Clinical trial NCT03061474
Conditions: Alzheimer's Disease Mild Cognitive Impairment
Keywords: Mild Cognitive Impairment Alzheimer's Disease Nicotinamide Niacinamide Niacin Nicotinic Acids Vitamin Neurodegenerative Diseases Tauopathies Dementia
Sponsor: University of California, Irvine
Start date: 2017-07-12; Completion date: 2022-08-30
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to test whether nicotinamide, also known as vitamin B3 or niacinamide, taken in high doses, can reduce phosphorylation of tau (the protein that accumulates in neurofibrillary tangles) in people with Mild Cognitive Impairment or mild Alzheimer's disease (AD) dementia.

Detailed description:
Nicotinamide, the amide of nicotinic acid (vitamin B3/niacin), is an oral therapy with a wealth of clinical data in a variety of therapeutic areas, including preliminary data supporting its safety in Alzheimer's disease (AD). Preclinical work in a mouse model that develops both plaques and tangles supports the hypothesis that nicotinamide can act as a histone deacetylase (HDAC) inhibitor to reduce phosphorylation of tau.

The study will implement a group sequential design, incorporating a futility analysis with a go/no-go decision conditional on cerebral spinal fluid CSF biomarker outcomes at 12-months. The primary outcome for the trial is change in p-tau231.

This study timeline includes a screening phase of up to 60 days and treatment phase which is expected to last about 48 weeks and will include 4 study visits.

An additional 12-month treatment and follow-up period is planned, contingent upon a "go" decision based on the primary outcome (CSF p-tau231) or one planned secondary outcome (CSF p-tau181)

Arms: arm 1: 1500mg twice daily: 2, 750mg tablets taken orally twice daily arm 2: 1500mg twice daily: 2, 750mg tablets taken orally twice daily
Interventions: intervention 1: Nicotinamide intervention 2: Placebo Comparator
Intervention descriptions: intervention 1: Niacinamide (nicotinamide; 99%) is produced in a 750 mg sustained release tablet. intervention 2: Oral Tablet

Protocol documents:
ICF_002.pdf: 
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UNIVERSITY OF CALIFORNIA 
CONSENT TO ACT AS A HUMAN RESEARCH SUBJECT 
 
UC Reliance #2471: A Phase 2, Proof-of-Concept, Double-Blind-Randomized, Placebo-
Controlled Adaptive Design Trial of Nicotinamide in MCI due to AD and Mild AD Dementia 
 
You are being asked to participate in a research study.  Participation is completely voluntary.  Please 
read the information below and ask questions about anything that you do not understand.  A researcher 
listed below will be available to answer your questions. 
 
RESEARCH TEAM 
Lead Researcher 
Joshua Grill, PhD 
Associate Professor of Psychiatry and Human Behavior 
Institute for Memory Impairments and Neurological Disorders 
University of California Irvine 
Phone: (949) 824-5905 
 
Other Researchers  
Steven Tam, MD 
Department of Neurology 
University of California Irvine 
Institute for Memory Impairments and Neurological Disorders 
(949) 824-2382 
24-Hour Telephone Number/Pager (714) 506-4744 
 
Sarah Kremen, MD 
Clinical Physician of Neurology 
University of California Los Angeles* 
Co-Director, Katherine and Benjamin Kagan AD Treatment Development Program 
Mary Easton Center for AD Research 
(310) 825-6301   
 
STUDY LOCATION(S):  
UCI 
1100 Gottschalk Medical Plaza 
University of California, Irvine 
Irvine, CA 92697-4285 
 
Institute for Clinical and Translational Science (ICTS) 
Hewitt Hall Clinic 843 Health Sciences Rd 
Irvine, CA 92697 
 
Newport Diagnostic Center 
1605 Avocado Avenue, 
Newport Beach, CA 92660 
 
 
UCLA: 
Center for Neurotherapeutics 
UCLA Medical Center 
300 Medical Plaza, Westwood Blvd 


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Los Angeles, CA 
 
STUDY SPONSOR(S):  
UC Cures Initiative, University of California Office of the President 
 
WHY IS THIS RESEARCH STUDY BEING DONE? 
The purpose of this research study is to test whether nicotinamide, also known as vitamin B3 or 
niacinamide, taken in high doses, can reduce phosphorylation of tau (the protein that accumulates in 
neurofibrillary tangles) in people with Mild Cognitive Impairment or mild Alzheimer’s disease (AD) 
dementia.  
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?   
Approximately 100 participants will take part in the research across two study sites.  UCI and UCLA* will 
enroll approximately 50 participants at each site. 
 
*As of March 2021, UCLA is no longer open to enrollment. 
 
AM I ELIGIBLE TO PARTICIPATE IN THIS STUDY? 
Please note this may not be a complete list of eligibility criteria. We have included a few examples of study 
criteria to help you better understand how your eligibility in the study will be determined; your study team 
will go through the study eligibility criteria with you to verify if you qualify for participation in this study. 
 
Inclusion Requirements 
You can participate in this study if you 
• 
are age 50 or older  
• 
have been diagnosed with Mild Cognitive Impairment or mild dementia due to Alzheimer’s 
disease 
• 
are willing and able to undergo lumbar punctures (also known as spinal tap) 
• 
have a study partner that you see at least 3 times a week, who can provide accurate information 
about your health and can attend required study visits with you 
• 
are able to swallow oral tablets 
 
Exclusion Requirements  
You cannot participate in this study if you  
• 
have a history of cancer within 3 years prior to screening  
• 
have a history of alcohol or substance abuse within 5 years of screening 
• 
live in a skilled nursing facility 
• 
are unable to have an MRI scan  
• 
are unable to have a lumbar puncture procedure 
• 
are participating in or have recently (in the last 6 months) participated in any other clinical trial for 
AD 
• 
are pregnant, lactating or of child bearing potential 
 
HOW LONG WILL THE STUDY GO ON? 
This study consists of a screening phase and treatment phase and is expected to last about 54 weeks 
total.  
 
The screening phase will take up to 60 days and will include 3 visits to our clinic. The treatment phase 
includes up to 6 trips to the clinic and at least 3 telephone interviews over a 48-week period.  
 
 
 


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WHAT PROCEDURES ARE INVOLVED WITH THIS STUDY? 
Screening: 
Before you can participate in the main part of the study, you will need to have “screening” exams, tests or 
procedures performed.  The screening process helps the researchers decide if you meet the study 
requirements listed below.  The screening procedures include  
• 
Informed consent: You and your study partner will need to read, confirm understanding, and sign 
this informed consent.  
• 
Medical history:  A complete medical history will be taken 
• 
Medication review 
• 
Physical exam & vital signs:  
• 
Efficacy and safety assessments. Tests will be done to assess how well you are thinking, how well 
you are performing your daily activities, and how well you are feeling.  
• 
Brain magnetic resonance imaging (MRI) scan.  MRI scans produce detailed pictures of the brain 
by using a magnetic field and radio waves.  You will have one MRI scan of the brain during 
Screening to determine if there are any abnormalities present in your brain (such as stroke or 
hemorrhage) which would prevent your continuation in the study. 
• 
Electrocardiogram (ECG):  ECGs measure electrical activity of your heart by putting small sticky 
patches on certain areas of your body.  
• 
Concomitant medication monitoring: The study doctor will record all the medications you take 
during the study. 
• 
You will have the following blood and urine tests:  
o Standard safety and health assessments 
o A blood test at the Screening visit to see if you carry a particular variant of a gene called 
apolipoprotein E (ApoE) that has been linked to AD. 
o Some of your blood will be stored for future research use.   


