOMA-IR, body composition, body mass index, age, 
sex and depression, will be evaluated. For within-person changes in measures at follow-up compared to 
baseline, paired t-tests will be used. We will also evaluate the SDMT at each study visit and other MACFIMS 
outcomes at week48 to establish the longevity of any therapeutic response to insulin. 
 
Aim 3. For the biomarker outcomes, to evaluate variability in the estimated means across groups, assuming that 
the within-group means are normally distributed, a one-way ANOVA will be conducted at the follow-up visits 
during the active treatment phase. If the within-group data are strongly non-Gaussian, a Kruskal-Wallis test will 
be used. A mixed effects longitudinal model will also be used to test if differences across groups exist at follow-
up visits. For within-person changes in measures at follow-up compared to baseline or before versus after 
calorie restriction days, paired t-tests will be used. Correlations between the biomarkers will be assessed. A 
bootstrap of subjects will be used to obtain 95% equal confidence intervals for these measures. We will also 
evaluate the biomarker changes after study therapy ends. 
 
Sample Size and Power: Sample size estimates are difficult given the novelty of the project but are based on 
the goal of detecting a benefit of insulin on cognition. In a pivotal study of two doses of intranasal insulin 
versus placebo in participants with mild cognitive impairment or mild to moderate Alzheimer’s Disease, the 
Dementia Severity Rating Scale score improved over the four-month treatment course in those receiving 
intranasal insulin.34 Using the scores in the 10 IU twice a day group, given a two-sided alpha of 0.05 and beta 
0.20 (80% power), assuming 3 follow-up cognitive tests and a correlation between baseline and follow-up 
results of 0.5, 29 subjects per group are required. To account for drop-outs and for the three-arm design, a total 
of 35 subjects per group is planned. With SDMT as the outcome, for a two-arm design, this sample size confers 
80% power (assuming SDMT standard deviation of 9 points and two-sided alpha of 0.05) to detect a 6-point 
improvement in SDMT which seems reasonable considering that transcranial stimulation with cognitive training 


Date: November 20, 2020 
PI: Ellen M. Mowry, M.D., M.C.R. 
Application #: IRB00095554 
15 
 
improved SDMT by an average of more than 8 points compared to cognitive training alone in a pilot study of 20 
subjects.64 We do not expect that this study will provide conclusive evidence of efficacy for cognition, but it 
will provide estimates of the mean and standard deviation of the distribution in change in cognitive tests that 
will inform the design of definitive, phase III trials. Aim 3 is exploratory, but given the relative abundance 
differences in MS versus controls in our preliminary data in C22:1, and assuming a similar absolute C22:1 
concentration as in women aged 55-64 years,65 with 35 subjects in a two-arm study of 35 subjects/arm and a 2-
sided alpha of 0.05, we will have 80% power to detect a 10 ng/mL difference in ceramide levels.  
 
 
 
 
 
 
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Application #: IRB00095554 
17 
 
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18 
 
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Trial Protocol for:  
Intranasal Insulin for Improving Cognitive Function in Multiple Sclerosis (NCT02988401) 
Date of Protocol 11/20/2020 
 

SAP_001.pdf: 
Trial: Intranasal Insulin for Improving Cognitive Function in Multiple Sclerosis (NCT02988401) 
Author: Kathryn Fitzgerald 
Statistical Analysis Plan  
Version 4.0 
12/9/2022 
 
