Clinical trial NCT03857321
Conditions: Mild Cognitive Impairment Cognitive Impairment
Keywords: Intranasal Delivery of Insulin Cognitive Testing Nasal Insulin
Sponsor: Wake Forest University Health Sciences
Start date: 2019-04-12; Completion date: 2019-09-30
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The SNIFF Device study will involve using a device to administer insulin through each participant's nose or intra-nasally. Insulin is a hormone that is produced in the body. It works by lowering levels of glucose (sugar) in the blood. This study is measuring how much insulin the device delivers. In addition, this study will look at the effects of insulin or placebo administered intra-nasally using a nebulizer-like device on memory, blood, and cerebral spinal fluid.

Detailed description:
The aim of this study is to determine the ability of an intranasal delivery device to increase levels of insulin in cerebrospinal fluid (CSF).

A growing body of evidence suggests that insulin plays a role in normal memory processes and that insulin abnormalities may contribute to cognitive and brain changes associated with Alzheimer's disease (AD). Interestingly, insulin administered to the nasal cavity is transported within a few minutes into the brain, but does not affect blood sugar or insulin levels.

The study will consist of a single site, randomized, double-blind trial comparing the acute effects of INI (20 International Units) or placebo delivered with nebulizer-like device on CSF insulin levels, AD biomarkers and memory. At study entry, participants will be randomized to receive either an acute dose of insulin or placebo first, and the other substance on a second visit. Participants who are cognitively normal or who have aMCI (n=30) will be enrolled. The primary outcome measure will be to test the hypothesis that CSF insulin levels will increase 30 minutes after receiving a 20 International Units dose of insulin delivered with a nebulizer-like device, compared to levels achieved 30 minutes after placebo.

Arms: arm 1: Participants will be randomly assigned to receive regular insulin (U100, 20 IU) administered with an intranasal nebulizer-like device. Participants in this arm will then receive placebo at visit 3 during second intervention period. arm 2: Participants will be randomly assigned to receive placebo administered with an intranasal nebulizer-like device. At visit 3 during second intervention period, participants in this arm will receive insulin.
Interventions: intervention 1: Insulin intervention 2: Placebo intervention 3: intranasal nebulizer-like device
Intervention descriptions: intervention 1: 20 IU Humulin® R U-100 (NDC: 0002-8215, Eli Lilly \& Company) intervention 2: Matching placebo (sterile saline) to 20 IU Humulin® R U-100 intervention 3: Participants will be assigned to receive placebo or regular insulin (U100, 20 IU) administered through an intranasal nebulizer-like device.

Protocol documents:
ICF_001.pdf: 
SNIFF Device
NCT03857321
IRB Approved Date:  9.20.2023


Page 1 of 13
SNIFF Device Consent Form
Version 5.0 – 07-DEC-2020
STUDY OF NASAL INSULIN TO FIGHT FORGETFULNESS 
DEVICE STUDY
“SNIFF – DEVICE”
Informed Consent Form to Participate in Research
Suzanne Craft, Ph.D. Principal Investigator
SUMMARY
You are invited to participate in a research study. The purpose of this research is to determine 
the ability of a device that delivers medications through the nose (Kurve ViaNase device) to 
deliver insulin to the brain effectively. The Kurve ViaNase has not received approval from the 
FDA for how it will be used in this study. 
You are invited to be in this study because you have expressed an interest in participating in a 
research study. Your participation in this research will involve 3 visits and last about 2 – 3 hours 
each for the next 6 weeks. 
Participation in this study will involve using a device to administer insulin through your nose or 
intra-nasally.  All research studies involve some risks.  A risk to this study that you should be 
aware of is a drippy nose.  There is not the possibility that you may benefit from participation in 
this study.  
Your participation in this study is voluntary.  You do not have to participate in this study if you 
do not want to.  There may be other choices available to you.  Some other choices may include 
not participating in this study and to continue to follow up with you doctor.  You will not lose 
any services, benefits, or rights you would normally have if you choose not to participate. 
The remainder of this form contains a more complete description of this study. Please read this 
description carefully. You can ask any questions if you need help deciding whether to join the 
study. The person in charge of this study is Dr. Suzanne Craft. If you have questions, 
suggestions, or concerns regarding this study or you want to withdraw from the study her 
contact information is: 
. 
If you have any questions, suggestions or concerns about your rights as a volunteer in this 
research, contact the Institutional Review Board at 
 or the Research Subject 
Advocate at Wake Forest at 
.
Department/Section of Internal Medicine/Gerontology & Geriatric Medicine
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


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INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. Your participation is voluntary. Please take 
your time in making your decision as to whether or not you wish to participate. Ask your study 
doctor or the study staff to explain any words or information contained in this informed 
consent document that you do not understand. You may also discuss the study with your 
friends and family.
WHY IS THIS STUDY BEING DONE?
Insulin is a hormone that is produced in the body. It works by lowering levels of glucose (sugar) 
in the blood.
During this study, we will determine the effects of insulin or placebo administered intra-nasally 
using the ViaNase device on memory, blood and cerebral spinal fluid. Spinal fluid is a clear, 
colorless fluid which protects your brain and spinal cord. 
Insulin is approved by the US Food and Drug Administration (FDA). However, using it in this way 
is experimental.
In this study you will receive insulin and placebo. Placebo is a substance that is not thought to 
have any effect on your disease or condition. Placebos are used in research studies to see if the 
drug being studied really does have an effect. In this study, we will use saline for the placebo. 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
A total of 30 people will take part in this study here at Wake Forest Baptist Health. In order to 
identify the 30 subjects needed, we may need to screen as many as 50 people because some will 
not qualify to be included in the study.
WHAT IS INVOLVED IN THE STUDY?
You will be randomized to receive either Insulin 20IU (International Units) or Saline (placebo) 
during your baseline study visit and you will receive the opposite at visit 3.  
The insulin or placebo will be administered with the Kurve ViaNase device.
Randomization means that you are put into a group by chance. It is like flipping a coin: you will 
have a one in two chance of being placed in either group. In this study you will receive both, 
insulin and placebo. However, you and the study team will not know which one you receive first 
or second.  
Neither you nor the investigator will know which study drug you are receiving. This is done so 
that a fair evaluation of results can be made. This information is available to the researchers if 
needed in an emergency.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


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Your participation will involve coming to the Sticht Center for Healthy Aging and Alzheimer’s 
Prevention at Wake Forest Baptist Medical Center up to 3 times over the next 6 weeks.  During 
this time, you will complete the series of measurements below. If you have had an evaluation 
with the Sticht Center within 12 months, you may only need to attend two visits. During your 
visits, you will be asked to:

Give blood samples (up to 3 times)

Have a physical exam (1 time)

Take tests of memory/thinking and answer questions about your daily activities (up to 3 
times)

Undergo a lumbar puncture (LP) (2 times)

Have an electrocardiogram (ECG) (1 time). An ECG measures the electrical signals from 
your heart
As a part of the study, we will provide you with ECG and blood test results that you may give to 
your physician. These tests can reveal more information about your heart, blood sugar, 
cholesterol levels, liver function, and kidney function. We will advise you to consult with your 
physician if your tests suggest that you have a medical problem.
DESCRIPTION OF STUDY VISITS
The following procedures will be completed during your screening visit: safety labs, screening 
cognitive testing, ECG, physical exam, collection of demographics, medications and medical 
history. If you have participated in a research study with the Alzheimer’s Disease Research 
Center at Wake Forest School of Medicine within the last 12 months, you may not have to 
repeat all of the screening procedures.  Data used during the completion of the previous study 
will be used in order to avoid duplicating those procedures. Other procedures that occur during 
and upon completion of the SNIFF Device Study will be completed as described.
You will be asked to fast (no food or drinks except water) for 8 hours prior to 2 visits during your 
participation in this study. 
During your participation, we may need to request medical records from your primary care 
doctor. We will ask you to sign a medical records release form giving us permission to request 
these records if needed. 
SCREENING VISIT  
After review of this consent form, you will have the opportunity to ask questions about this 
study.  After your questions have been answered, you will be asked to sign this consent form.
If this information has not previously been collected within the past 12 months, we will 
complete the following: 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


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
Memory screening

Collection of demographic information

Collect a list of current medications

Medical history 

Vital signs - such as pulse, heart rate and blood pressure

Height and weight will be measured

Physical exam, including a nasal examination

Electrocardiogram (ECG) will be completed

About 2 teaspoons of blood will be drawn 
BLOOD COLLECTION
Approximately 2 ½ teaspoons of blood will be drawn from a vein for routine laboratory tests to 
ensure that there are no other medical conditions that might interfere with your participation. 
In the event any of your lab results fall just outside of the required range, you may be asked to 
return to the clinic for a repeat blood collection. About 1 teaspoon will be drawn for optional 
DNA storage and to determine your apolipoprotein (ApoE) genotype. 
Previous studies have shown that the ApoE gene may be linked to how well some people do on 
memory tests and can also identify volunteers who may have an increased risk of developing 
AD. However, this test alone does not predict who will or will not develop AD as there are many 
other factors involved. The ApoE test is for research purposes only; you will not receive the 
results and they will not become part of your medical record.
This visit will last between 3 and 4 hours.
BASELINE VISIT 2
This visit will take approximately 2 hours to complete. You will be asked to fast for 8 hours prior 
to this visit. 
Visit 2 includes the following: 

A nasal exam will take place

You will receive a dose of 20IU insulin or placebo administered with the ViaNase device 

We will review your current medications and any changes in your health since your last 
visit 

A brief memory test will be completed

About 3 teaspoons of blood will be collected 

A lumbar puncture will be performed
Study staff will call you the following day after your baseline visit to see how you are.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


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SNIFF Device Consent Form
Version 5.0 – 07-DEC-2020
VISIT 3 
This visit will take approximately 2 hours to complete and will occur from 2 to 6 weeks after 
Visit 2. You will be asked to fast for 8 hours prior to this visit. 
Visit 3 includes the following:

A nasal exam will take place

You will receive a dose of 20IU insulin or placebo administered with the ViaNase device 

We will review of your current medications and any changes in your health since your 
last visit 

A brief memory test will be completed

About 3 teaspoons of blood will be collected 

A lumbar puncture will be performed
Study staff will call you the following day to see how you are.
LUMBAR PUNCTURE  
An LP is a procedure in which a small amount of the fluid that 
surrounds the brain and spinal cord is removed from the lower 
back. You will be asked not to eat or drink anything other than 
water for at least 8 hours before the lumbar puncture visit. 
However, because you will need to be well hydrated, please 
drink plenty of water. You will be positioned sitting up and bent 
forward or lying on your side and your lower back will be 
cleaned with antiseptic. Local anesthetic (lidocaine, 1%) will be 
injected into the skin of your lower back. When the area is 
numb, a very thin needle will be inserted into the spinal canal in 
the lower back, well below the level where the spinal cord ends, 
and about 25 milliliters (less than 2 tablespoons) of fluid will be 
removed.  Your body replaces this spinal fluid within 1-2 hours.  
After the LP is complete, you will remain in the clinic while 
resting quietly for about half an hour. You will be given 
something to eat and drink and detailed instructions on self-
care after the LP will be provided.  Specifically, you will be asked 
to avoid any strenuous physical activity for 24 hours.  
MEMORY ASSESSMENTS
You will be asked to do several tasks, such as remembering stories and lists of words. You may 
choose not to answer any questions or items in any assessment.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


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BLOOD COLLECTION 
Approximately 10 teaspoons of blood will be drawn from a vein during your participation. Your 
blood will be used for routine laboratory tests and stored for future research.
KURVE VIANASE DEVICE
The Kurve ViaNase device will be used in this study to administer the insulin or placebo intra-
nasally.  This device is investigational and has not been approved by the FDA. By participating 
in this research study, you will not have ownership rights to the Kurve ViaNase device. 
This device has been previously used in research here at Wake Forest School of Medicine to 
administer insulin intra-nasally.  
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for about 2 months. You can stop participating at any time. If you 
decide to stop participating in the study, we encourage you to talk to the investigators or study 
staff first to learn about any potential health or safety consequences. 
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you.  You should discuss the risk of being in this study 
with the study staff.  There are no known risks associated with receiving the study placebo. 
Risks and side effects related to your participation in this study are outlined below:
NASAL INSULIN ADMINISTRATION 
No serious adverse reactions to insulin given through the nasal passages have been observed 
in similar studies. Insulin given in this manner has not been associated with low blood sugar 
in our previous studies. 
A few subjects in previous studies complained of “drippy nose” after being given the study 
drug, but these symptoms did not persist beyond the initial use of the study drug.  As with 
any drug, there may be unexpected side effects that we are not aware of. 
RISKS ASSOCIATED WITH USE OF THE NASAL DEVICE 
There are risks that may occur from use of the nasal device, although these are not expected 
to be serious, as you will be shown how to use the device by study personnel who will be 
present during its use. Risks may include discomfort to your eyes, face and/or nose. These 
risks are not long lasting and will subside without medical treatment.
BLOOD COLLECTION 
Removal of blood by a needle and syringe poses a small risk of pain or bruising at the site of the 
needle stick, but this is temporary.  Some people may experience fainting or dizziness, and 
there is also a slight risk of infection at the site of the needle stick.  To minimize these risks, 
experienced medical personnel will collect all blood and sterile conditions will be maintained.  
About 10 teaspoons of blood will be taken during the entire course of this study and your body 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