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o A total of 50 milliliters (approximately 3.5 tablespoons) of blood will be taken during the 
Screening period of the study. 
• 
Cerebral spinal fluid (CSF) collection:  
During lumbar puncture procedure, you 
will lie on your side with your knees 
drawn up to your chest; or you will sit in 
a bent forward position, depending on 
your doctor’s instructions. A long, thin 
needle will be put in the spinal canal in 
the area of your lower spine and up to 
approximately 1.5 tablespoons (20 
milliliters [mL]) of CSF will be removed. 
Before the doctor inserts the needle you 
will be given medicine to make the area 
numb. The entire procedure takes 
about 30 minutes. Because CSF is 
continually being made, the small 
amount of fluid that is removed will be 
quickly 
replaced. 
Some 
of 
your 
collected CSF will be tested for sugar 
level, protein, and cell count. The tests 
will be used to monitor each patient for 
any unusual results.  
• 
In some cases, it may be necessary for 
the doctor to perform the lumbar 
puncture with the help of an imaging 
tool called fluoroscopy. Fluoroscopy is 
a type of x-ray that allows the doctor to see your spine in order to determine where to insert the 
needle.   
 
LP involves inserting a small 
needle near the base of the spinal 
cord. A small amount of fluid is 
collected below the vertebrae. 
There is no risk of paralysis. 


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Screening Phase 
Visit Number 
SC1 
SC2 
SC3 
Approximate Length of Visit (hours) 
3 
2 
2 
Sign Informed Consent 
 
 
Review of Inclusion/Exclusion Criteria 
 
 
 
Medical History 
 
 
Memory & Thinking Skills Tests 
 
 
Review Concurrent Medications 
 
 
Behavioral and Functional Rating Scales 
 
 
Vital Signs 
 
 
Physical/Neurological Exams 
 
 
 
Electrocardiogram (ECG) 
 
 
Blood draw 
 
Urine collected 
 
 
Fasting Lumbar Puncture* 
 
 
MRI Scan* 
 
 
*The visit order of the lumbar puncture and the MRI may be reversed  
During the main part of the study 
If the screening tests show that you can continue to be in the study, and you choose to take part, you will 
participate in some additional “baseline” testing before you will be randomized to receive either the active 
study drug or the placebo.  You have a 50/50 chance of receiving the study drug. Neither you nor the study 
personnel will know who is receiving the nicotinamide or the placebo 
Group 
Dose 
Dosing Schedule 
Nicotinamide 
3000 mg/day 
2 oral tablets taken twice a day 
Placebo 
[no active drug] 
2 oral tablets taken twice a day 
 
Once you have been assigned to a treatment group, you will be asked to come to the clinic up to 5 more 
times for testing and to receive more medication. Additionally, we will call you on the telephone routinely 
to ask you about any adverse events.  
• 
You will be given memory and thinking skills tests and you and your study partner will be asked 
questions about your daily functioning.   (occurs at visits 1, 3, 4) 
• 
You will return unused medication (occurs at visits 2-4) 
• 
You will be issued new medication (occurs at visits 1-3) 
• 
Your height, weight and vital signs (blood pressure, heart rate, breathing rate and temperature) will 
be recorded) (occurs at visits 1-4) 
• 
Physical and neurological exam will be performed. (occurs at visits 1, 3, 4)  
• 
Your medical history will be reviewed. (occurs at visits 1-4 and all telephone interviews) 
• 
A list of medications you are currently taking will be collected. During the study, your reactions to 
the study drug will be carefully monitored. The study doctor must be informed of any medications, 
vitamins and herbal substances that you take or any medication that you may plan to start taking 


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during the study. (occurs at visits 1-4 and all telephone interviews)  
• 
Blood will be drawn from a vein in your arm and you will be asked for a urine sample. These samples 
are for routine laboratory tests and to measure the levels of nicotinamide and its metabolites in your 
body. Some of your blood will be stored for future research use. The total amount of blood drawn 
for this study will be approximately 170 mL of blood (roughly 11.5 tablespoons).  The routine 
laboratory tests ensure that there are no medical conditions that might interfere with your 
participation in the study or that could be responsible for any changes in your well-being throughout 
the study period. (occurs at visits 1, 3, 4)  
• 
You will be asked about any adverse events (changes in health, any side effects/ reactions to 
medications, injuries or illnesses) that you may have experienced since your last visit. (occurs at 
visits 1-4 and all telephone interviews)  
• 
MRI (occurs at visit 4)  
• 
CSF sampling (occurs at visit 4) 
 
Study Timeline 
Treatment Phase 
Visit Number* 
1 
Telephone 
Telephone 
2 
3 
Telephone 
4 
week 
0 
2 
4 
12 
24 
36 
48 
Answer Questionnaires 
Return unused study medication 
 
 
 
Memory & Thinking Skills Tests 
 
 
 
 
Physical & Neurological Exam 
 
 
 
 
 
 
 
Vital Signs 
 
 
 
ECG 
 
 
 
 
Blood collected 
 
 
 
Urine collected 
 
 
 
 
MRI Scan 
 
 
 
 
 
 
Fasting Lumbar Puncture 
 
 
 
 
 
 
Receive study medication 
 
 
 
 
*visits may occur over multiple days 
WHAT ARE THE POSSIBLE SIDE EFFECTS OR RISKS RELATED TO THE STUDY? 
You may have side effects while on the study.  Everyone taking part in the study will be watched carefully 
for any side effects.  However, researchers don't know all the side effects that may happen.  Side effects 
may be mild or very serious.  The researchers may give you medicines to help lessen side effects.  Many 
side effects go away soon after you stop taking the drug.  In some cases, side effects can be serious, long 
lasting, or may never go away.   
You should talk to the research team about any side effects you experience while taking part in the study. 
In large controlled studies, no risks or side effects related to nicotinamide that occurred more frequently 
than placebo have been reported for doses of 3000mg or lower. At higher doses than are being used in 
this study, the following side effects have reported:  
• 
Nausea  
• 
Headache  


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• 
Lightheadedness  
• 
Vomiting  
• 
Diarrhea 
To avoid overdosing, do not take any over-the-counter products during the study that contain niacin and 
niacinamide, which are both forms of Vitamin B3.  Overdosing may result in abnormal results from liver 
function tests which may signal liver toxicity.  
 
Randomization:  You will be assigned to a study group by chance (like a coin flip) rather than by a medical 
decision made by the researchers. The treatment you receive may prove to be less effective or to have 
more side effects than the other study group(s), or than standard treatments available for your condition.   
 