 
I. 
Title: Intranasal Insulin (INI) for Improving Cognitive Function in Multiple Sclerosis 
II. 
Investigators: Dr. Ellen Mowry (PI) and Dr. Scott Newsome (PI)  
III. 
Intervention 
a. Low dose Intranasal insulin 10 international units BID (LDINI) 
b. High dose Intranasal insulin 20 international units BID (HDINI) 
c. Placebo (PLAC) 
IV. 
Outcomes: 
a. Primary outcome 
i. Change from baseline in cognitive function as assessed by the Symbol Digit Modalities Test (SDMT) using 
raw scores  
b. Secondary outcomes  
i. Adverse events 
1. Adverse events are defined as occurrence or worsening of an undesirable or unintended sign, 
symptom, or abnormal laboratory test potentially associated with INI. Adverse events for this study 
will consider: outcomes for which ≥5% experienced. Adverse events will be characterized overall and 
stratified by treatment arm).  
2. Evaluation of glucose levels (from finger-stick) for first 15 participants following first dose of 
medication.  
3. Number of adverse events comparing any INI versus placebo or HDINI versus LDINI versus placebo 
(e.g., two level any exposure to INI versus three level incorporating dosages). 
ii. Change from baseline cognitive function in the tests listed below. Cognitive outcomes will be assessed 
as raw scores  
1. Change from baseline cognitive function in Controlled Oral Word Association Test (COWAT) 
assessing fluency (adjusted for form type) 
a. Number of words produced in one minute for each of the three letters (raw score) 
b. Number of words produced in one minute for each of the three letters (adjusted score) 
2. Change from baseline using Benton Judgement of Line Orientation (JLO) test assessing participant 
ability to match the angle and orientation in space 
a. Total correct 
3. Change from baseline using PASAT-3 test assessing processing speed 
a. Total correct 
4. Change from baseline using Brief Visuospatial Memory Test – Revised (BVLT-R) assessing learning 
and memory. The following aspects from the BVLT-R will be considered.  
a. Total recall 
b. Delayed recall 
5. Change from baseline using Delis-Kaplan Executive Function System sorting (DKEFS) test for 
executive functioning. The following aspects from the DKEFS will be considered: 
a. Total description score 
b. Number of correct sorts 
6. Change from baseline using California Verbal Learning Test (CVLT) for learning and memory. The 
following aspects from the CVLT will be considered and combined into a composite outcome for 
CVLT using Z scores.  
a. Long-delay free recall correct 
iii. Change in multiple sclerosis (MS) functional composite (MSFC) 
1. Change in components of MSFC. These include walking speed, 9-hole peg test, and PASAT-3.  
2. MSFC will be considered as a Z score; MSFC component tests will be assessed as raw and Z scores.  


3. Sustained 20% worsening from baseline MSFC that is confirmed at a subsequent visit.  
a. This test will only be performed if at least 10 events have occurred.  
iv. Change in health-related quality of life using the functional assessment in MS (FAMS) scores 
1. These include the total FAMS score and components for symptoms, mobility, fatigue, emotional 
well-being, social well-being 
2. 1 SD improvement in FAMS total and component scores  
v. Change in sleep quality 
1. Total Pittsburgh Quality Sleep Index global score 
vi. Change in depression using Beck Depression Inventory-II 
1. Change in total depression score 
V. 
Descriptive analyses 
a. Calculate frequencies of the version of the protocol participants were enrolled.  
b. Characterize baseline cohort overall and by randomization arm for demographic, clinical, and patient 
characteristics in a table with 5 columns (overall, placebo, either INI, HDINI, LDINI) using descriptive statistics 
based on the variable in question (e.g., means and standard deviations, median and interquartile range, and 
percentages).  
i. These characteristics will be included: age, sex, race, ethnicity, years of education, ADI (if possible),  
disease subtype (relapsing remitting MS vs. progressive MS), body mass index (BMI), disease duration, 
MS disease modifying therapy (DMT; categorized as injectable, oral, infusion/monoclonal ab), number of 
relapses in the past year, EDSS score, anti-depressant, stimulant use, total number of symptomatic 
therapies, DXA scan results (total body mass, total fat mass, total lean mass, visceral fat mass, body 
fat%), version of protocol enrolled under, fasting insulin, fasting glucose, HOMA-IR.  
c. Characterize SDMT scores overall and by randomization arm at baseline and over time. Two versions of this 
analysis will be created: 1) including baseline, and weeks, 6, 12 and 24, 2) including baseline and weeks 6, 
12, 24, 36 and 48.  
i. Characterize missing data in SDMT by randomization arm and by time 
ii. Calculate descriptive statistics for SDMT levels by randomization arms and by time.  
iii. Plot means (SD) of SDMT levels by randomization arm over time 
iv. Create spaghetti plots with overlaid loess curves for SDMT by randomization arm over time.  
v. Plot SDMT by month of study enrollment and by randomization arm and time to confirm no differences 
in allocation by calendar time. 
 
VI. 
Outline of protocol changes 
Outline of timing of protocol changes by calendar time.  
 
VII. 
Consort diagram 
a. A consort diagram will be created with the following levels: assessed for eligibility, randomized, treatment 
allocation, follow-up and analytic cohort.  
 