Page 7 of 13
SNIFF Device Consent Form
Version 5.0 – 07-DEC-2020
will readily produce new blood to make up for the loss. 
COGNITIVE TESTING 
Memory tests may be slightly frustrating or produce fatigue and boredom.
LUMBAR PUNCTURES (LP) 
During and after the procedure, you may have temporary pain or discomfort at the insertion 
site in your back. You may feel faint. You may experience a mild headache, backache or sore 
muscles in your neck from the positioning required for the procedure.  Rarely, a low pressure 
headache may develop after the procedure due to leakage of spinal fluid. If this headache 
persists it may require additional treatment.  Uncommonly a blood patch (injection of some of 
your blood into the puncture site to patch the spinal fluid leak) may be required. This typically 
relieves the headache immediately.  Because we use a very small, specialized needle in our 
study, the risk of a low pressure headache after a lumbar puncture is less than 1-2%. 
Although very rare, it is possible that you may have an allergic reaction to the local anesthetic 
(lidocaine l%) used for the LP. This would cause swelling and a rash on your skin where the 
anesthetic was injected. Please tell us if you have ever had a reaction to local anesthetic before 
(such as when you were visiting the dentist). Potential but very rare risks of an LP include 
infection of the skin or in the spinal fluid space (meningitis), bleeding, or damage to nerves in 
your back. The risk of these is very small. To minimize these risks, the LP procedure will be 
performed by experienced medical professionals who are specifically trained to carry out this 
procedure.
OTHER POTENTIAL RISKS
There also may be other side effects that we cannot predict. You should tell the research staff 
about all the drugs, vitamins and supplements you take and any medical conditions you have. 
This may help avoid side effects, interactions and other risks.
CONFIDENTIALITY  
Taking part in this research study may involve providing information that you consider 
confidential or private. Efforts, such as coding research records, keeping research records 
secure and allowing only authorized people to have access to research records, will be made to 
keep your information safe. We will do our best to protect your confidential information.
CERTIFICATE OF CONFIDENTIALITY
To help us protect your privacy, the National Alzheimer’s Coordinating Center has obtained a 
Certificate of Confidentiality from the National Institutes of Health. The Certificate of 
Confidentiality is needed because sensitive information will be collected during the course of 
this study. The researchers can use this Certificate to legally refuse to disclose information that 
may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings, for example, if there is a court subpoena. The researchers will use the Certificate 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


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to resist any demands for information that would identify you, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of Federally-funded projects or for 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA). You should understand that a Certificate of Confidentiality does not 
prevent you or a member of your family from voluntarily releasing information about yourself 
or your involvement in this research.
If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers may not use the Certificate to withhold that information. The 
Certificate of Confidentiality does not prevent the investigator from notifying state or local 
authorities of North Carolina if he/she obtains evidence of abuse or if you threaten violence to 
yourself or others.
FUTURE RESEARCH & STORAGE OF BIOLOGICAL SAMPLES
If you agree to participate in this study, blood and spinal fluid will be stored and used for future 
research to learn more about other diseases. Your samples will be obtained in the Sticht Center 
at Wake Forest Baptist Medical Center. The samples will be stored at Wake Forest Baptist 
Medical Center. Your samples may be shared with other researchers when that is the best way 
to advance scientific knowledge and public health. The National Institutes of Health (NIH) and 
other central repositories have developed special data (information) banks that collect the 
results of genetic studies, especially when the research looks at all or large sections of 
individual’s genetic code. This is often called whole genome sequencing. Genomic information 
relates to the structure and function of all of the genetic material in the body. These central 
banks will store your genetic information and give them to other qualified and approved 
researchers to do more studies. The data that we share with federal repositories will be coded 
in such a way that you would not be able to be identified. We will not share your name, birth 
date, or any other information that could directly identify you. The link to the code would be 
kept securely at the Wake Forest Baptist Health. Even so, there is a possibility that when your 
genomic information is combined with other information available to researchers, either now 
or in the future, they may be able to identify a group you belong to (like an ethnic group or a 
disease population) or, less likely, you personally. NIH prohibits people from trying to identify 
individuals whose genomic information is in an NIH-designated repository. 
Your blood and spinal fluid samples will be used only for research and will not be sold. The 
findings from this research may result in the future development of products that are of 
commercial value. There are no plans to share any of the profits with you which may occur as a 
result of the research.
We do not think that there will be further risks to your privacy and confidentiality by sharing 
your genetic information with these banks. However, we cannot predict how genetic 
information will be used in the future. The genetic data could be used to study a wide variety of 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


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diseases.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
There is no benefit to you from participating in this study. The results of the study will be 
used to guide the development of future studies of intranasal insulin as a therapy for 
Alzheimer’s disease and memory loss.
WHAT OTHER CHOICES ARE THERE?
This is not a treatment study. You may choose not to participate. 
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you about your health or behaviors 
is considered Protected Health Information. Some of the information we will collect for this 
research study includes:
•
demographic information
•
social security number (required in order to receive travel reimbursement)
•
emergency contact information
•
medical record release form (required if we need to request your medical records)
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study may be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical 
Center operations.
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health 
information”) may be given to others during and after the study. This is for reasons such as to 
carry out the study, to determine the results of the study, to make sure the study is being done 
correctly, to provide required reports and to get approval for new products.  
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; 
investigators at other sites who are assisting with the research; central laboratories, reading 
centers or analysis centers; the Institutional Review Board; representatives of Wake Forest 
University Health Sciences and North Carolina Baptist Hospital; representatives from 
government agencies such as the Food and Drug Administration (FDA) or the Office of Human 
Research Protections (OHRP), the Department of Health and Human Services (DHHS) and 
similar agencies in other countries. 
 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


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Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state 
privacy regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
Monitors, auditors, IRB or other regulatory agencies will be granted direct access to the 
participant’s original medical record for verification of clinical trial procedures or data, without 
violating confidentiality of the participant and to the extent permitted by other applicable laws.
If required by law or court order, we might also have to share your Protected Health 
Information with a judge, law enforcement officer, government agencies, or others. If your 
Protected Health Information is shared with any of these groups it may no longer be protected 
by federal or state privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for an indeterminate period of time. This authorization does not 
expire. You will not be able to obtain a copy of your Protected Health Information in the 
research records until all activities in the study are completely finished.
You can tell Dr. Suzanne Craft that you want to take away your permission to use and share 
your Protected Health Information at any time by sending a letter to this address:
Dr. Suzanne Craft
However, if you take away permission to use your Protected Health Information you will not be
able to be in the study any longer. We will stop collecting any more information about you, but
any information we have already collected can still be used for the purposes of the research
study. By signing this form, you give us permission to use your Protected Health Information for 
this study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important 
information is available to doctors in case of an emergency.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time.
WHAT ARE THE COSTS?
There are no costs to you for taking part in this study. All study costs, including any study
drugs and procedures related directly to the study, will be paid for by the study. Costs for
your regular medical care, which are not related to this study, will be your own responsibility.
WILL YOU BE PAID FOR PARTICIPATING?
You will receive $100 for the completing the Baseline Visit 2 and $100 for completing Visit 3 for 
a total of $200. 
To receive payment, you must provide your social security number, name and address so that 
we can comply with IRS (Internal Revenue Service) reporting requirements. When payments are
reported to the IRS we do not let them know what the payment is for, only that you have been
paid. If you do not wish to provide this information you can still take part in this study but you
will not be paid.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by the Sticht Center for Healthy Aging and Alzheimer’s Prevention 
at Wake Forest School of Medicine. 
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A RESULT OF 
PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this 
policy the reasonable costs of these necessary medical services will be paid, up to a maximum 
of $25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. 
The Wake Forest University School of Medicine, and the North Carolina Baptist Hospitals, 
Incorporated does not assume responsibility to pay for these medical services or to provide any 
other compensation for such injury or illness. Additional information may be obtained from the 
Medical Center’s Director of Risk and Insurance Management, at 
.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required 
by law to report any payments made to cover the care of any persons who are members of a 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


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government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study, we 
encourage you to talk to the investigators or study staff first to learn about any potential health 
or safety consequences. The investigators also have the right to stop your participation in the 
study at any time. This could be due to unexpected reactions to the study drug, failing to follow 
instructions or if the study is stopped early.
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Dr. Suzanne Craft at 
 (after hours number 
 ask for the 
Geriatrician on call and reference the SNIFF Device study).
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
.
You will be given a copy of this signed consent form. 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024


Page 13 of 13
SNIFF Device Consent Form
Version 5.0 – 07-DEC-2020
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
We can send copies of your test results to your personal physician. Even if you do not wish to 
have any of your medical information sent to your physician, you can still participate in this 
research study. 
Do you request that we send important medical findings from your study ECG and/or 
laboratory tests to your personal physician? 
[   ] Yes
[   ] No______Initials____________
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
  
Legally Authorized Representative Name (Print):_________________________
 
Relationship to the Subject:_____________________________
Legal Representative Signature: _________________________ Date:_________ Time:________ am pm
The above named Legally Authorized Representative has legal authority to act for the research 
subject based upon (specify health care power of attorney, spouse, parent, etc.).
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00055429
Meeting Date Approved 9/20/2023          
Version Valid Until: 9/19/2024

Prot_SAP_002.pdf: 
Official Title:  Study of Nasal Insulin to Fight Forgetfulness - Device Study
NCT03857321
IRB Approval Date:  12/07/2020


07-December-2020
IND #: 119232
Page 1 of 33 
Device Study for Intranasal Delivery of Insulin 
SNIFF Device 
IND #: 119232 
PROJECT DIRECTOR / 
IND SPONSOR 
Suzanne Craft, Ph.D. 
Wake Forest University 
School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC  27157-1207 
suzcraft@wakehealth.edu 
Tel: 336-713-8832 
PROTOCOL VERSION 
Final Protocol v5.0 
07-December-2020


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TABLE OF CONTENTS 
1.0       INTRODUCTION ............................................................................................................ 8 
1.1 
Primary Aim ................................................................................................................ 8 
1.1.1 Secondary Aim 1 ......................................................................................................... 8 
1.1.2 Secondary Aim 2 ......................................................................................................... 8 
2.0 
BACKGROUND AND SIGNIFICANCE.............................................................................. 8 
2.1 
Rationale for Insulin..................................................................................................... 8 
2.2 
Insulin as a Therapeutic Agent .................................................................................... 9 
2.2.1 Intranasal Pathways to the CNS .................................................................................. 9 
2.2.2 Intranasal Delivery System Devices .......................................................................... 10 
3.0 
PRELIMINARY STUDIES ................................................................................................ 10 
3.1 
Participants ............................................................................................................... 11 
3.2 
Procedures ................................................................................................................ 12 
3.3 
Safety and Compliance ............................................................................................. 12 
3.4 
Statistical Analyses ................................................................................................... 12 
3.5 
Results: Cognitive and Functional Outcome Measures ............................................. 13 
3.6 
Results: AD Biomarkers ............................................................................................ 14 
3.7 
Results: FDG-PET CMRglc ....................................................................................... 14 
3.8 
Safety and Compliance ............................................................................................. 15 
3.9 
Implications ............................................................................................................... 15 
4.0 
PRELIMINARY STUDY 2 ................................................................................................ 15 
4.1 
Rationale for Dosage Selection ................................................................................. 17 
4.2 
Rationale for Primary and Secondary Outcome Measures ........................................ 17 
4.3 
Rationale for Design of Trial ...................................................................................... 17 
4.4 
Rationale for Biofluids ............................................................................................... 17 
5.0 
STUDY OVERVIEW ........................................................................................................ 17 
5.1 
Study Population ....................................................................................................... 17 
5.2 
Diagnosis Criteria ...................................................................................................... 18 
5.3  
Inclusion Criteria ....................................................................................................... 18 
5.4 
Exclusion Criteria ...................................................................................................... 18 
5.5 
Recruitment and Retention Strategies ....................................................................... 19 
6.0 
STUDY TIMELINE ........................................................................................................... 19 
7.0 
DESCRIPTION OF STUDY VISITS ................................................................................. 19 
7.1 
Screening (Visit 1) ..................................................................................................... 19 
7.2 
Baseline (Visit 2) ....................................................................................................... 20 
7.3 
Visit 3 ........................................................................................................................ 20 
8.0 
STUDY-SPECIFIC PROCEDURES ................................................................................. 20 
8.1 
Memory Evaluation Instruments Administered to the Participant ............................... 20 
8.2 
Clinical and Functional Evaluations ........................................................................... 20 
8.2.1 Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB) ....................................... 20 
9.0 
STUDY METHODS .......................................................................................................... 21 
9.1 
Safety Assessments .................................................................................................. 21 
9.2 
Physical and Neurological Examination ..................................................................... 21 
9.3 
Electrocardiogram (ECG) .......................................................................................... 21 
9.4 
Clinical Laboratory Evaluations ................................................................................. 21 
10.0 BIOMARKER STUDIES .................................................................................................. 21 
10.1 
CSF ........................................................................................................................... 21 
10.2 
Blood Collection at Lumbar Puncture Visits ............................................................... 22 