Placebo: A placebo is an inert substance that is indistinguishable from the active study treatment. In this 
study, the placebo is a tablet that does not contain nicotinamide. During this study there is a 50% chance 
that you will receive a placebo. During this time you may experience worsening of your condition, such as 
cognitive decline. The researchers will carefully monitor your condition. If your symptoms worsen and make 
you uncomfortable, you can withdraw from the study. 
 
Blood draw:  Removing blood by a needle may cause temporary pain, bruising, bleeding, swelling, 
dizziness, and on rare instances fainting or infection.  
 
Psychological discomforts: Some of the procedures may cause anxiety, or the questions the 
researchers ask you may be upsetting or make you uncomfortable.  If you do not wish to answer a question, 
you can skip it and go to the next question.  If you do not wish to participate you can stop. 
 
MRI  
The MRI procedure uses a powerful magnetic field to generate detailed images of the body. The magnet 
could move objects within your body that contain metal, such as implants, clips and pacemakers. Tell the 
doctor if you have any metal items within your body.  
 
MRI scanning is painless but you might experience discomfort in the machine. You may be bothered by 
feelings of claustrophobia when placed inside the MRI, or by lying in one position for a long time. In 
addition, loud noises occur during the study when the scanner is collecting measurements. These noises 
are beeping and hammering sounds and may bother you. Temporary hearing loss has been reported from 
this loud noise.  This is why you will be asked to wear ear plugs.  
 
Lumbar Punctures 
There are 2 lumbar punctures in this study - one at the beginning of the trial, during the screening phase 
and one at the end of the trial. A total of up to 40 mls (less than 3 tablespoons) of cerebrospinal spinal fluid 
(CSF) may be taken during this entire study and your body will make up for this loss. 
 
For most people, a lumbar puncture does not cause any serious problems. The most common problem is 
a headache. For example, in one study, only 7% of people having a lumbar puncture experienced a mild, 
moderate, or severe headache. The frequency of severe headache in this study was less than 1%. If you 
experience a headache that does not go away after 1 or 2 days, it may be due to a leak of the spinal fluid. 
A leak can be treated with a blood “patch”. A blood “patch” is made with a small amount of your blood. 
Your blood is injected into the area where the leak is and typically resolves post-lumbar puncture 
headaches. 
 
Some people also complain about back pain or stiffness, pain at the place where the needle was placed, 
and neck or shoulder pain. These complaints are not as common as a headache and can be treated. 
 


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Rare or very uncommon complaints include low blood pressure and dizziness, bleeding into the spinal 
canal, or an infection of the spinal fluid (known as meningitis). These rare complaints could be serious. 
They could require you to be put in the hospital.  
 
During this study you may have up to 2 fluoroscopy x-ray scans of your spine.  These scans are solely 
for the purpose of this research and you would not have these scan(s) if you decide not to participate 
in this research study.  A fluoroscopy x-ray scan uses radiation to create pictures of the structures 
inside the body.  The total radiation dose that you will receive from 2 scan(s) of this type is about 
400mrem.  A millirem is a unit used to quantify radiation dose.  Typically persons in the U.S. receive a 
radiation dose of about 310 millirem per year from natural sources of radiation, including from the sun, 
air, water and soils.  Therefore your total radiation dose will be about the same as approximately 15 
months of natural background radiation.     
 
There is no known health effects associated with this amount of radiation exposure, and no radiation 
remains in the body after the scan.  If you are especially concerned about radiation exposure, you should 
discuss this with the researcher listed at the top of this form.   
 
Incidental finding:  
There is a risk of an unexpected finding from your MRI scans.  The results will be shared with you and if 
necessary, you will be referred to your primary care physician or other specialist for additional consultation. 
 
Unknown risks:  
There may be risks related to the research that we don't know about yet.  However, you will be informed 
of any additional risks to which you may be exposed, and any changes that are made to the study, as a 
result of any newly-identified risks.  
 
ARE THERE BENEFITS TO PARTICIPATING IN THIS STUDY? 
Participant Benefits 
Taking part in this study may or may not make your health better.  While researchers hope the study drug 
will be more effective than the standard (usual) treatment, there is no proof of this yet. 
 
If you are in the group that receives nicotinamide and it proves to treat your condition more effectively, you 
may benefit from participating in the study, but this cannot be guaranteed 
 
Benefits to Others or Society 
This study will help researchers learn more about nicotinamide, and it is hoped that this information will 
help in the future treatment of patients with Mild Cognitive Impairment and mild Alzheimer’s disease. 
 
WHAT OTHER CHOICES DO I HAVE IF I DON’T WANT TO PARTICIPATE?  
If you decide not to participate, or if you withdraw from this study before it is completed, your other choices 
may include: 
• 
Getting no treatment 
• 
Getting standard treatment for your condition without being in a study. 
• 
Getting a different experimental treatment/taking part in another study. 
As an alternative to being in the study, you may ask your doctor about Aduhelm (an antibody also 
known as Aducanumab). Aduhelm received accelerated approval by the FDA for the treatment of 
Alzheimer’s disease in June of 2021.  There is evidence that Aduhelm can reduce amyloid levels 
in the brain, but it is not clear whether it slows the clinical progression of Alzheimer’s disease. 
People taking Aduhelm cannot participate in this study. 


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WILL I BE PAID FOR TAKING PART IN THIS STUDY? 
Compensation 
You are eligible to receive the following compensation in cash during the course of this study: 
Visit 1 completion: $50  
Visit 2 completion: $50 
Visit 3 completion: $50 
Visit 4 completion: $100 
 
The grand total compensation for this study is a maximum of $250 in cash at UCI or by check at UCLA.  
 
You will also receive a handmade quilt.  
 
If you decide to withdraw from the study or are withdrawn by the research team, you will receive 
compensation for the visits and/or procedures that you have completed. 
 
Reimbursement  
You will not be reimbursed for any out of pocket expenses, such as transportation fees.  
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?  
There is no cost to you or your insurer/third party payer for study procedures. The study drug will be 
provided at no cost to you. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY AT UCI?  
It is important that you promptly tell the researchers if you believe that you have been injured because of 
taking part in this study.  You can tell the researcher in person or call him/her at the number listed at the 
top of this form. 
 
If you are injured as a result of being in this study, UCI will provide necessary medical treatment. The costs 
of the treatment may be covered by the University of California or the study sponsor, or billed to you or 
your insurer just like other medical costs, depending on a number of factors. The University and the study 
sponsor do not normally provide any other form of compensation for injury.  For more information about 
this, you may call UCI Human Research Protections (949) 824-6068 or (949) 824-2125 or by e-mail at 
IRB@research.uci.edu 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY AT UCLA? 
If you are injured as a result of being in this study, UCLA will provide necessary medical treatment. The 
costs of the treatment may be covered by the University of California or the study sponsor, UC Irvine or 
billed to you or your insurer just like other medical costs, depending on a number of factors. The University 
and the study sponsor do not normally provide any other form of compensation for injury. For more 
information about this, you may call the UCLA Office of the Human Research Protection Program at 310-
825-5344 or send an email to mirb@research.ucla.edu. 
 