VIII. 
Regression models: Modified intention to treat analyses 
a. Analyses will adjust for age, sex, and years of education. We will also incorporate variables with differences 
between the treatment arms that exceed 10% as identified using results of the descriptive analyses.  
b. For analytic models for each outcome, the primary hypothesis test will compare INI (regardless of dose) 
versus PLAC and will be conducted first. Secondary pairwise tests comparing LDINI versus PLAC, HDINI 
versus PLAC, HDINI versus LDINI will then be conducted.  
c. Analyses will first be conducted first through the week 24 measure (0, 6, 12, 24). Secondary analyses will 
include weeks 36 and 48 (0, 6, 12, 24, 36, 48) to evaluate a potential sustained effect post cessation of 
treatment.   
i. The week 24 visit must have occurred within 25 weeks (i.e., the protocol outlines a 1 week visit 
window).  
d. Eligible participants for the primary analysis are those with baseline or screening SDMT data  
e. Missing values for key baseline covariates of interest is expected to be small; however, primary analyses will 
include a missing indicator level for the categorical variable if it is included in analytic models.  


f. 
For mixed effects models, time will be considered as a linear variable in primary analyses.  
i. Sensitivity analyses will evaluate potential non-linearity in changes over time using appropriate methods 
(e.g., quadratic terms for time or splines).  
g. Primary outcome: change in SDMT using raw scores over time 
i. Change in the raw SDMT score over time will be assessed using a linear mixed effects model with 
unstructured covariance structure, random intercepts. If model fit is improved with the addition of 
random slopes, they will be added. The term of interest will be the coefficient for the cross-product 
term between INI and time.   
h. Secondary outcomes 
i. Adverse events 
ii. Change from baseline cognitive function in the tests listed below.  
1. Rate of change in each cognitive test will be assessed using a linear mixed effects model with 
unstructured covariance structure, random intercepts. If model fit is improved with the addition of 
random slopes, they will be added. The term of interest will be the coefficient for the cross-product 
term between INI and time.   
iii. Change in multiple sclerosis (MS) functional composite (MSFC) 
1. Rate of change in MSFC Z scores (and component Z scores) using a linear mixed effects model with 
unstructured covariance structure, random intercepts. If model fit is improved with the addition of 
random slopes, they will be added. The term of interest will be the coefficient for the cross-product 
term between INI and time.   
2. Rate of change in raw components using a linear mixed effects model with unstructured covariance 
structure, random intercepts. If model fit is improved with the addition of random slopes, they will 
be added. The term of interest will be the coefficient for the cross-product term between INI and 
time.  A log transformation will be applied in if data are skewed based on visual inspection.  
3. For 20% change models, we will fit statistical models if ≥10 events occurred. Time to 20% worsening 
in MSFC (and components) using a Cox proportional hazards model. 
4. Plot unadjusted results using Kaplan Meier curves for time to event outcomes and test for 
significance using log-rank test (or other appropriate test if assumptions are not met for log-rank). 
iv. Change in health-related quality of life using the functional assessment in MS (FAMS) score.  
1. Rate of change in quality of life using a linear mixed effects model with unstructured covariance 
structure, random intercepts. If model fit is improved with the addition of random slopes, they will 
be added. The term of interest will be the coefficient for the cross-product term between INI and 
time.   
2. For ≥1 SD improvement, we will fit statistical models if ≥10 events occurred. Time to ≥1 SD 
improvement in FAMS total score and subscale scores will be assessed via Cox proportional hazards 
model.  
3. Plot unadjusted results using Kaplan Meier curves and test for significance using log-rank test (or 
other appropriate test if assumptions are not met for log-rank).  
v. Change in sleep quality 
1. Rate of change in global sleep quality using PSQI using a linear mixed effects model with 
unstructured covariance structure, random intercepts. If model fit is improved with the addition of 
random slopes, they will be added. The term of interest will be the coefficient for the cross-product 
term between INI and time.   
vi. Change in depression using Beck Depression Inventory-II 
1. Rate of change in total depression using a linear mixed effects model with unstructured covariance 
structure, random intercepts. If model fit is improved with the addition of random slopes, they will 
be added. The term of interest will be the coefficient for the cross-product term between INI and 
time.   
 
IX. 
Regression models: Planned per protocol analyses 
a. For planned per protocol analyses, we will consider the following analyses for the primary outcome raw 
change in SDMT (or corresponding measures of processing speed)  
b. Overview of planned per-protocol analyses  


i. Adjusted analyses for additional covariates including DXA-derived body fat, bone density, lean mass, 
BMI, HOMA-IR 
ii. Stratified analyses by pre-shutdown and shutdown/post-shutdown.  
1. Pre-shutdown will be considered as all study visits occurring before March 13, 2020, shutdown will 
be considered from after March 13, 2020.  
iii. Analyses including excluding any screening SDMT for those missing the baseline SDMT.  
iv. Stratified analyses by key covariates of interest; these will be tested using an interaction term.  
1. Disability status (EDSS< median, EDSS≥median), history of depression, number of non-MS 
medications (<5, ≥5), MS subtype (RRMS, progressive), DMT (yes, no)  
v. Assessing predictors of drop-out/early censoring 
1. Baseline covariates will be used to assess whether certain characteristics were associated with 
follow-up time.