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10.3 
Genetic Samples, Storage and Future Use ............................................................... 22 
11.0 STATISTICAL PLAN ....................................................................................................... 22 
11.1 
Power Analyses ........................................................................................................ 22 
12.0 POTENTIAL RISKS ........................................................................................................ 22 
12.1 
Safety of Intranasal Insulin ........................................................................................ 22 
12.2 
Risks associated with use of the ViaNase® device .................................................... 23 
12.3 
Lumbar Puncture ....................................................................................................... 23 
12.4 
Blood Draw ............................................................................................................... 23 
13.0 PERSONNEL REQUIREMENTS ..................................................................................... 23 
14.0 STUDY DRUG ................................................................................................................. 24 
14.1 
Humulin® R U-100 Insulin .......................................................................................... 24 
14.2 
Placebo (Sterile Saline) ............................................................................................. 24 
14.3 
Randomization .......................................................................................................... 24 
14.4 
Blinding ..................................................................................................................... 24 
14.5 
Study Drug Dispensing .............................................................................................. 24 
14.6 
Intranasal Administration ........................................................................................... 24 
14.7 
Storage ..................................................................................................................... 24 
14.8 
Drug Accountability ................................................................................................... 25 
15.0 ADVERSE EVENTS ........................................................................................................ 25 
15.1 
Definition ................................................................................................................... 25 
15.2 
Following Up on AEs ................................................................................................. 25 
16.0 SERIOUS ADVERSE EVENTS (SAE) ............................................................................. 25 
16.1 
Definition ................................................................................................................... 25 
16.2 
Reporting SAEs ......................................................................................................... 25 
17.0 ETHICS & REGULATORY CONSIDERATIONS ............................................................. 26 
17.1 
Ethical Standard ........................................................................................................ 26 
17.2 
Institutional Review Board (IRB) ................................................................................ 26 
17.3 
Informed Consent & HIPAA Authorization ................................................................. 26 
17.4 
Participant Confidentiality | HIPAA ............................................................................ 26 
18.0 GENETIC RESEARCH & STORAGE OF GENETIC MATERIAL .................................... 27 
18.1 
Storage of Biospecimen Samples.............................................................................. 27 
19.0 RISKS AND BENEFITS ASSOCIATED WITH THIS STUDY .......................................... 27 
19.1 
Potential Benefits of the Proposed Research to Human Subjects.............................. 27 
19.2 
Inclusion of Women and Minorities ............................................................................ 27 
19.3 
Inclusion of Children as Participants in Research Involving Human Subjects ............ 27 
19.4 
Data and Safety Monitoring Plan and Board .............................................................. 28 
20.0 PUBLICATION POLICY .................................................................................................. 28 
21.0 SHARING OF FINAL RESEARCH DATA ....................................................................... 28 
22.0 TABLE 4: SCHEDULE OF PROCEDURES AND ASSESSMENTS ................................ 29 
23.0 LITERATURE CITED ...................................................................................................... 30 
 
 


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STUDY GLOSSARY 
 
3MSE 
MODIFIED MINI-MENTAL STATUS EXAM 
AΒ 
BETA AMYLOID 
AD 
ALZHEIMER’S DISEASE 
ADAS-COG 
ALZHEIMER’S DISEASE ASSESSMENT SCALE – COGNITIVE 
SUBSCALE 
ADCS 
ALZHEIMER’S DISEASE COOPERATIVE STUDY 
ADCS-ADL 
ALZHEIMER’S DISEASE COOPERATIVE STUDY - ACTIVITIES OF 
DAILY LIVING 
ADEAR 
ALZHEIMER’S DISEASE EDUCATION AND REFERRAL CENTER 
ADNI 
ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE 
AE 
ADVERSE EVENT 
AMCI 
AMNESTIC MILD COGNITIVE IMPAIRMENT 
ANCOVA 
ANALYSIS OF COVARIANCE 
APOE/APOE4 
APOLIPOPROTEIN (APOE) EPSILON 4 (APOE4) 
BDNF 
BRAIN-DERIVED NEUROTROPHIC FACTOR 
BID | BID 
BIS IN DIE (TWICE A DAY) 
BUN 
BLOOD UREA NITROGEN 
CDR-SB 
CLINICAL DEMENTIA RATING – SUM OF BOXES 
CFR 
CODE OF FEDERAL REGULATIONS 
CMRGLC 
CEREBRAL METABOLIC RATE OF GLUCOSE UTILIZATION 
CNS 
CENTRAL NERVOUS SYSTEM 
CPD 
CONTROLLED PARTICLE DISPERSION 
CPK 
CREATINE PHOSPHOKINASE 
CREB 
CAMP RESPONSE ELEMENT-BINDING PROTEIN 
CRF/E-CRF 
CASE REPORT FORM/ELECTRONIC CASE REPORT FORM  
CSF 
CEREBRAL SPINAL FLUID 
DNA 
DEOXYRIBONUCLEIC ACID 
DSMB 
DATA & SAFETY MONITORING BOARD 
DSM-IV 
DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL 
DISORDERS, FOURTH EDITION 
DSRS 
DEMENTIA SEVERITY RATING SCALE 
EAG 
ESTIMATED AVERAGE GLUCOSE 
ECG 
ELECTROCARDIOGRAM 
EDC 
ELECTRONIC DATA CAPTURE 


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EDTA 
ETHYLENE DIAMINE TETRA ACETIC ACID 
ELISA 
ENZYME-LINKED IMMUNOSORBENT ASSAY 
FCSRT 
FREE AND CUED SELECTIVE REMINDING TEST  
FDA 
FOOD AND DRUG ADMINISTRATION 
FDG PET 
FLUORO DEOXY GLUCOSE POSITRON EMISSION TOMOGRAPHY 
GCP 
GOOD CLINICAL PRACTICE 
GEE 
GENERALIZED ESTIMATING EQUATION 
GGT 
GAMMA GLUTAMYL TRANSPEPTIDASE 
GSK3Β 
GLYCOGEN SYNTHASE KINASE 3 BETA 
HGA1C 
HEMOGLOBIN A1C 
HC 
HOMOCYSTEINE 
HCT 
HEMATOCRIT 
HCY 
HOMOCYSTEINE 
HEENT 
HEAD | EARS | EYES | NOSE | THROAT 
HGB 
HEMOGLOBIN 
HIPAA 
HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT 
HOMA-IR 
HOMEOSTATIS MODEL ASSESSMENT OF INSULIN RESISTANCE 
ICF 
INFORMED CONSENT FORM 
ICH 
INTERNATIONAL CONFERENCE ON HARMONISATION 
IDE 
INSULIN DEGRADING ENZYME 
IGF-1 
INSULIN-LIKE GROWTH FACTOR-1 
INI 
INTRANASAL INSULIN  
IRB 
INSTITUTIONAL REVIEW BOARD 
ITT 
INTENT-TO-TREAT 
LDH 
LACTATE DEHYDROGENASE 
LP 
LUMBAR PUNCTURE 
LTP 
LONG TERM POTENTIATION 
MCV 
MEAN CORPUSCULAR VOLUME 
ML 
MILLILITER 
MMA 
METHYLMALONIC ACID 
MMSE 
MINI MENTAL STATE EXAMINATION 
MPRAGE 
MAGNETIZATION PREPARED RAPID GRADIENT ECHO 
MR/MRI 
MAGNETIC RESONANCE / MAGNETIC RESONANCE IMAGING 
NBAC 
NATIONAL BIOETHICS ADVISORY COMMISSION 


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NIA 
NATIONAL INSTITUTE ON AGING 
NIH 
NATIONAL INSTITUTES OF HEALTH 
NINCDS/ADRDA 
NATIONAL INSTITUTE OF NEUROLOGICAL AND COMMUNICATIVE 
DISEASES AND STROKE / ALZHEIMER'S DISEASE AND RELATED 
DISORDERS ASSOCIATION 
NBDA 
N-METHYL – D-ASPARTATE 
NSAID 
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS 
OHRP 
OFFICE FOR HUMAN RESEARCH PROTECTIONS 
PBMC 
PERIPHERAL BLOOD MONONUCLEAR CELL 
PD 
PROJECT DIRECTOR  
PCP 
PRIMARY CARE PHYSICIAN 
PET 
POSITRON EMISSION TOMOGRAPHY 
PHI 
PROTECTED HEALTH INFORMATION 
PI 
PRINCIPAL INVESTIGATOR 
PID 
PARTICIPANT ID  
RBC 
RED BLOOD CELL 
RE 
RANDOM EFFECTS 
ROI 
REGIONS OF INTEREST 
SAE 
SEVERE ADVERSE EVENT 
SD 
STANDARD DEVIATION 
SGOT 
SERUM GLUTAMIC OXALOACETIC TRANSAMINASE 
SGPT 
SERUM GLUTAMIC PYRUVIC TRANSAMINASE 
T 
TESLA 
TSH 
THYROID STIMULATING HORMONE 
U/A 
URINALYSIS 
WBC 
WHITE BLOOD COUNT 
 
 
 


07-December-2020 
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TITLE 
 
 
 
Device Study for Intranasal Delivery of Insulin 
PROJECT DIRECTOR 
Suzanne Craft, Ph.D. 
STUDY SPONSOR 
Wake Forest University Health Sciences 
STUDY PHASE 
 
 
 
Phase II 
INDICATION 
 
 
 
Preclinical AD, Amnestic mild cognitive impairment (aMCI) or mild 
Alzheimer’s disease (AD) 
AIM OF STUDY 
To determine the ability of an intranasal delivery device (Kurve ViaNase 
device) to increase levels of insulin in cerebrospinal fluid (CSF) 
PRIMARY OBJECTIVE 
To test the hypothesis that CSF insulin levels will increase 30 minutes 
after receiving a 20 International Units dose of insulin delivered with 
either the ViaNase device, compared to levels achieved 30 minutes 
after placebo.  
SECONDARY OBJECTIVES 
1. To test the hypothesis that memory performance measured 
with a list learning test (Auditory Verbal Learning Test) will be 
enhanced after insulin administration relative to placebo 
2. To test the hypothesis that the CSF Aβ42/40 and the CSF 
Aβ/tau ratios will increase after insulin administration relative 
to placebo 
PRIMARY OUTCOME MEASURE 
CSF insulin 
SECONDARY OUTCOME MEASURES  
Memory test, CSF insulin, A40, A42, total tau, and phospho-tau 181 
STUDY DESIGN 
 
Single-site, double-blind, placebo-controlled study  
SAMPLE SIZE 
 
• 
n=30 
SUMMARY OF KEY ELIGIBILITY 
CRITERIA  
 
• 
Cognitively normal or 
• 
 Diagnosis of aMCI (Petersen criteria)  
• 
Age: 55 to 85 yrs (inclusive) 
DRUG DOSAGE & FORMULATION 
20  International Units Humulin® R U-100 or matching placebo (saline) 
DURATION OF PARTICIPATION 
The approximate timeline for this 21 month study is projected as: 1) 
approximately 1 months for study startup activities including IND 
submission and IRB approval, and training; 2) approximately 18 months 
for data collection; 3) 2 months for assay and data analysis 
PLACEBO 
A matching placebo (sterile saline) will be used 
ROUTE OF ADMINISTRATION 
 
Intranasal 
PROCEDURES 
 
Physical and neurological exam, nasal examination, lumbar puncture, 
Vitals, Clinical Labs, CSF and blood analysis & banking and 
genotyping. 