WHAT HAPPENS IF I WANT TO STOP TAKING PART IN THIS STUDY?  
You are free to withdraw from this study at any time. If you decide to withdraw from this study, you 
should notify the research team immediately. The research team may also end your participation in 
this study if you do not follow instructions, miss scheduled visits, the study sponsor decides to stop the 
study or your safety and welfare are at risk. 
 
If you experience any of the side effects listed above, if your health worsens, or if you are injured during 
the research, you may need to be withdrawn from the study, even if you would like to continue.  The 
research team will make this decision and let you know if it is not possible for you to continue.  The decision 


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may be made to protect your safety and welfare, or because the research plan does not allow people who 
develop certain conditions to continue to participate.  
 
If you withdraw or are removed from the study, the researcher may ask you to return for a final close-out 
evaluation and return unused study medication.   
 
If you elect to withdraw or are withdrawn from this FDA-regulated research study, the data collected from 
your participation in this study must remain in the trial database in order for the study to be scientifically 
valid. 
 
 
HOW WILL INFORMATION ABOUT ME AND MY PARTICIPATION BE KEPT? 
Subject Identifiable Data  
Identifiable information collected about you will be removed and replaced with a code.  A list linking the 
code and your identifiable information will be kept separate from the research data.  
 
Data Storage  
Research data will be maintained in paper format in a secure location at UCI and UCLA. Only authorized 
individuals will have access to it.  Data will also be stored electronically on a secure network in an encrypted 
file with password protection. 
 
Data Retention  
The researchers intend to keep the research data in a repository indefinitely. Other researchers may have 
access to the data for future research. Any data shared with other researchers, will not include your name 
or other personal identifying information.  
 
WHO WILL HAVE ACCESS TO MY STUDY DATA? 
The research team, authorized UC personnel, the study sponsor, the coordinating site at UC San Diego 
and regulatory entities such as the Food and Drug Administration (FDA) and the Office of Human Research 
Protections (OHRP), may have access to your study records to protect your safety and welfare.   
 
While the research team will make every effort to keep your personal information confidential, it is possible 
that an unauthorized person might see it.  We cannot guarantee total privacy. 
 
ClinicalTrials.gov is a Web site that provides information about clinical trials.  A description of this clinical 
trial will be available on http://www.clinicaltrials.gov/, as required by U.S. Law.  This Web site will not 
include information that can identify you.  At most, the Web site will include a summary of the results. You 
can search this Web site at any time.  
 
ARE THERE OTHER ISSUES TO CONSIDER IN DECIDING WHETHER TO PARTICIPATE IN THIS 
STUDY?  
 
Use of Specimens  
Biospecimens (such as blood, tissue, or saliva) collected from you for this study and/or information 
obtained from your biospecimens may be used in this research or other research, and shared with other 
organizations. You will not share in any commercial value or profit derived from the use of your 
biospecimens and/or information obtained from them. 
 
Genetics  
In the event of an unexpected breach of confidentiality, a federal law called the Genetic Information Non-
Discrimination Act (GINA) will help protect you from health insurance or employment discrimination based 
on genetic information obtained about you. In California, state law (CalGINA) requires that employers with 
5 or more employees may not use your genetic information, obtained from this research when making a 


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decision to hire, promote, or fire you or when setting the terms of your employment. However, these laws 
do not protect you against discrimination by companies that sell life insurance, disability insurance, or long-
term care insurance.  
 
If 
you 
would 
like 
more 
information 
about 
the 
federal 
GINA 
law 
go 
to: 
http://www.genome.gov/Pages/PolicyEthics/GeneticDiscrimination/GINAInfoDoc.pdf 
or 
CalGINA: 
http://www.leginfo.ca.gov/pub/11-12/bill/sen/sb_0551-0600/sb_559_bill_20110906_chaptered.pdf 
 
Investigator Financial Conflict of Interest  
No one on the study team has a disclosable financial interest related to this research project. 
 
 
Future Recruitment Opportunities 
You may be approached by the study team for permission to use your images and information related to 
your research participation for promotional purposes.   
 
Request for Donation of Specimens and/or Data for Future Use  
This is a request for donation of your blood, CSF, urine, DNA, and data for medical research. Please 
read each sentence below and think about your choice. After reading each sentence, check either the 
"Yes" or "No" box and provide your initials.  If you have any questions about this request for donation, 
please talk to the researchers. If you choose not to donate your specimens, any leftover tissue or blood 
that is not needed for diagnosis or the discussed study outcomes will be thrown away and/or no 
additional normal tissue or blood will be removed for research purposes. Checking “YES” permits 
researchers to perform additional analyses with your tissue and data, beyond those immediately 
described in this consent form.  
 
 
You may keep my blood, CSF, urine, DNA, and data for future research to learn about, prevent, or treat 
any health problem such as Alzheimer’s disease, diabetes, genetic research, heart disease, or be kept 
for general research purposes.  My blood, CSF, urine, DNA, and data will be stored in a way that does 
not directly identify me. 
 
       YES 
 
        NO 
 
Subject Initials 
 
If you were referred to this study by the Brain Health Registry (BHR), are you willing to have your 
screening data shared back to the BHR organizers? 
 
 
 YES 
 NO 
 Not Applicable 
 
Subject Initials 
 
Optional Research Opportunities:  
 
Study Extension 
 Yes, I would be interested in learning more about participating in a 12-month extension of the treatment 
phase of this study if it becomes available. 
 No, I would not be interested in learning more about participating in a 12-month extension of the 
treatment phase of this study 
 
 
 
 


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Prot_000.pdf: 
Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
1
 
1. CLINICAL RESEARCH PROTOCOL 
 
Study Title: 
A Phase 2, Proof-of-Concept, Double-Blind-Randomized, Placebo-
Controlled Adaptive Design Trial of Nicotinamide in MCI due to AD 
and Mild AD Dementia 
 
Short Title: 
 
 
Nicotinamide as an Early AD Treatment (NEAT) Trial 
 
IRB #:   
 
 
UC Reliance # 2016-10797 
 
Project Director: 
Joshua Grill, PhD, UC Irvine 
 
ADCS Principal Investigator: 
Howard Feldman, MD, UC San Diego 
 
Sponsor: 
UC Irvine Institute for Memory Impairments and Neurological 
Disorders 
 
Funding source: 
UC Cures Initiative, University of California Office of the President 
 
Protocol version: 
 
Version 4.0; December 28, 2017 
 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
2
 
 
2. STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following:  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312)   
• 
ICH E6  
 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
 completed Human Subjects Protection Training.   
 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments.  
 
 
Project Director: 
  
________________________________  
Print/Type Name  
 
 
Signed:  
 
__________________________________ Date:______________  
Signature  
 
 
 
Site Principal Investigator:  ________________________________  
Print/Type Name  
 
 
Signed:  
 
__________________________________ Date:______________  
Signature  
 
 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
3
 
3. Protocol Synopsis 
Title of study: A Phase 2, Proof-of-Concept, Double-Blind-Randomized, Placebo-Controlled Adaptive 
Design Trial of Nicotinamide in MCI due to AD and Mild AD Dementia 
Background: Nicotinamide, the amide of nicotinic acid (vitamin B3/niacin), is an oral therapy with a 
wealth of clinical data in a variety of therapeutic areas, including preliminary data supporting its safety 
in Alzheimer’s disease (AD). Preclinical work in a mouse model that develops both plaques and tangles 
supports the hypothesis that nicotinamide can act as a histone deacetylase (HDAC) inhibitor to reduce 
phosphorylation of tau.1, 2 In this mouse model of AD, treatment with nicotinamide reduced p-tau, 
increased microtubule stability and rescued cognitive function.  
Developmental phase: Phase 2 
Research objectives:  
1: Determine if daily treatment with high dose nicotinamide can reduce levels of phosphorylated tau in 
individuals with mild AD dementia or MCI due to AD. 
2: Assess the safety and tolerability of high dose nicotinamide treatment in individuals with mild AD 
dementia or MCI due to AD.  
Study design: Group sequential design, incorporating a futility analysis with a go/no-go decision 
conditional on CSF biomarker outcomes at 48-weeks. 
Duration of study:  
Screening period: Up to 60 days 
Treatment period: 48-weeks 
Sample size: 48 
Study population: Patients age 50 or older who meet criteria for MCI due to AD or Mild AD dementia 
(Mini-Mental State Exam [MMSE] ≥ 20) not otherwise excluded.  
Dose and administration: Nicotinamide is an oral tablet that will be administered at 1500 mg (two 750 
mg tablets) BID.  
Primary outcome: Change in CSF p-tau231 
Secondary outcomes:  
1. Change in CSF p-tau181 
2. Change in CSF total tau 
3. Change in CSF Aβ42 
4. Change in CSF Aβ40 
5. Change in ADAS-cog13 
6. Change in ADCS-ADL 
7. Change in CDR-SB 
Safety parameters: Adverse events, symptom checklist, vital signs, physical, neurological examination 
and laboratory tests. 
Go/No-go decision: An additional 48-weeks treatment and follow-up period is planned, contingent upon 
a “go” decision based on the primary outcome (CSF p-tau231) or one planned secondary outcome (CSF 
p-tau181) 
Statistical methods:  The study will implement a seamless phase 2a-2b sequential design with a go/no-
go futility analysis based upon change in CSF biomarkers after 48-weeks. The primary outcome for the 
trial is change in p-tau231. Inference for the initial go/no-go decision will be based upon the difference in 
within-subject change in p-tau231 or p-tau181 over 48-weeks between treatment and control.  
 
 
 
 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
4
4. TABLE OF CONTENTS 
 
1. TITLE PAGE ……………………………………………………………………………..….. 1 
 
2. STATEMENT OF COMPLIANCE…………………………………………………….…… 2 
 
3. SYNOPSIS ……………………………………………………………………………….…… 3 
 
4. TABLE OF CONTENTS …………………………………………………………………..… 4 
 
5. ABBREVIATIONS ..………………………………………………………………………… 
5 
 
6. INVESTIGATORS…………………………………………………………………………… 6 
 
7. BACKGROUND ...…………………………………………………………………………… 8 
 
8. STUDY OBJECTIVES ……………………………………………………………………… 9 
 
9. INVESTIGATIONAL PLAN ..……………………………………………………………… 10 
 
10. STUDY POPULATION…………………………………………………………………...…  12 
 
11. TREATMENT  …………………………………………………………………………….…  15 
 
12. OUTCOME MEASURES…..…………………..………………………………………….…  16 
 
13. SAFETY ASSESSMENTS …………………………………………………………….……..  18 
 
14. SAMPLE SIZE AND STATISTICAL METHODS……..……………………………….…  19 
 
15. ETHICS..….…………………………………………………..…………………………….…  21 
 
16. DATA HANLDLING AND RECORDING.…………..………..……………………………  22 
 
17. REFERENCES .…………..…………………………………………...………………………  24 
 
 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
5
5. List of abbreviations 
3xTg 
Triple Transgenic mouse 
AE 
Adverse Event 
Aβ 
Amyloid Beta 
AD 
Alzheimer’s Disease 
ADAS-cog 
Alzheimer’s Disease Assessment Scale – Cognitive subscale 
ADCS 
Alzheimer’s Disease Cooperative Study 
ADCS-ADL-
MCI 
Alzheimer’s Disease Cooperative Study Activities of Daily Living 
Scale in Mild Cognitive Impairment 
ADRC 
Alzheimer’s Disease Research Center 
APOE 
Apolipoprotein 
BID 
Twice daily 
CBC 
Complete Blood Count 
CDR 
Clinical Dementia Rating Scale 
CDR-SB 
Clinical Dementia Rating Scale Sum of Boxes 
CFR 
Code of Federal Regulations 
CBIC 
Clinician Based Impression of Change 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
C-SSRS 
Columbia Suicidality Severity Rating Scale 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EKG 
Electrocardiogram 
FCSRT 
Free and Cued Selective Reminding Task 
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
GMP 
Good Manufacturing Practices 
HDAC 
Histone Deacetylase 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
LFT 
Liver Function Test 
MCI 
Mild Cognitive Impairment 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Exam 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
NAD 
Nicotinamide Adenine Dinucleotide 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
UA 
Urinalysis 
WNL 
Within Normal Limits 
 
 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
6
6. INVESTIGATORS 
 
UC Irvine:  
Project Director, Joshua Grill, PhD 
Associate Professor of Psychiatry & Human Behavior 
Institute for Memory Impairments and Neurological Disorders 
Alzheimer’s Disease Research Center 
Institute for Clinical Translational Science 
3204 Biological Sciences III  
Irvine, CA 92617 
(949) 824-5905 
 
Co-Investigator, Dan Gillen, PhD 
Professor and Chair, Department of Statistics 
Institute for Memory Impairments and Neurological Disorders 
Alzheimer’s Disease Research Center 
 
Site Principal Investigator, Aimee Pierce, MD 
Assistant Clinical Professor of Neurology 
Medical Director, Memory Assessment and Research Center  
Co-Leader, UCI ADRC Clinical Core  
 
Site Co-Principal Investigator, Steven Schreiber, MD 
Professor of Neurology  
 
Site Coordinator, Beatriz Yanez, RN 
Institute for Memory Impairments and Neurological Disorders 
 
Site Coordinator, Robin Lawrence, RN, MS, AGPCNP-BC 
Institute for Memory Impairments and Neurological Disorders 
 
Consultant, Kim Green, PhD 
Associate Professor, Neurobiology and Behavior 
Institute for Memory Impairments and Neurological Disorders 
Alzheimer’s Disease Research Center 
 
UCLA:  
Site Principal Investigator, Sarah Kremen, MD 
Staff neurologist 
Co-Director, Katherine and Benjamin Kagan AD Treatment Development Program  
Mary Easton Center for AD Research 
 
Site Co-Investigator, Maryam Beigi, MD  
Staff neurologist  
Katherine and Benjamin Kagan AD Treatment Development Program 
Mary Easton Center for AD Research 
 
Site Coordinator, Celine Ossinalde, MA 
Katherine and Benjamin Kagan AD Treatment Development Program 
 
Consultant, Gregory Cole, PhD 
Interim Director, UCLA Mary Easton Center for AD Research 
  