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1.0       INTRODUCTION  
An urgent need exists to find effective treatments for AD that can arrest or reverse the disease at its 
earliest stages. The emotional and financial burden of AD to patients, family members, and society is 
enormous, and is predicted to grow exponentially as the median population age increases. Current 
FDA-approved therapies are modestly effective at best. This study will provide information to assist in 
examining a novel therapeutic approach using intranasally administered insulin (INI) that has shown 
promise in short-term clinical trials. In a recent longer term trial in which INI was delivered with two 
devices (Kurve ViaNase device and Impel Precision Olfactory Delivery (POD) device, a different pattern 
of results was observed between the two devices, suggesting that differences in delivery systems can 
impact the therapeutic effects of insulin. The proposed proof of concept study will examine whether the 
device that was associated with clinical improvement is able to increase CSF insulin levels 30 minutes 
after administration, a timepoint which has been show to represent the greatest increase in CSF insulin 
in a previous study (Born et al. Nature Neuroscience, 2002 Jun;5(6):514-6). If successful, information 
gained from the study will inform the design of future Phase III trials of intranasal insulin.  
 
1.1 
Primary Aim 
To test the hypothesis that CSF insulin levels will increase 30 minutes after receiving a 20 International 
Units dose of insulin delivered with the ViaNase or device, compared to levels achieved 30 minutes 
after placebo 
 
 Secondary Aim 1 
1. To test the hypothesis that memory performance measured with a list learning test (Auditory 
Verbal Learning Test) will be enhanced after insulin administration relative to placebo  
 
 Secondary Aim 2 
 
1. To test the hypothesis that the CSF Aβ42/40 and the CSF Aβ42/tau ratios will increase after 
insulin administration relative to placebo 
 
2.0 
BACKGROUND AND SIGNIFICANCE 
 
2.1 
Rationale for Insulin 
The rationale for the study is derived from growing evidence that insulin carries out multiple functions 
in the brain, and that insulin dysregulation may contribute to AD pathogenesis (Craft and Watson 2004). 
Insulin receptors are densely localized in the hippocampus and in entorhinal, frontal, and other cortical 
areas; they are found primarily in synapses, where insulin signaling modulates synaptogenesis and 
synaptic remodeling (Chiu, Chen et al. 2008, Zhao and Townsend 2009). Insulin facilitates memory at 
optimal levels, possibly through synaptic effects and enhanced hippocampal glucose utilization (Grillo, 
Piroli et al. 2009).  
 
The importance of insulin in normal brain function is underscored by evidence that insulin dysregulation 
contributes to the pathophysiology of AD, a disorder characterized in its earliest stages by synaptic loss 
and memory impairment. Hoyer and colleagues first identified a reduction in insulin receptors and 
signaling markers in the AD brain (Frolich, Blum-Degen et al. 1998). This initial finding has been 
confirmed and extended by other investigators, who have demonstrated reduced CSF insulin in patients 
with AD and MCI (Craft, Peskind et al. 1998, Gil-Bea, Solas et al. 2010), and reduced insulin and IGF-
I messaging with increasing AD pathology and cholinergic deficit (Rivera, Goldin et al. 2005). Insulin 
has a close relationship with β-amyloid, the toxic peptide produced by cleavage of the amyloid precursor 
protein (Zhao and Townsend 2009). In AD, insoluble Aβ peptides deposit in brain parenchyma and 
vasculature. Soluble Aβ species, particularly oligomers of the 42 amino acid specie (Aβ42), have 
synaptotoxic effects, possibly resulting in synapse loss, which is the earliest structural defect observed 
in AD (Selkoe 2008). Insulin reduces oligomer formation and protects against Aβ-induced 


07-December-2020 
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Page 9 of 33 
synaptotoxicty and LTP disruption (Gasparini, Gouras et al. 2001, De Felice, Vieira et al. 2009, Lee, 
Kuo et al. 2009). Interestingly, Aβ also regulates brain insulin signaling. Soluble Aβ binds to the insulin 
receptor and disrupts insulin signaling and LTP induction in mouse hippocampal slice preparations 
(Townsend, Mehta et al. 2007). These effects could be prevented by exposing tissue to insulin prior to 
Aβ exposure. Insulin pre-treatment also prevented synthetic soluble Aβ oligomers from downregulating 
plasma membrane insulin receptors and reducing dendritic spines in primary hippocampal neurons (De 
Felice, Vieira et al. 2009). Insulin may also modulate Aβ degradation by regulating expression of insulin 
degrading enzyme (IDE), a metalloprotease that catabolizes insulin (Zhao, Teter et al. 2004). 
Collectively, these findings suggest that soluble Aβ may induce central nervous system (CNS) insulin 
resistance and synapse loss, and that treatment with insulin may prevent these pathological processes. 
 
A role for insulin has also been suggested for other AD-related mechanisms. Insulin inhibits 
phosphorylation of tau, through its regulation of glycogen synthase kinase 3β, a downstream target in 
the insulin signaling pathway (Hong and Lee 1997). Insulin dysregulation is also associated with 
oxidative stress, inflammation, and impaired neurogenesis (Craft and Watson 2004). Thus, insulin has 
been implicated in numerous processes related to AD pathophysiology, suggesting that correction of 
insulin dysregulation may be a therapeutic strategy with considerable clinical and scientific significance. 
 
2.2 
Insulin as a Therapeutic Agent 
The study uses insulin as a therapeutic agent and intranasal administration focusing on nose to brain 
transport as a mode of delivery. As reviewed above, insulin has pleiotropic effects on pathways 
implicated in AD pathogenesis. As such, augmenting CNS insulin is an alternative approach to AD 
therapy, in contrast to the majority of therapeutic approaches that focus on narrowly defined 
mechanisms such as acetylcholine modulation or amyloid accumulation. Restoring normal brain insulin 
levels in persons with AD may improve cognition and AD pathologic processes. Such an approach is 
possible with an intranasal administration technique. 
 
 Intranasal Pathways to the CNS  
Olfactory sensory neurons are directly exposed to the external environment in the upper nasal cavity 
while their axons extend through the cribriform plate to the olfactory bulb. Following intranasal 
administration, drugs can be directly transported to the CNS, bypassing the periphery. Several 
extraneuronal and intraneuronal pathways from the nasal cavity to the CNS are possible. The 
extraneuronal pathways appear to rely on bulk flow transport through perineural channels to the brain 
or CSF. In recent studies, labeled INI or a closely related peptide, insulin-like growth factor-I (IGF-I), 
were administered to rodents (Thorne, Pronk et al. 2004, Francis, Martinez et al. 2008). Within 30 
minutes, signal was detected along olfactory and trigeminal channels, as well as in the hippocampus, 
amygdala and rostral and caudal cortex. An additional extracellular pathway was identified with quick 
access to the CSF after absorption into the submucosa along the olfactory nerve and cribriform plate 
(Born, Lange et al. 2002, Frey 2002, Thorne, Pronk et al. 2004). These extracellular pathways provide 
direct access to the CNS within minutes of intranasal administration. Additionally, an intraneuronal 
pathway delivers drugs to the CNS hours or days later (Broadwell and Balin 1985, Shipley 1985, Baker 
and Spencer 1986, Balin, Broadwell et al. 1986). Viruses and microorganisms (Fairbrother and Hurst 
1930, Faber 1938, Bodian and Howe 1941), amino acids (Weiss and Holland 1967), and proteins 
(Kristensson and Olsson 1971, Shipley 1985, Thorne, Emory et al. 1995) can also enter the CNS via 
nasal routes. In particular, substances with lower molecular weights are more likely to be transported 
to the CNS along intranasal pathways (Sakane, Akizuki et al. 1995). Insulin’s molecular weight of about 
5800 g/mol makes it a good candidate for intranasal delivery. Animal studies show labeled uptake to 
hippocampus and rostral and caudal cortex following INI administration (Francis, Martinez et al. 2008). 
In a murine diabetes model, INI reduced brain atrophy, while increasing synaptic markers and activation 
of Akt, CREB, and GSK3β. Memory enhancement was also observed on Water Maze and radial arm 
tasks (Francis, Martinez et al. 2008). Human functional and cognitive studies of INI also support insulin’s 
transport to the CNS. INI treatment increases CSF insulin levels and induces changes in auditory-
evoked brain potentials compared to placebo (Kern, Born et al. 1999). INI improves verbal memory 


07-December-2020 
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Page 10 of 33 
acutely in persons with AD and aMCI without affecting plasma insulin or glucose levels at the dose 
included in the study (Reger, Watson et al. 2006). Regarding chronic effects, several studies reported 
that 2 months of daily insulin administration (160 International Units/day) significantly improves verbal 
memory in young healthy adults (Benedict, Hallschmid et al. 2004, Stockhorst, de Fries et al. 2004, 
Benedict, Kern et al. 2008, Hallschmid, Benedict et al. 2008, Stockhorst, de Fries et al. Submitted for 
publication). Finally, Section 3.0 presents results in a preliminary study in which insulin was 
administered to adults with AD or aMCI for 4 months. 
 
 Intranasal Delivery System Devices 
The intranasal delivery device investigated in this study has been used in ongoing and previous studies 
at Wake Forest:  
 
1) An investigational device (ViaNaseTM) developed by Kurve Technology (Bothell, WA) will be 
used in this study; the current device is identical to the model used two studies approved by the 
Wake Forest IRB, SNIFF Long, IRB number 00023230 and Dr. Carol Bushnell’s study of 
Intranasal Insulin and Post Stroke Cognition, IRB00029022.Typical spray bottle administration 
results in large droplets that penetrate only within the first 20% of the lower nasal cavity, and 
due to gravity and insufficient airflow, ~90% of the droplets wind up in the stomach. The 
ViaNaseTM device delivers a substance throughout the nasal cavity (to the olfactory region and 
paranasal sinuses), thereby maximizing access to nose-to-brain channels. This controlled 
particle dispersion (CPD) occurs because droplet size is adjusted according to the weight of the 
substance through an individually optimized droplet generator resulting in maximal vertical 
distribution. 
 
3.0 
PRELIMINARY STUDIES 
A preliminary study examined the impact of 4-month INI administration using the ViaNase device (10 
or 20 International Units bid vs. placebo) on the primary outcome measures of delayed story recall and 
the Dementia Severity Rating Scale (DSRS) as well as on measures of global cognition and function 
used in traditional AD clinical trials. In a subset of participants, effects on CSF AD biomarkers (Aβ42 
and tau/Aβ42 ratio), and on cerebral metabolic rate of glucose utilization (CMRglc) assessed by 
F18FDG PET were also examined (Craft, Baker et al. 2012). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


07-December-2020 
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3.1 
Participants 
A total of 111 older adults were 
randomized in the study (Fig. 1). Data 
from 104 participants were analyzed. 
 
Sample composition (aMCI, n=64; AD 
with MMSE >15, n=40), size, and 
diagnostic criteria were based on a 
previous study (Reger, Watson et al. 
2008). Forty participants (15 placebo, 13 
low dose insulin and 12 high dose 
insulin) completed the PET sub-study, 
and 23 participants (n=8 placebo and 15 
insulin) completed the LP sub-study. 
Diagnoses were determined by expert 
physician and neuropsychologist 
consensus. Participants, caregivers, and 
all personnel involved in data collection 
were blinded to treatment assignment. 
Groups did not differ in education, body mass index, MMSE, gender, diagnosis, cholinesterase 
inhibitor treatment, or apolipoprotein E (APOE) ε4 allele carriage (Table 1).  
 
Table 1 | Participant Characteristics 
 
 
Participants in the high dose insulin group were younger than placebo-assigned participants (p=0.02), 
whereas no differences were observed between placebo and low dose insulin groups. Age was included 
as a covariate in all analyses. 
Figure 1 | Trial Enrollment Flow 


07-December-2020 
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3.2 
Procedures 
Participants were randomized to receive 10 International Units INI bid for a total daily dose of 20 
International Units INI (n=36), 20 International Units INI bid for a total dose of 40 International Units 
(n=38) or placebo (saline bid, n=30) for 4 months. Participants were stratified by APOE-ε4 carriage. 
Saline or insulin (Novolin R, Novo) was administered after breakfast and dinner with ViaNase™, an 
intranasal delivery system (Craft, Baker et al. 2012). Parallel versions of the cognitive protocol were 
administered at baseline, and months 2 and 4 of treatment. Co-primary outcome measures were 
delayed story recall and the DSRS which had previously demonstrated beneficial effects of insulin 
(Reger, Watson et al. 2008). Secondary measures included the AD Assessment Scale for Cognition 
(ADAS-Cog) (Reger, Watson et al. 2008), a test comprised of measures of memory, orientation, and 
language, with higher scores reflecting impairment ranging from 0 (best) to 70 (worst), and the ADCS-
Activities of Daily Living scale (ADCS-ADL) (Galasko, Bennett et al. 1997). Baseline and post-treatment 
fasting CSF was analyzed for Aβ42 and tau with multi-parameter bead-based immunoassay INNO-BIA 
AlzBio3 (Innogenetics NV). Resting PET images were obtained using a GE Advance PET scanner (GE 
Medical Systems, Milwaukee, WI) using a previously described protocol (Baker, Cross et al. 2011). 
 