UC San Diego/ADCS:  


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
7
ADCS PI, Howard Feldman, MDCM, FRCP(C) 
Professor of Neurosciences 
Dean for Alzheimer’s and Related Neurodegenerative Research 
 
ADCS Biostatistics Core Director, Ron Thomas, PhD 
Professor and Division Chief of Biostatistics and Bioinformatics 
Department of Family and Preventive Medicine 
 
ADCS Biomarker Core Director, Robert Rissman, PhD 
Associate Professor of Neuroscience 
 
ADCS Neuroimaging Core Director, James Brewer, MD, PhD  
Professor of Neurosciences 
Interim Director of the UCSD ADRC 
  
ADCS Interim Medical Safety Core Director, Tilman Oltersdorf, MD 
Department of Neurosciences 
 
ADCS Medical Monitor, Branko Huisa, MD 
Department of Neuroscience 
 
 
 
 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
8
7. BACKGROUND 
Treatments capable of slowing the progression of Alzheimer’s disease (AD) are desperately needed. 
Though a variety of promising candidates are in development,3 there are no approved drugs able to slow 
AD.4 Anti-amyloid therapies dominate the clinical pipeline but if shown to be effective will have great 
cost, may require routine infusions, and may be associated with substantial risk for serious adverse 
events.5 Some experts argue that there is an over-emphasis on amyloid beta (Aβ)-targeting therapies in 
clinical development and most agree that there is a need to explore alternate hypotheses and therapeutic 
targets.6 Safe and effective oral therapies that are capable of slowing the disease process represent a major 
therapeutic goal in AD research.  
 
Neurofibrillary tangles represent the pathological hallmark of AD that is most strongly correlated with 
cognitive decline.7, 8 Neurofibrillary tangles are composed of hyperphosphorylated tau, a microtubule 
associated protein critical to neuronal viability. Elevated levels of tau phosphorylated at threonine 231 (p-
tau231) in the cerebrospinal fluid (CSF) can be used to distinguish AD from normal controls and other 
neurodegenerative conditions,9, 10 are correlated with neurofibrillary tangle burden at autopsy,11 and are 
predictive of progression to dementia among patients with mild cognitive impairment (MCI).12 Therefore, 
this biomarker substrate of AD pathology may be a meaningful target for candidate disease-modifying 
therapies.  
 
Nicotinamide, or niacinamide, is a key component of nicotinamide adenine dinucleotide (NAD), a co-
enzyme involved in many cellular oxidation-reduction reactions and vital for cellular respiration. 
Nicotinamide also acts as a free radical scavenger, and modulates both immune cell function and 
apoptosis. In addition to these crucial roles, high doses of nicotinamide function to inhibit the class 3 
histone deacetylases (HDACs), or sirtuins. Sirtuins are a unique class of NAD(+)-dependent deacetylases 
required for diverse biological processes including autophagy, transcription, and apoptosis. Sirtuins 
function to remove acetyl groups from their substrate proteins, and in doing so regulate cellular pathways.  
In this process the acetyl group is passed from the substrate to an NAD molecule.  The presence of 
nicotinamide within the cell competes with free pools of NAD, however, and thereby prevents this 
process from occurring. It has been found that regulating protein acetylation can be broadly protective and 
as such HDAC inhibitors are being pursued as potential treatments for numerous neurodegenerative 
diseases.13 Four months of nicotinamide treatment (200 mg/kg/day) in triple transgenic AD mice (3xTg), 
which develop both amyloid plaques and neurofibrillary tangles,14 selectively decreased the accumulation 
of p-tau231 by 60% in AD-vulnerable brain regions and significantly ameliorated cognitive decline, 
without affecting levels of Aβ.1 Treatment also increased acetylated alpha-tubulin and microtubule-
associated protein 2c levels, enhancing microtubule stabilization.1 Importantly, laboratories at the 
National Institute on Aging have replicated the effects of nicotinamide on tau phosphorylation in 3xTg 
mice. This group also found beneficial effects on Aβ pathology as well as improved brain bioenergetics 
with preserved functionality of mitochondria and the autophagy system.2 Thus, there is a strong pre-
clinical rationale for testing the hypothesis that nicotinamide can act as an HDAC inhibitor to reduce p-
tau in AD.  
 
Notably, trials in other neurologic conditions support the hypothesis that nicotinamide can act as an 
HDAC inhibitor. In Friedreich’s ataxia, high dose nicotinamide (3.5-6g/day) resulted in a dose-response 
upregulation of expression of frataxin mRNA and overall increases in frataxin protein levels,15 
presumably due to HDAC inhibition, as protein changes were accompanied by decreased heterochromatin 
modifications in the FXN gene.15, 16 Nicotinamide has also been shown to be beneficial/protective in 
animal models of stroke,17 traumatic brain injury,18-20 Parkinson’s disease,21, 22 and Huntington’s disease,23 
emphasizing the rationale that nicotinamide may be therapeutic in CNS diseases, and that it modulates 
specific pathways implicated in AD pathogenesis. 
 
Large human clinical trials demonstrate the safety of high dose nicotinamide. For example, in a study of 
more than 550 participants with a first-degree family history of Type I diabetes, no differences between 
nicotinamide and placebo were observed for any adverse event.24 The daily dose in this study was mean 
1.2 g/m2 up to a maximum of 3g/day for five years. Similarly, in a phase 3 study of twice daily 500 mg 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
9
nicotinamide to prevent recurrent non-melanoma skin cancer (n=386), no differences were observed in 
adverse event profiles between those randomized to nicotinamide and those randomized to placebo. 
Treatment with nicotinamide also reduced the occurrence of new basal cell and squamous-cell carcinomas 
by 20% and 30%, respectively.25  
 
We previously performed a single-site safety trial in humans with mild-to-moderate AD (Schreiber et al., 
in preparation). Participants age 50 or older with a diagnosis of probable AD and Mini-Mental State 
Exam (MMSE) scores 13-26, inclusive, were enrolled. Exclusion criteria were a diagnosis of non-AD 
dementia, unstable psychiatric disease or medical illness, history of alcoholism, drug abuse, liver disease 
or peptic ulcer disease, and Hachinski Ischemic Score >4 or evidence of stroke on magnetic resonance 
imaging (MRI) or computed tomography scan. Participants were required to be on stable medications for 
at least 30 days, including FDA-approved therapies for AD. Participants were not permitted to take 
supplements containing nicotinamide. Participants were required to have a study partner who could 
accompany them to visits and ensure compliance with the study treatment. 
 
We randomized 31 participants to receive nicotinamide (Endur-amide [Niacinamide, vitamin B3] 1500 
mg orally bid, Endurance Products Company, Tigard, OR), or a matching placebo for 24 weeks. The 
randomization was 1:1, with no stratifications. The dose of nicotinamide approximated that used in 
preclinical studies and was comparable to other human trials.24, 25 Adverse events were recorded at weeks 
6, 12, 18 and 24. Safety laboratories (tests of liver function [LFTs], serum electrolytes and complete 
blood count [CBC]) were assessed at week 4. Vital signs, physical and neurological examinations were 
assessed at baseline and week 24. Pill counts assessed compliance. In addition to safety assessments, we 
completed the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog11), 
Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), Alzheimer’s 
Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL), and the Clinical Dementia 
Rating Scale (CDR) at baseline and weeks 6, 12, 18, and 24. 
 
Participants in the active and placebo groups were mean age 79.7±6.9 and 79.0±8.4, respectively, and had 
mean MMSE scores of 22.1±3.17 and 21.3±3.6. Fifty-six percent of subjects in the treatment group were 
male, compared to 80% in the placebo group. Twenty-eight participants (90%) completed the study. 
Treatment compliance was 72% in both groups.  
 
No adverse events resulted in participant withdrawal from the study. We observed no adverse effects of 
nicotinamide on serum electrolytes, CBC or LFTs. The most frequent adverse event was visual 
hallucination or delusions (n=4 nicotinamide, n=4 placebo). There was no difference between the groups 
on clinical outcome measures. The conclusion of this Phase 2a study is that nicotinamide can be safely 
administered at a dose of 3000 mg/day in patients with mild-to-moderate AD. 
 
In summary, nicotinamide is a promising intervention for neurodegenerative disease that may specifically 
target neurofibrillary pathology in AD. Nicotinamide is safe at high doses and over long durations of 
treatment in humans. No study has tested the hypothesis that nicotinamide can inhibit HDAC to reduce 
phosphorylation of tau in people with AD.  
 
 
8. STUDY OBJECTIVES 
 
8.1. Primary Objectives  
Objective 1: Determine if daily treatment with high dose nicotinamide reduces levels of phosphorylated 
tau (p-tau231) in individuals with mild AD dementia or MCI due to AD. 
 
Objective 2: Assess the safety and tolerability of high dose nicotinamide treatment in individuals with 
mild AD dementia or MCI due to AD.  
 
8.2. Secondary Objectives 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
10
Secondary Objective 1: Determine if daily treatment with high dose nicotinamide can affect CSF levels of 
amyloid beta (Aβ42), phosphorylated tau (p-tau181), total tau (t-tau), or the ratio of total tau/Aβ in 
individuals with mild AD dementia or MCI due to AD. 
 
Secondary Objective 2: Determine if daily treatment with high dose nicotinamide reduces the rate 
cognitive decline in individuals with mild AD dementia or MCI due to AD. 
 
Secondary Objective 3: Determine if daily treatment with high dose nicotinamide reduces the rate of 
functional decline in individuals with mild AD dementia or MCI due to AD. 
 
8.3. Exploratory Objectives 
Exploratory Objective 1: Determine if daily treatment with high dose nicotinamide reduces the rate of 
brain volume atrophy in individuals with mild AD dementia or MCI due to AD. 
 
Exploratory Objective 2: Determine the effect size of 48-weeks change in phosphorylated tau in 
individuals with mild AD dementia or MCI due to AD. 
 
 
9. INVESTIGATIONAL PLAN 
 
9.1. Overall Study Design and Plan 
This is a Phase 2a group sequential design, incorporating a futility analysis with a go/no-go decision 
conditional on CSF biomarker outcomes at 48-weeks. With a go-decision, follow-up will be extended to 
96-weeks in a Phase 2b trial, with dual co-primary outcomes of the 13-item cognitive subscale of the 
Alzheimer’s Disease Assessment Scale (ADAS-cog13) and the Alzheimer’s Disease Cooperative Study-
Activities of Daily Living Scale (ADCS-ADL). The purpose of the Phase 2b trial is to provide 
preliminary measures of efficacy to facilitate the design of a larger registration trial. 
 
The initial trial primary outcome is CSF p-tau231. We will randomize 48 participants to 1500 mg BID 
nicotinamide or matched placebo at a 1:1 ratio. Additional CSF analyses (p-tau181, total tau, Aβ40, Aβ42) 
will be performed as secondary outcomes in the proposed Phase 2a trial. A portion of the CSF sample will 
be stored for future biomarker analyses. Clinical measures will be collected every 24-weeks throughout 
the study and will be considered secondary outcome measures in the initial trial. Cognitive and functional 
outcomes will include ADAS-cog13, ADCS-ADL, and CDR sum of boxes (CDR-SB). Additionally, we 
will examine change in brain volume (whole brain volume, ventricular volume, hippocampal volume, and 
cortical thickness) as exploratory secondary outcome measures. 
 
9.2. Study Procedures 
9.2.1. Visit schedule (see Appendix 1). 
• 
Screening period: Three visits will determine eligibility. An initial clinical visit will 
include completion of informed consent, MMSE, Wechsler Logical Memory II, FCSRT, 
CDR-SB, GDS, physical and neurological examinations including vital signs, medical 
history and collection of concomitant medications, and assessment of inclusion and 
exclusion criteria. This visit will also include a blood draw for apolipoprotein E (APOE) 
genotyping, safety labs, urinalysis (UA), and electrocardiogram (EKG). Assuming that 
participants have had clinical neuroimaging within the previous 12-months to exclude the 
possibility of space-occupying lesion, the second visit will include lumbar puncture (LP) 
and fasting blood draw for future biomarker research. A third visit will include MRI for 
screening and baseline volumetric assessment. For participants lacking clinical 
neuroimaging in the previous 12-months, the order of LP and MRI visits may be reversed. 
If needed, redraw of blood can be performed to check platelet level and coagulation 
parameters within 30 days prior to LP. 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
11
• 
Active period: Eligible participants will have a brief physical and neurological exam 
including vital signs, collection of adverse events and concomitant medications, cognitive 
testing (MMSE and ADAS-cog), be administered the C-SSRS, GDS, and ADCS-ADL-
MCI, will receive study medication, and undergo safety labs (blood and urine) at the 
baseline exam. Telephone follow-up at 2, 4, and 36-weeks will assess safety. At 12-weeks, 
an in-person visit will include a brief physical and neurological exam including vital signs, 
collection of adverse events and concomitant medications, blood collection for drug levels, 
fasting blood collection for future biomarkers, EKG, assessment of treatment compliance 
and administration of study medication. At 24 and 48-weeks, participants will undergo 
blood safety labs, urinalysis (UA), blood collection for drug levels, blood collection for 
future biomarkers, and EKG. Participants will complete the MMSE, ADAS-cog13, 
ADCS-ADL-MCI, CDR-SB, GDS, C-SSRS physical and neurological examinations, 
including vital signs, collection of adverse events and concomitant medications. MRI, LP, 
and fasting blood collection for future biomarkers will be performed at 48-weeks. 
• 
End of study: At 48-weeks, participants will complete all study assessments. Participants 
will be provided additional study drug (6-months supply) for the period of time for go/no-
go analysis.  
• 
Early termination: In the event of early termination due participant withdrawal of consent 
or removal by the investigator from the trial, the 48-weeks/early termination visit should 
be completed in all possible cases, if the participant has been randomized to therapy or 
placebo. No new investigational product will be administered. 
• 
Unscheduled visits: If needed, unscheduled visits can be performed at the discretion of the 
Site Principal Investigator. Unscheduled visits should include collection of adverse events, 
concomitant medications, brief neurological and physical examination, and clinical blood 
laboratories, if indicated.  
• 
Go/no-go: At the completion of the go/no-go analyses, participants will complete an 
additional visit to assess safety and collect study medication (no-go) or to be enrolled in 
the 48-weeks extension study (go). In the event of a “go” decision, trial duration will be 
extended to 96-weeks. Participants will remain blinded to randomization and group 
assignment will be unchanged. A safety visit will be performed at 74-weeks. The end of 
study visit will be performed at 96-weeks, and will include the co-primary outcome 
measures of the ADAS-cog13 and the ADCS-ADL-MCI, as well as the CDR-SB, 
neurological and physical exams, blood laboratories, assessment of adverse events, MRI, 
and lumbar puncture for CSF protein analysis. 
 