3.3 
Safety and Compliance 
Support persons supervised participants’ intranasal administration. Blood glucose was measured daily 
for the first week and then weekly; no group changes were observed over the course of the study (Craft, 
Baker et al. 2012). Compliance was monitored by quantifying unused drug. Safety data were reviewed 
semi-annually by a Data and Safety Monitoring Board. Adverse event reporting followed standard 
guidelines. 
 
3.4 
Statistical Analyses 
For the intent-to-treat (ITT) sample, co-primary (delayed story recall and DSRS) and secondary (ADAS-
Cog and ADAS-ADL) scores were log transformed. Scores were first subjected to mixed model repeated 
ANCOVA including all treatment groups (placebo, low dose insulin or high dose insulin) as the between 
subjects factor, and time (baseline, month 2, month 4) as the repeated factor using the SAS v9.2 
General Linear Models procedure. After a significant (p<0.05) time by treatment group interaction 
reflecting a different pattern of change, each of the two insulin groups was compared separately with 
the placebo group using repeated measures ANCOVAs. Effect sizes (Cohen’s f2) were calculated for 
all significant effects. Age was included as a covariate in all analyses. Diagnosis (aMCI or AD), gender, 
APOE-ε4 carriage status (yes or no), baseline 3MSE score, and years of education were also included 
as covariates. Non-significant covariates were dropped from the model. Significant relationships with 
covariates were explored with Pearson correlation (continuous variables) or follow-up ANOVAs (class 
variables). Missing values were treated with multiple imputation (Rubin 1987). For exploratory CSF 
biomarker analyses, because only a subset of participants elected to undergo LP and no differences 
were observed between the two insulin dose arms, the groups were combined into a single insulin-
treated group to maximize power. Biomarkers were analyzed with the repeated ANCOVA strategy 
described above and, due to the small sample size, exploratory Spearman correlations were conducted 
to examine relationships among changes in biomarkers and outcome measures. Only study completers 
underwent post-treatment FDG-PET. Pre and post treatment scans were co-registered within subject 
and anatomically standardized to Talairach and Tournoux stereotactic coordinates (Talairach and 
Tournoux 1988, Minoshima, Koeppe et al. 1994). Pixel intensity was normalized to pontine values 
(Minoshima, Frey et al. 1995). Interval regional CMRglc changes within groups were assessed using 
voxel-wise one-sample t statistics (pre-/post-treatment pair) and probability integral conversion to z 
scores (Worsley, Evans et al. 1992). Interval changes in regional CMRglc were then compared between 
1) low insulin vs. placebo groups, and 2) high insulin vs. placebo groups. Based on the number of voxels 
and smoothness of the statistical map, a Type I error rate was controlled at 0.05 to account for multiple 
comparisons (Worsley, Evans et al. 1992). The resulting statistical maps were visualized in three-
dimensional stereotactic surface projections. 
 


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3.5 
Results: Cognitive and Functional Outcome Measures 
The three groups did not differ at baseline on any outcome measure; change from baseline is 
represented in figures for ease of interpretation. A significant overall treatment group by time interaction 
was observed for primary outcome delayed story recall (p=0.005). Compared to placebo, the low dose 
group had improved delayed recall (Fig. 2A; treatment by time p=0.02, 
Cohen’s f2=0.36), whereas no effect was observed for the high dose group. Exploratory post-hoc 
analyses were then conducted to more closely examine the relationship of insulin dose to story recall, 
as this was a primary goal of this pilot clinical trial. Given findings that delayed recall may not be a 
sensitive measure for AD subjects due to increased variability and floor effects (Sano, Raman et al. 
2011) we constructed a total story recall score (immediate and delayed), which showed improvement 
for the high-dose group (time by treatment interaction p<0.05, mean log total story recall change score 
with SEM = -.15(.1) for placebo vs.12 (.09) for the high dose group). A significant overall treatment by 
time interaction was observed for the other primary outcome measure, the DSRS (p=0.008). Compared 
with placebo, DSRS scores were preserved for both low and high dose groups (Fig.2B; treatment by 
time ps=0.01 and 0.01, Cohen’s f2=0.38 and 0.41). For secondary measures, significant effects were 
observed for the ADAS-Cog (overall treatment by time interaction p=0.004). Both low and high insulin 
groups had less decline in cognition compared with placebo (Fig. 2C; treatment by time ps=0.04 and 
p=0.002, Cohen’s f2=0.27 and .40). Treatment effects on the ADAS-Cog interacted with age; for the 
high dose insulin group, greater improvement (lowered score) tended to be associated with younger 
age (r=.31, p=0.06). For the ADCS-ADL, no overall effects of treatment on daily function were observed. 
However, a significant interaction with diagnosis was observed for this measure (overall treatment by 
time by diagnosis interaction p=0.02). Participants with AD receiving either dose of insulin had 
preserved function compared with placebo-assigned participants with AD who showed slight decline, 
whereas participants with aMCI showed no change regardless of treatment assignment (interactions 
for the participants with AD in low and high dose groups compared with placebo, ps=0.01 and 0.02, 
Cohen’s f=0.45 and 0.43; Fig. 2D). Adjustment for APOE-ε4 status, baseline MMSE score, 
cholinesterase inhibitor treatment, gender, and education did not affect the pattern of any result. 
Figure 2 | Change (Month 4-baseline) in log scores for (A) delayed story recall, (B) DSRS, (C) ADAS-Cog 
and (D) ADCS-ADL. 
 
 
 
 
 
 


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3.6 
Results: AD Biomarkers  
CSF Aβ42, Aβ40 and tau did not change for the placebo or insulin-treated groups as a whole. In 
exploratory analyses, however, for insulin-treated participants, increased CSF Aβ42 concentrations 
were associated with improved delayed story recall and ADCS-ADL scores, whereas decreased Aβ42 
was associated with worse performance (Spearman rhos=.59, p=0.02 and .60, p=0.02). Similarly, 
decreased tau/Aβ42 ratios over the 4-month study period correlated with improved delayed story recall 
and better daily function on both ADAS-ADL and DSRS for insulin-treated participants (Spearman 
rhos=-.52, p=0.05, -.50, p=0.07, and .53, p=0.05). No significant correlations were observed for the 
placebo group. 
 
3.7 
Results: FDG-PET CMRglc 
Compared with placebo-assigned participants, the lower dose insulin group showed reduced 
progression of hypometabolism in bilateral frontal, right temporal, bilateral occipital, and right precuneus 
and cuneus regions over the 4-month treatment period (Fig. 3 and Table 2). The higher dose insulin 
group showed even greater treatment effects (higher Z scores) indicating less hypometabolism 
progression in most regions and in left parietal cortex. 
 
Figure 3 | Areas of hypometabolism at baseline (scan 1) and month 4 (scan 2), along with changes in 
hypometabolism (time 2-time 1) within each group and differences in change between placebo and low or 
high insulin groups (nasal insulin-placebo).  Hotter floors indicate areas of greater hypometabolism from 
time 1 to time 2, and from placebo to insulin groups. 
 
 
Table 2 | Z scores and stereotactic coordinates for areas of reduced progression for low and high does 
insulin groups compared to placebo 
 
 


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3.8 
Safety and Compliance 
No treatment-related serious adverse events (SAEs) occurred during the study; most adverse events 
(AEs) were minor, such as mild rhinitis. AEs with an occurrence of >5% in any group are listed in Table 
3. The total AE mean was higher for the low dose group compared with placebo (low dose mean total 
AEs with standard error=1.44±0.20, placebo =0.80±.22, p=0.04), with a similar trend for the high dose 
and placebo group comparison (high dose mean total AEs =1.21±0.16, placebo =0.80±.22, p=0.10). 
Mean compliance (number of completed doses) ranged from 95-97% and did not differ across groups. 
Table 3 | Total number of adverse events and percent of sample for all events occurring for at least 5% of 
the participants in any treatment group. 
 
 
3.9 
 Implications 
These results suggest that adults with aMCI or AD may benefit from INI treatment. Compared with 
placebo, the lower dose of insulin improved delayed memory, and both insulin doses preserved 
caregiver-rated ability to carry out daily functions. General cognition as assessed with the ADAS-Cog, 
the primary outcome measure for the current trial, was also preserved by both doses of INI. In 
exploratory analyses, changes in CSF Aβ42 and tau/Aβ42 ratios were associated with cognitive and 
functional changes for insulin-treated participants. Placebo-assigned participants showed decreased 
CMRglc values in frontal, temporal, and parietal cortices as well as precuneus and cuneus over the 4-
month period, whereas insulin-treated participants showed no decline. The longstanding FDG PET 
finding of posterior cingulate, precuneus and cuneus hypometabolism in AD has been hypothesized to 
be due to functional disconnection of the hippocampal formation, so enhanced metabolism and memory 
with INI may reflect enhanced hippocampal input to this region. Similarly there are strong connections 
between the posterior cingulate, precuneus, cuneus and prefrontal and superior temporal cortex 
(Cavanna and Trimble 2006), which may also be affected by INI. Finally, no treatment-related SAEs 
occurred. These promising results provide a strong rationale for the longer, larger, multi-site trial 
proposed in this application. 
 
4.0 
PRELIMINARY STUDY 2 
A follow-up study has recently concluded and preliminary results have been analyzed. 
 
Objectives: This study tested the effects of 40 International Units of intranasal insulin administered 
daily for 12 months, compared with placebo, on cognition, daily function and safety in adults with MCI 
or mild AD. Longer-term effects were examined in a six-month open-label extension offered to all 
participants. Safety and feasibility issues relating to the use of intranasal delivery devices were also 
evaluated. The trial is nearing completion; all participants have concluded the blinded phase. 
 
Methods: Twenty-six sites enrolled 289 participants with MCI or mild AD in this randomized, double-
blind, Phase II/III trial (NCT01767909). Adults 55 to 85 years of age with diagnoses of amnestic MCI 
or AD (National Institute on Aging-Alzheimer’s Association criteria) with Mini-Mental State Exam 
(MMSE) scores >19, Clinical Dementia Ratings (CDR) of 0.5 or 1, and delayed Logical Memory 
scores within a specified education-adjusted range were eligible. Participants with diabetes requiring 
medication were excluded, as were participants who had used insulin within one year of the screening 


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visit. Participants were randomized on a 1:1 basis using a covariate-adaptive algorithm that weighted 
MMSE, apolipoprotein E-4 (APOE-4) allele carriage, study site, sex, and age based on previous 
work indicating these factors may impact treatment response. Participants received 40 International 
Units of insulin or insulin diluent placebo (Humulin R U-100 or insulin diluent, Eli Lilly, Indianapolis, 
USA) daily for 12 months. At the end of the 12-month blinded phase, all participants were offered 
open-label insulin treatment for 6 months.  The primary outcome (Alzheimer’s Disease Assessment 
Scale for Cognition-12/ADAS-Cog12) was administered at baseline and then at 3 month intervals. 
Secondary functional outcomes (Alzheimer’s Disease Cooperative Study-Activities of Daily Living 
Scale for MCI; CDR Sum of Boxes) were assessed at 6 month intervals, as was a memory composite 
(Free and Cued Selective Reminding Test and Story Recall). Cerebrospinal fluid biomarkers (A42 
and A42/tau ratio) and magnetic resonance imaging hippocampal and entorhinal cortex volumes 
were measured at baseline and after 12 months.  
 
Device issues. Intranasal delivery device monitoring revealed no safety issues. However, for the first 
49 participants, the delivery device had frequent malfunctions (i.e. failure to turn on) that impacted 
dosing reliability. At that time, a newly available device was introduced (Precision Olfactory 
Device/POD, Impel NeuroPharma, Seattle, USA) which was used by the remaining 240 participants 
with good reliability.  
 
Results: Demographic characteristics of enrolled participants are 
presented in Table 1. Retention was excellent, with only 25 
participants discontinuing treatment during the blinded phase, 
and 15 also discontinuing study visits during the blinded phase. 
Quarterly DSMB reviews did not detect any safety issues and 
approved unmodified continuation of the trial.  
 
Data from the subgroup of participants who used the POD were 
analyzed separately from the ViaNase group. The primary 
analysis of the POD group showed was negative; no difference in ADAS-Cog12 scores were 
observed after 12 months of INI treatment compared with placebo (Fig.1). In contrast, analysis of the 
ViaNase group showed beneficial effects of insulin compared with placebo; the effect was significant 
at 6 months (p<0.01), and persisted at 12 months (p=0.09; Fig. 2). 
 
 
 
 
Implication: These results suggest that the two delivery devices may be providing different doses of 
insulin to the CNS. The ViaNase device results are consistent with multiple previous studies. The 
POD had not been used previously in clinical trials with insulin, and thus was relatively untested in 
terms of delivery efficacy, although modeling in organoid nasal cavities was conducted to verify that 
the target amount of insulin was dispersed to the target location in the nasal cavity. These divergent 
results can potentially be clarified by conducting a proof of concept study, in which insulin or placebo 
will be administered and then insulin in CSF will be measured 30 minutes after administration. Results 
Table 1. Baseline Participant 
Characteristics 
N (F/M) 
289 (134 / 155) 
Age (years) 
70.95  7.1 
Diagnosis (MCI/AD) 
   105 / 184 
MMSE 
  24.8  2.7 
Logical Memory 
    2.1  2.7 
APOE (4+/4-) 
    193 / 96 
p=0.01 p=0.12
p=0.09
ADAS12MeanChangefromBLforViaNase
§ Insulin
§ Placebo
Fig. 1 
Fig. 2 


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of this proof of concept study will help confirm the delivery capabilities of the ViaNase device, 
information that is essential to the design of a future Phase III trial.  
 
4.1 
Rationale for Dosage Selection 
The dosage selected (20 International Units INI) has been used in two prior studies with positive results 
as described above. 
 
4.2 
Rationale for Primary and Secondary Outcome Measures  
Previous work demonstrates that following intranasal insulin administration, insulin levels are increased 
in the CSF, reflecting entry into the CNS, and with the greatest increases observed 30 minutes after 
administration (Born et al. Nature Neuroscience, 2002 Jun;5(6):514-6). The observation that CSF levels 
are increased following insulin administration with the ViaNase device will validate that insulin was 
delivered to the CNS and thus that the positive results for the ADAS-Cog12 for the POD cohort in the 
recent study are possibly due to its ability to successfully deliver insulin to the CNS. 
 
Regarding secondary measures, in previous studies intranasal insulin acutely improved memory 
performance and affected CSF levels of AD biomarkers (Reger et al. 2008; Craft et al. 2012). Thus 
examining effects on these measures will provide supportive information about access to and efficacy 
in the CNS. 
 
4.3 
Rationale for Design of Trial  
This study is designed as an acute administration, proof of concept study to determine whether 
administration of intranasal insulin results in increased delivery to the CNS as evidenced by increased 
CSF insulin levels relative to placebo. 
 
4.4 
Rationale for Biofluids 
The CSF biomarkers insulin, Aβ42, Aβ40 and total tau will be measured. Plasma biomarkers including 
Aβ42, and Aβ40 will be also assessed. Plasma and CSF samples obtained in this study will be banked 
so that other putative biomarkers may be measured by qualified investigators in the future given 
adequate rationale and feasibility.  
 
Several previous studies suggest that response to insulin may differ according to APOE genotype. In 
dose response studies that acutely elevated insulin through intravenous or intranasal administration, 
the greatest cognitive benefit was observed for adults with AD who were not ε4 carriers (Reger, Watson 
et al. 2008). The current study will examine ε4 carriage as a treatment response predictor.  
 
5.0 
STUDY OVERVIEW 
The study will consist of a single site, randomized, double-blind trial comparing the acute effects of INI 
(20 International Units) or placebo delivered with the ViaNase device on CSF insulin levels, AD 
biomarkers and memory. At study entry, participants will be randomized to receive either an acute dose 
of insulin or of placebo first, and the other substance on a second visit. Participants who are cognitively 
normal or who have aMCI (n=30) will be enrolled. The primary outcome measure will consist of CSF 
insulin levels. Secondary measures will include a memory test and CSF biomarker levels.  
 
5.1 
Study Population 
A total of 30 adults who are cognitively normal or diagnosed with aMCI will be enrolled in this trial. We 
expect to enroll approximately 50% of participants from each group. To determine eligibility, all 
participants will undergo cognitive assessment, physical and neurological examination, ECG, 
clinical/safety laboratory assessment, and interviews of the participant and study partner conducted by 
the investigators and staff of the Clinical Core of the Wake Forest Alzheimer’s Disease Research Center 
(ADRC). 
 
 
 


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5.2 
Diagnosis Criteria 
Diagnoses will be assigned by consensus of investigators from the Clinical Core of the Wake Forest 
ADRC using criteria specified by the NIA and Alzheimer’s Association MCI workgroup (Petersen, Doody 
et al. 2001, Albert, Dekosky et al. 2011). 
 
Criteria for cognitively normal adults: 
a) No evidence of significant cognitive impairment on objective testing 
b) Clinical Dementia Rating Scores of 0 
 
Diagnosis of aMCI requires:  
a) Evidence of a decline in episodic memory (memory scores below age and education-based 
norms)  
b) General preservation of independence in functional abilities 
c) Absence of dementia  
 
5.3  
Inclusion Criteria 
The following inclusion criteria* will be used:  
1. 
Age 55 to 85 (inclusive)  
2. 
Fluent in English  
3. 
Cognitively normal or diagnosis of aMCI by criteria described above 
4. 
MMSE ≥ 24 at screening. Approval for exceptions can be requested to the Project Director for 
minority or low education participants 
5. 
CDR 0-0.5 (inclusive) at screening 
6. 
Stable medical condition for 3 months prior to screening visit 
7. 
Stable medications for 4 weeks prior to the screening and study visits  
8. 
Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be 
clinically insignificant by the study physician  
*Exceptions to these criteria may be considered on a case-by-case basis at the discretion of the Project 
Director and study physician, and must be approved in advance by the IRB. 
 
5.4 
Exclusion Criteria 
The following exclusion criteria* will be used:  
1. 
A diagnosis of dementia  
2. 
History of a clinically significant stroke 
3. 
Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with 
loss of consciousness or DSM IV criteria for any major psychiatric disorder including psychosis, 
major depression, bipolar disorder, alcohol or substance abuse  
4. 
Sensory impairment that would preclude the participant from participating in or cooperating with 
the protocol 
5. 
Diabetes (type I or type II) requiring pharmacologic treatment (including both insulin dependent 
and non-insulin dependent diabetes mellitus) 
6. 
Current or past use of insulin or any other anti-diabetic medication within 5 years of Screening 
visit.  
7. 
Evidence of any significant clinical disorder or laboratory finding including clinically significant 
or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, 


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metabolic, renal or other systemic disease or laboratory abnormality  
8. 
Active neoplastic disease, history of cancer five years prior to screening (history of skin 
melanoma or stable prostate cancer are not exclusionary) 
9. 
History of seizure within past five years 
10. Pregnancy or possible pregnancy. Participant is not pregnant, lactating, or of childbearing 
potential (i.e. women must be two years post-menopausal or surgically sterile) 
11. Contraindications to LP: prior lumbosacral spine surgery, severe degenerative joint disease or 
deformity of the spine, platelets <100,000 or history of a bleeding disorder 
12. Use of anticoagulants warfarin (Coumadin) and dabigatran (Pradaxa) (due to LP requirement) 
13. Residence in a skilled nursing facility at screening 
14. Use of an investigational agent within two months of screening visit 
15. Regular use of narcotics, anticonvulsants, medications with significant anticholinergic activity, 
antiparkinsonian medications, or any other exclusionary medications 
*Exceptions to these criteria may be considered on a case-by-case basis at the discretion of the Project 
Director and Study Physician, and must be approved in advance by the IRB. 
 
5.5 
Recruitment and Retention Strategies 
Recruitment will occur primarily from the Clinical Core of the Wake Forest ADRC. Some participants 
may also be identified from community recruitment efforts.  
 
6.0 
STUDY TIMELINE  
The approximate timeline for this twenty-one-month study is projected as follows: 1) approximately one 
months for study startup activities; 2) study visits and data collection will occur over an eighteen-month 
period; 3) CSF and blood analyses, data analyses and study dissemination will occur over the final 2 
months.  
 
7.0 
DESCRIPTION OF STUDY VISITS 
The “Schedule of Study Procedures and Assessments” in Table 4 provides an overview of study visit 
activities.  The primary and secondary outcome measure will be measured at both study visits. 
Genotyping will occur at Screening for participants who have not previously received APOE 
genotypes through the ADRC.  
 
7.1 
Screening (Visit 1) 
The purpose of this visit is to determine study eligibility.  Potential participants must sign an informed 
consent form and HIPAA Authorization prior to administration of any study-related procedures. After 
consent is obtained, participants will be given the MMSE, the CDR and Story Recall to determine study 
eligibility. Screening may be waived for participants who have received evaluations from the ADRC 
within the past 12 months.  
 
In addition, information regarding demographics, concurrent medications, medical history and adverse 
events will be gathered from the participant. Vital signs, height and weight will be measured. A brief 
physical and neurological examination (which include a nasal examination) and a standard 12-lead 
resting ECG will be performed. The ECG report will be reviewed, signed, and dated by the investigator 
or a medically qualified staff member as delegated by the Principal Investigator. Those with clinically 
significant ECG findings will be referred for follow-up as deemed appropriate by the investigator. These 
procedures may be waived for participants who have received evaluations from the ADRC within the 
past 12-months. 
 
 


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Blood will be drawn for routine clinical laboratory evaluations. If values are outside of the laboratory’s 
normal range and determined clinically significant by the investigator, lab tests may need to be repeated 
and may be considered exclusionary for participation in the study. Blood samples will also be collected 
for ApoE genotyping and optional DNA storage.  
 
7.2 
Baseline (Visit 2) 
Results from all screening procedures must be reviewed and all inclusion/exclusion criteria must be met 
prior to proceeding to baseline. For participants whose screening visit was waived because they had 
received ADRC evaluations within the past 12-months will sign an informed consent form and HIPAA 
Authorization prior to administration of any study-related procedures. 
 
According to the randomization schedule, the participant will receive a dose of 20 International Units 
insulin or placebo administered with the ViaNase device. They will then begin preparations for the 
lumbar puncture. After preparation, the immediate recall section of the AVLT will be administered. Blood 
for plasma biomarkers will then be collected immediately before and after participants undergo the 
lumbar puncture. Fasting plasma insulin, glucose, Aβ40 and Aβ42 will be measured. Additional plasma 
and serum will be collected and banked. 
 
Lumbar puncture will then be performed in the morning after a minimum 8-hour overnight fast. CSF 
samples will be used to measure levels of insulin, A42, A40, total tau, and phospho-tau181. 
Additionally, CSF sample will be banked for future exploratory analysis. CSF will be collected and 
immediately frozen upright on dry ice. Site staff will call the participant within 24 hours from the lumbar 
puncture procedure to inquire about the participant’s well-being and possible adverse events. Following 
the lumbar puncture, the delayed recall section of the AVLT will be administered. Participants will then 
receive a snack and instructions about post-lumbar puncture care.  
 
7.3 
Visit 3 
Visit 3 will be scheduled within 2 to 6 weeks following Visit 1. Vital signs and weight will be obtained, a 
nasal examination will be conducted, adverse events and concurrent medications will be recorded. 
Procedures will follow the schedule outlined for Visit 1, except that the alternate compound (either saline 
or 20 International Units insulin) will be administered.  
 
8.0 
STUDY-SPECIFIC PROCEDURES 
 
8.1 
Memory Evaluation Instruments Administered to the Participant 
Objective tests of cognitive function will include MMSE, Story Recall, and the Rey Auditory 
Verbal Learning Test.  
 
8.2 
Clinical and Functional Evaluations  
 
 Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB) 
The CDR (Hughes, Berg et al. 1982, Morris 1993) is a clinical scale that rates the severity of dementia 
as absent, questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 2, or 3, respectively). The 
score is based on interviews with the participant and study partner, using a structured interview that 
assesses six domains: memory, orientation, judgment and problem solving, community affairs, home 
and hobbies, and personal care. 
 
At Screening the CDR global score will be used for eligibility purposes. For all other administrations, 
the 6 domain scores will be summed to get the Sum of Boxes (SB) score. Training on the use of the 
CDR will be conducted to standardize its administration across sites. The CDR online training tool 
resides on the Washington University, St. Louis website, with oversight provided by Dr. John C. Morris 
(Morris, Ernesto et al. 1997). 
 
 
 


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9.0 
STUDY METHODS 
 
9.1 
Safety Assessments 
At each study visit, all participants will undergo a nasal examination and any occurrence of adverse 
events will be reviewed and documented; concomitant medications will be recorded as well. In addition, 
24 hours after the Lumbar Puncture, each study participant, or a person designated to speak for them 
will be contacted by phone to confirm the participant’s well being and queried about any new adverse 
events. All adverse events will be reported to the Wake Forest DSMB. Safety reports will be prepared 
by study team and submitted to the DSMB for periodic review.  
 
9.2 
Physical and Neurological Examination 
A brief physical examination will be performed by a medically qualified professional at the screening 
visit. 
A 
review 
of 
the 
major 
body 
systems 
will 
be 
performed 
for 
example: 
skin, 
head/ears/eyes/nose/throat (HEENT), cardiovascular, pulmonary, abdomen, musculoskeletal, 
neurological, and gastrointestinal. Assessments of height (Screening visit only), weight, and vital signs 
(systolic and diastolic blood pressure, pulse, temperature, and respiration) are included. Neurological 
examination will include an assessment of cranial nerves, strength, coordination, reflexes, sensation, 
tremor and gait at every study visit. A nasal examination will also be performed. The examination will 
assess irritation or other abnormalities of the nares.  
 
9.3 
Electrocardiogram (ECG) 
A standard 12-lead resting ECG will be performed at Screening visit.  The ECG report will be reviewed, 
signed, and dated by the investigator.  Those with clinically significant ECG findings will be referred for 
follow-up as deemed appropriate by the investigator and may be excluded from the study. 
  
9.4 
Clinical Laboratory Evaluations 
All routine laboratory samples will be analyzed by a central laboratory, which will provide a procedures 
manual and supplies. Lab reports will be reviewed, signed and dated by the Study Physician.  If a value 
is outside of the laboratory’s normal range, the clinician will indicate if it is clinically significant or not. If 
clinically significant, lab tests may need to be repeated and follow up with the participant’s PCP should 
occur.    
 
10.0 
BIOMARKER STUDIES 
 
10.1 
CSF 
All CSF samples will be collected in the morning before breakfast and after an overnight fast.  
Participants who are taking anticoagulants, warfarin (Coumadin) and dabigatran (Pradaxa) should not 
be screened for this trial, as these are prohibited medications. Based on clinician judgment and 
depending on the clinical indication, it may be suitable to discontinue participants from their anti-platelet 
agent (e.g., aspirin, Plavix, NSAIDs) for 5-7 days prior to lumbar puncture and until at least 24 hours 
after lumbar puncture.  It is not required that participants be discontinued from their anti-platelet agent 
in order to screen and enroll in the study.  
 
A minimal total volume of CSF (25 ml) will be required for this study.  To clear any blood from minor 
trauma associated with needle insertion, the first 1-2 mL of CSF are discarded (or more if 
needed).  Collected CSF is aliquoted into sterile microtubes. Approximately 2ml of CSF or volume per 
local laboratory requirements will be sent at ambient temperature to the CRU laboratory for protein, 
glucose and cell count. The remaining CSF will be immediately frozen upright on dry ice for at least 20 
minutes then stored at -70 until analysis.  
 
CSF samples will be used to measure levels of insulin, A42, A40, total tau, and phospho-tau181. 
Assays will be performed by the Wake Forest ADRC Biomarker Service. CSF samples will also be 
frozen and stored for future analysis of putative biomarkers. 


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10.2 
Blood Collection at Lumbar Puncture Visits 
All samples will be collected in the morning before breakfast and after a minimum 8-hour overnight fast. 
Blood samples will be collected before CSF collection, which would be processed for fasting plasma 
insulin, glucose, A42, and A40. Additional blood for plasma and serum will be processed and banked. 
 
10.3 
Genetic Samples, Storage and Future Use 
DNA will be extracted from participant blood samples and will be analyzed for ApoE genotyping. ApoE 
genotyping will be used as a weighting factor for the minimization strategy during randomization.  This 
will allow secondary analyses of data on the impact of the ApoE genotype on putative biomarkers of 
AD, clinical outcome measures, and adverse events. Participants will be asked to consent to optional 
DNA banking for future research studies. ApoE genotyping will be performed by Dr. Don Bowden under 
the auspices of the ADRC Biomarker service using established protocols.  
 
11.0 
STATISTICAL PLAN  
Statistical analyses will be conducted by the ADRC Biostatistics Core. To address the Primary Aim, 
CSF insulin values will be subjected to a repeated measures analysis of variance with treatment (saline 
vs. placebo) as the repeated measure, with age and baseline MMSE as covariates. Secondary analyses 
will examine the effect of diagnostic status (cognitively normal vs. MCI) and APOE genotype. Secondary 
analyses will also examine treatment-related differences for other CSF and plasma biomarkers, and for 
memory scores.  
 
11.1 
Power Analyses 
As this study is designed as a proof of concept study to determine whether the ViaNAse device is able 
to deliver insulin to the CNS as evidenced by increased CSF insulin levels following insulin 
administration relative to saline placebo, power calculations have not been conducted. However, the 
proposed sample size is larger than two previous studies (Born et al. 2002; Fishel et al. that showed 
that administering insulin increased CSF insulin levels.  
 
12.0 
POTENTIAL RISKS 
 
12.1 
Safety of Intranasal Insulin 
Safety issues pertaining to INI administration for the treatment of diabetes have been extensively 
explored for over two decades (Pontiroli, Alberetto et al. 1982). For diabetes treatment, absorption 
enhancers must be used to increase the transport of insulin across the nasal membrane to the periphery 
due to the fact that peripheral bioavailablity of insulin without absorption enhancers is less than 1% 
(Illum 2002). A recent safety study of INI administration without absorption enhancers demonstrated no 
treatment induced changes in blood glucose levels, nasal airway patency, or transnasal pressure 
gradient (Kupila, Sipila et al. 2003). There are no known serious risks associated with INI without 
enhancers. A recent industry report raised the issue of rare but significant increases in lung cancer in 
smokers treated with inhaled insulin; six of 4740 patients taking inhaled insulin developed lung cancer 
compared with one of 4292 patients who received an active comparator (incidence per 100 patient 
years exposure, 0.13 vs 0.02). However, the inhaled insulin protocol used for diabetes treatment in this 
report included absorption enhancers to maximize delivery to lungs, whereas the nose-to-brain delivery 
device to be used in this study greatly minimizes lung delivery.  
 
Regarding the risk of hypoglycemia, at least five peer reviewed human studies (Kern, Born et al. 1999, 
Born, Lange et al. 2002, Kupila, Sipila et al. 2003, Benedict, Hallschmid et al. 2004, Stockhorst, de Fries 
et al. Submitted for publication)  and four preliminary studies (Reger, Watson et al. 2006, Reger, Watson 
et al. 2008, Reger, Watson et al. 2008) (Craft, Baker et al. 2012) revealed no change in blood glucose 
levels following intranasal insulin administration with doses that included 40 International Units 4 times 
daily for two months. There was one exception with the case of a single participant who experienced 
mild hypoglycemia (52 mg/dl) after skipping a meal and engaging in sustained vigorous exercise. In 


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addition, a recent safety study (Kupila, Sipila et al. 2003) examined intranasal insulin administration of 
60 International Units once a day for three weeks in 21 healthy adults. This randomized, double-blind, 
placebo-controlled crossover trial measured blood glucose levels six times a day during the first two 
and the last two days of treatment. Pre- and post-treatment blood laboratory tests and nasal 
examinations were performed. The nasal studies included rhinoscopy to detect local irritation, a 
saccharin particle test to analyze mucocilary clearance, and rhinomanometry to evaluate nasal airway 
patency and transnasal pressure gradient. Results indicated no change in blood glucose values with 
insulin, and no change in the frequency of glucose values above 3.0 mmol/L. The only symptomatic 
hypoglycemic value occurred during placebo treatment. Insulin treatment had no effect on other 
laboratory values (C-peptide, total cholesterol, HDL, LDL, triglycerides, creatinine, glutamyl 
transferase), blood pressure, or body weight. In addition, nasal examinations revealed no adverse 
effects or functional disturbances following intranasal insulin administration. No serious adverse effects 
of treatment were observed in the preliminary studies (Reger, Watson et al. 2006, Reger, Watson et al. 
2008, Reger, Watson et al. 2008, Craft, Baker et al. 2012). 
 
12.2 
Risks associated with use of the ViaNase® device  
Because the use of the device will be supervised directly by the study nurse the risks of adverse events 
is extremely low. Participants could experience some discomfort to their eyes or face if they do not hold 
the device to their nose as directed; however, again, the study nurse will carefully instruct and oversee 
device use so that any errors can be immediately corrected.  
 
12.3 
Lumbar Puncture 
Lumbar puncture may be associated with pain during the performance of the procedure. This is usually 
temporary and confined to the lower back. Headache may occur in about 5% of elderly people who 
undergo lumbar puncture. Less commonly, in about 1-4% of participants, a persistent low-pressure 
headache may develop, probably due to leakage of CSF. Lower rates of post-LP headache have been 
noted in elderly patients, and when atraumatic (Sprotte) needles are used. If a post-LP headache 
persists it may need additional treatment, e.g. with fluids and analgesics. Uncommonly a blood patch 
(injection of some of the participant’s blood to patch the CSF leak) may be needed. Potential but rare 
risks of lumbar puncture include infection, damage to nerves in the back, and bleeding into the CSF 
space. The risk of these is much less than 1%.   
 
12.4 
Blood Draw 
The risks of blood draw include pain from the needle, bruising or infection at the site of venipuncture, 
or fainting as a response to blood draw.  Approximately 50mls of blood will be drawn for routine and 
biomarker laboratory assessments over the course of this study.   
 
13.0 
PERSONNEL REQUIREMENTS 
The following staff-member roles will be required to conduct the protocol.   
 
▪ 
Principal Investigator: The Principal Investigator (PI; Suzanne Craft, PhD) is responsible for the 
overall conduct of the study. The PI will perform or supervise clinical evaluation of all participants 
and ensure protocol adherence. The PI will supervise project personnel and ensure that clinical 
raters maintain a high level of skill and accuracy in conducting assessments.  
▪ 
Study Physician: Benjamin Williams, MD, PhD will serve as Study Physician for the trial. He will 
be responsible for conducting and supervising the medical evaluation (nasal examination, physical 
and neurological examinations), reviewing adverse events, interpreting laboratory results, and 
supervising clinical care provided to the participant during the study. He will also supervise, and on 
some occasions may perform the lumbar punctures. 
▪ 
Study Nurse/Coordinator: Deborah Dahl, RN will serve as Study Nurse/Coordinator for the trial. 
She will be responsible for managing the day-to-day conduct of the trial.  Duties may include tracking 
recruitment, ensuring accurate administration of all instruments at the site, maintaining case report 


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forms, processing of laboratory samples, and coordinating clinic visits. She will also oversee the use 
and maintenance of the devices, and coordinate with the Pharmacy regarding ordering and storage 
of saline and insulin.  
▪ 
Interviewer/Psychometrician:  This person will be responsible for administering the memory 
assessments.   
▪ 
CDR Rater: This person will render the CDR-SB rating based on clinical assessment of participant 
and study participant.  
▪ 
Regulatory Affairs: Sarah Bohlman will be responsible for managing all regulatory related 
documents for the duration of the trial. 
 
14.0 
STUDY DRUG 
All participants will take receive one dose of INI (20 International Units) or placebo, administered 
approximately 30 minutes prior to the LP.  
 
14.1 
Humulin® R U-100 Insulin 
Humulin® R U-100 (NDC: 0002-8215, Eli Lilly & Company) is a polypeptide hormone structurally 
identical to human insulin synthesized through rDNA technology in a special non-disease-producing 
laboratory strain of Escherichia coli bacteria. Humulin R U-100 has the empirical formula 
C257H383N65O77S6 and a molecular weight of 5808 Da. Humulin R U-100 is a sterile, clear, aqueous, and 
colorless solution that contains human insulin (rDNA origin) 100 units/mL, glycerin 16 mg/mL and 
metacresol 2.5 mg/mL, endogenous zinc (approximately 0.015 mg/100 units) and water for injection. 
The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to 
adjust the pH. 
 
More information about the Humulin® R U-100 insulin, including risks, contraindication and adverse 
reactions can be found in the the US package insert (USPI).  
 
14.2 
Placebo (Sterile Saline) 
The placebo will consist of sterile saline. 
 
14.3 
Randomization 
Eligible participants will be randomized on a 1:1 schedule to receive either insulin or saline first.  
 
14.4 
Blinding 
Neither participants or site personnel will know whether insulin or saline is being administered. 
Exceptions will be the study nurse who is directly involved in preparing the insulin or placebo, as well 
as preparing DSMB reports. 
 
 
14.5 
Study Drug Dispensing 
Study drug will be inserted into the chamber of the ViaNaseTM by the study nurse. 
 
14.6 
Intranasal Administration 
Insulin or placebo will be administered with a ViaNaseTM drug delivery device (Kurve Technology, 
Bothell, WA). ViaNaseTM specifically targets olfactory delivery to maximize drug transport to the CNS. 
This device releases a metered insulin dose into a chamber covering the participant’s nose. The insulin 
or placebo is then inhaled by breathing evenly over a specified period. This method allows 
administration of smaller particle sizes to increase deposition in the upper nasal cavity while minimizing 
transport to the lungs. A volume of about 0.7 mL of insulin or placebo will be administered each time.  
 
14.7 
Storage   
Insulin and placebo will be maintained at a controlled temperature. 
 


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14.8 
Drug Accountability   
The study nurse coordinator will maintain a log of study drug usage.  
 
15.0 
ADVERSE EVENTS 
 
15.1 
Definition 
An adverse event (AE) is defined as per the Code of Federal Regulation Title 21 Part 312. 
 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32 
 
Adverse events which occur after informed consent is signed include but are not limited to: (1) 
worsening or change in nature, severity, or frequency of conditions or symptoms present at the start of 
the study; (2) participant deterioration due to primary illness; (3) intercurrent illness; and (4) drug 
interaction. An abnormal laboratory value will only be reported as an AE if the investigator considers it 
to be an AE, or if it leads to the participant being withdrawn from the study. 
 
The investigator should attempt to establish a diagnosis of the event based on signs, symptoms, and 
or other clinical information. In such cases, the diagnosis should be documented as the AE and not the 
individual signs or symptoms.  Symptoms and conditions present at the beginning of the study will be 
characterized, so that AEs can be defined as any new symptom, or any increase in frequency or severity 
of an existing symptom. 
 
Following questioning and evaluation, all AEs, whether determined to be related or unrelated to the 
study drug by a medically qualified site PI or clinician (MD, DO, NP or PA), must be documented in the 
participant’s medical records, in accordance with the investigator’s normal clinical practice, and on the 
AE e-CRF. Each AE is evaluated for duration, severity, seriousness, and causal relationship to the study 
drug. 
 
15.2 
Following Up on AEs 
The investigator is obliged to follow participants with AEs until the events have subsided, the conditions 
are considered medically stable, or the participants are no longer available for follow up. Participants 
who discontinue due to adverse experiences will be treated and followed according to established 
medical practice. All adverse events will be reported to the Wake Forest DSMB. Adverse events will be 
rated as mild, moderate or severe.  This will also pertain to abnormal laboratory values deemed clinically 
significant by the site clinician.  
 
16.0 
SERIOUS ADVERSE EVENTS (SAE) 
 
16.1 
Definition  
A serious adverse event is defined as per the Code of Federal Regulation Title 21 Part 312  
 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32 
 
16.2 
Reporting SAEs 
Any serious and adverse event due to any cause, which occurs during the course of the investigation 
(i.e. anytime after informed consent, regardless of study drug exposure), will be reported to the PI and 
study physician within 24 hours of learning of the event. All serious adverse events will be reported to 
the Wake Forest IRB and DSMB within 7 days of study personnel learning of the event. 
 
 
 
 
 
 


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17.0 
ETHICS & REGULATORY CONSIDERATIONS 
 
17.1 
Ethical Standard 
Study investigators are charged with conducting this study in full conformity with: 
1. Good Clinical Practice (GCP) guidelines, as defined by the International Conference on 
Harmonisation (ICH) Guideline, Topic E6 
2. The United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) – Protection of 
Human Subjects 
3. 21CFR56 – Institutional Review Boards (IRBs) 
4. HIPAA 
5. State and Federal regulations and all other applicable local regulatory requirements and laws.    
 
Study personnel involved in conducting this study will be qualified by education, training and experience 
to perform their respective task(s) in accordance with GCP.   
 
17.2 
Institutional Review Board (IRB) 
This protocol and the associated informed consent documents and recruitment material will be 
approved by the Wake Forest IRB which is registered with the Office for Human Research Protections 
(OHRP). Any amendments to the protocol or consent materials must also be approved before they are 
placed into use. The investigator shall notify the IRB of deviations from the protocol or serious adverse 
events occurring at the site, in accordance with local procedures.  
 
17.3 
Informed Consent & HIPAA Authorization 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin 
in the Declaration of Helsinki.  Prior to the beginning of the trial, the investigator should have the IRB’s 
written approval of the written informed consent form (ICF) and any other written information to be 
provided to participants.  Participants, their relatives, guardians, or authorized representatives and study 
partners will be given ample opportunity to inquire about the details of the study. Prior to a subject’s 
participation in the trial, the written informed consent form and HIPAA Authorization should be signed 
and personally dated by the subject and/or the subject’s legally authorized representative, the study 
partner and by the person who conducted the informed consent discussion.  Participants should be 
provided a copy of the signed ICF. 
 
The informed consent will not only cover consent for the trial itself, but for the genetic research, 
biomarker studies and biological sample storage. The consent for storage will include consent to access 
stored data and biological samples for secondary analyses. Consent forms will specify that DNA and 
biomarker samples are for research purposes only; the tests on the DNA and biomarker samples are 
not diagnostic in nature and participants will never receive results.  
 
17.4 
Participant Confidentiality | HIPAA 
Participant confidentiality is strictly held in trust by the participating investigators, research staff, and the 
sponsoring institution and their agents.  This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. The study 
protocol, documentation, data and all other information generated will be held in strict confidence.  No 
information concerning the study or the data will be released to any unauthorized third party, without 
prior written approval. Any data, specimens, forms, reports, and other records that leave the site will be 
identified only by a subject identification number to maintain confidentiality.  All records will be kept in a 
locked file cabinet.  All computer entry and networking programs will be done using subject IDs only. 
Information will not be released without written permission of the subject, except as necessary for 
monitoring by the IRB, DSMB, FDA, NIA, and the OHRP. 


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Information about subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed HIPAA Authorization informing the subject of the following:  
 
• What protected health information (PHI) will be collected from participants in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research participant to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization. Each 
site PI, under the guidance of his/her IRB, is responsible for ensuring that all applicable HIPAA 
regulations and State laws are met. 
 
18.0 
GENETIC RESEARCH & STORAGE OF GENETIC MATERIAL  
The DNA is banked in locked freezers in the ADRC Biomarker Service.  Sample tubes are bar-coded 
and linked to participant ID number only and banked without personal identifiers.  
 
Only DNA from consenting participants will be banked and used to facilitate future research on aging 
and dementia, particularly in the discovery of genetic polymorphisms that may influence risk of 
developing AD.  Collection of DNA will permit investigators to probe candidate genetic polymorphisms 
as predictors of outcome in future studies.  The samples will be stored by the ADRC.   
  
18.1 
Storage of Biospecimen Samples  
All biospecimens being banked for future AD biomarker research will be stored by the ADRC Biomarker 
Service.  
 
19.0 
RISKS AND BENEFITS ASSOCIATED WITH THIS STUDY 
 
19.1 
Potential Benefits of the Proposed Research to Human Subjects 
There is an urgent need to identify promising treatments for patients with AD and its prodrome aMCI. 
In a previous trial (Craft, Baker et al. 2012), intranasal insulin safely improved delayed memory and 
function in these patients. In a recent trial, these results were replicated with the subgroup of participants 
who used the ViaNase device, but not with the POD cohort. The proposed trial is designed to answer 
the important question of whether the ViaNase device is effective in delivering intranasal insulin into the 
CNS. This knowledge will enable the conduct of future Phase III trials of intranasal insulin.  
 
There are no significant potential clinical benefits for the participants in this study. Rather, there is a 
clear scientific benefit for the field as a whole. The relatively minor risks posed by the acute intranasal 
administration, cognitive testing, and LP are outweighed by the value of the scientific investigations 
outlined in this study. 
 
19.2 
Inclusion of Women and Minorities 
There are currently no studies that definitively support or negate the existence of significant differences 
in response to intranasal insulin in subgroups defined by gender or ethnic background. A specific goal 
percentage for women and minority enrollment is not set for this study. However, we will monitor minority 
enrollment throughout the study and make special effort to encourage minority enrollment. Minority 
enrollment will be facilitated through minority outreach effort coordinated by the Recruitment Core at 
the ADRC. No participant will be excluded due to his or her sex, race, or ethnic group.  
 
19.3 
Inclusion of Children as Participants in Research Involving Human Subjects 
Children will not be included. 
 
 


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19.4 
Data and Safety Monitoring Plan and Board 
The principal investigator will be responsible for the overall monitoring of the data and safety of study 
participants, with assistance by members of the study staff, and the WFUHS Institutional Data and 
Safety Monitoring Board (I-DSMB), which will be responsible for monitoring the safety of research 
participants.  
 
The WFUHS Institutional Data & Safety Monitoring Board (I-DSMB) is a Dean-appointed multi-
disciplinary, standing committee that is available to provide independent oversight for human research 
studies conducted by WFUHS or by WFUHS-affiliated faculty investigators. I‐DSMB 
recommendations are reported to the study PI, who is responsible for forwarding them to the IRB and 
to the study sponsor.   
 
While most I-DSMB reviews are conducted via electronic interactions, face-to-face meetings would 
occur as needed (e.g., for unplanned interim analyses, based on safety concerns).  
All individual study discussions (online or face-to-face) are preceded by inquiring if any I‐DSMB 
members have either a perceived or actual conflict of interest that could bias their ability to objectively 
monitor and make judgments about the study. Actual conflicts would mandate recusal from all closed‐
session discussions and relinquishment of voting for the study, while perceived conflicts may be dealt 
with by having the member in question simply abstain from voting. Conflict of interest (COI) 
management of studies monitored by the I‐DSMB will be determined on a case‐by‐case basis.  
 
Information regarding serious adverse events (SAEs) will be presented to the DSMB every six 
months. The DSMB may recommend stopping the trial before its planned conclusion if convincing 
evidence is observed of a treatment difference in adverse events.  Recommendations of the DSMB 
after each review will be presented to the study PI and IRB. Participants will be screened at the 
beginning of the study and will be monitored carefully at each study visit.   
 
20.0 
PUBLICATION POLICY 
The results of this study will be published.  To coordinate dissemination of data from this study, a 
publication committee will be formed.  The committee will consist of the Protocol Committee, interested 
Principal Investigators and appropriate ADCS personnel.  The committee will solicit input and 
assistance from other Investigators as appropriate and adhere to all ADCS Publications Policies. 
 
21.0 
SHARING OF FINAL RESEARCH DATA 
Data from this research will be shared with other researchers pursuant to the 02/26/2003 “NIH Final 
Statement on Sharing Research Data”. NIH believes that data sharing is important for further translation 
of research results into knowledge, products, and procedures to improve human health.  The NIH 
endorses the sharing of final research data to serve these and other important scientific goals.  To 
protect subjects’ rights and confidentiality, identifiers will be removed from the data before they are 
shared. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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22.0 
TABLE 4: SCHEDULE OF PROCEDURES AND ASSESSMENTS 
 
Visit # 
1 
2 
3 
Visit Name 
Screen 
Study 
1  
Study 
2 
 
 
 
 
Informed Consent 
X 
 
 
Demographics 
X 
 
 
Medical History 
X 
 
 
Concomitant Meds 
X 
X 
X 
Nasal Exam 
X 
X 
X 
Physical and Neurological Exam 
X 
 
 
Vital Signs 
X 
X 
X 
Height 
X 
 
 
Weight 
X 
 
 
ECG 
X 
 
 
Story Recall 
X 
 
 
MMSE 
X 
 
 
CDR 
X 
 
 
Adverse Events 
X 
X 
X 
Blood Draw 
X 
 
 
- Clinical Labs 
X 
 
 
- ApoE Genotyping | DNA Banking1 
X 
 
 
- Biomarkers | Plasma|Serum | Sample Banking 
 
X 
X 
LP 
 
X 
X 
- CSF Biomarkers | Banking2 
 
X 
X 
- post-procedure safety telephone check 
 
X 
X 
Auditory Verbal Learning Test 
 
X 
X 
1DNA banking is optional  
2CSF banking is optional 


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