9.2.2. Safety assessments. Participants will undergo brief physical and neurological examinations, 
laboratory testing, and EKG at all follow-up visits (12, 24, and 48-weeks /early termination). Adverse 
events will be assessed by the study site clinician. Adverse events include signs or symptoms that may or 
may not be related to study medication, abnormalities detected during physical examination, or clinically 
significant laboratory abnormalities. The Columbia Suicidality Severity Rating Scale (C-SSRS) will be 
performed at the baseline, 24-week, and 48-week visits. Adverse events will be graded as mild, moderate, 
or severe according to section 13.1.1, and recorded on case report forms. Regular safety reports will be 
prepared by the ADCS and submitted to an independent Data and Safety Monitoring Board (see section 
13.3.3). 
 
9.2.3. Laboratory evaluations. Routine safety laboratory studies will include CBC, chemistries and 
urinalysis at screening, and lipids and liver function tests at follow-up visits (24 and 48-weeks/early 
termination).  
 
9.2.4. Treatment compliance. At each follow-up visit (12, 24, and 48-weeks/early termination), 
participants will bring their study medication diaries and their study medications for the purpose of 
standard pill counts. The over-the-counter availability of nicotinamide presents the challenge that 
participants could purchase and take the study intervention. We will assess blood levels of N1-


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
12
Methylnicotinamide, 2-Pyridone (a nicotinamide metabolite) and blood levels of NAD at the 12-, 24- and 
48-week visits.26, 27 For these visits, study medication should be held until in the clinic, to optimize 
measures of compliance. Eighty percent compliance is expected. If there is an insufficient level of drug 
compliance, the site must consult with the Project Directors and Medical Monitor regarding timing and 
procedures. It is possible that subjects will be discontinued early from the study due to insufficient 
compliance. 
 
9.2.5. Lumbar puncture. Within 30 days prior to lumbar puncture, participants’ coagulation panel and 
platelet count will be measured and verified within normal limits.  Lumbar puncture (LP) will be 
performed under fasting conditions (minimum 8-hour fast).  Only water (and any medications that can be 
taken without food) is permitted until LP is complete.  LP will be performed as close to 08:00AM as 
possible.  Participants will be in a seated position for the LP, if possible.  LP will be performed using a 
small caliber atraumatic needle (e.g. 22 or 24 gauge Sprotte needle.)  LPs will be permitted to be 
performed under guided fluoroscopy if CSF is unable to be obtained by bedside LP.  CSF will be 
collected by gravity flow or aspiration method, at the discretion of the site clinician. All syringes, tubing, 
collection tubes, and transfer tubes will be polypropylene.  A total of 18mL of CSF will be collected.  The 
first 2mL fraction of CSF will be sent to local lab for measurement of cell counts and differential, 
glucose, and protein.  The next 16mL of CSF will be immediately placed on ice during transfer and 
aliquot procedures, frozen at -80°C, then shipped overnight on dry ice on the day of collection to ADCS 
Biomarker Core.  Time of collection, verification of fasting status, type and gauge of needle, method of 
collection, and total volume of CSF collected will be recorded. 
 
9.2.6. Data Management. Data will be collected on Case Report Forms (CRFs), identifying subjects only 
by study ID number. Electronic data will be entered into the ADCS Electronic Data Capture (EDC) 
System. 
 
10. STUDY POPULATION 
 
10.1. Participants 
Modern AD trials have moved toward patient samples that meet biomarker criteria for AD. This includes 
MCI due to AD28 or prodromal AD,29 as well as dementia due to AD.30 The rationale for implementing 
these criteria include 1) the desire to ensure that participants enrolled in trials truly have AD, 2) the need 
to limit exposure of non-AD patients to drugs targeting AD pathology (e.g., giving amyloid-lowering 
therapy only to patients with elevated brain amyloid), and 3) the resultant implications to trial design and 
primary outcome assessments (i.e., trials enrolling patients who are not likely to benefit from therapy 
reduce power31). In this study, the safety of the treatment has been demonstrated through numerous 
human studies, reducing the implications to participant health. Thus, the need to characterize the disease 
of participants and the implications to trial design and power instructed the enrollment criteria. The 
criteria for enrollment in this study will be intentionally liberal, due to the limited study resources, the 
safety profile of the intervention, and to ensure maximal recruitment. We will enroll participants meeting 
criteria for MCI due to AD or dementia due to AD, provided that all other criteria are met. AD biomarker 
status will be assessed through lumbar puncture and CSF protein analysis, and an algorithm whereby 
multiple criteria can be used to include a participant (low Aβ or the ratio of total tau to Aβ) will be 
implemented. In a recent prodromal AD trial that permitted enrollment with a similar algorithm, only 
about half of participants would have been eligible based on Aβ criteria alone, whereas nearly 90% of 
enrolled participants were eligible based on the ratio of total tau to Aβ.32 Nearly 75% of amnestic MCI 
patients may meet CSF eligibility requirements33 and rates are anticipated to be even higher among those 
with probable AD dementia.34 
 
10.1.1. Inclusion Criteria 
1. Age 50 or older 
2. MCI or dementia due to AD 
 
MCI due to AD28:  
• 
Subjective memory complaint by the participant or an informant 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
13
• 
Memory impairment demonstrated by at least one of the following: 
o CDR memory box ≥0.5 
o Wechsler Logical Memory II >1.5 standard deviations below 
education adjusted mean 
 
Less than or equal to 11 for 16 or more years of education 
 
Less than or equal to 9 for 8-15 years of education 
 
Less than or equal to 6 for 0-7 years of education 
o Free and Cued Selective Reminding Test (FCSRT) Total Recall 
score ≤ 39 
o FCSRT Free Recall score ≤24 
o FCSRT Delayed Free Recall score ≤ 8 
• 
Preserved functional independence/not demented, based on investigator 
clinical assessment 
 
Probable AD dementia30: 
• 
Cognitive impairment to a minimum of two domains that interferes with 
ability to function at work or at usual activities and represents a decline from 
previous levels 
o Insidious onset with gradual progression 
o Amnestic presentation or nonamnestic presentation (language, 
visuospatial, or executive dysfunction) 
o The presentation is not indicative of non-AD pathology (e.g., history 
of stroke or core features of Lewy body dementia, behavioral variant 
frontotemporal dementia, or non-AD primary progressive aphasia) 
3. Biomarker criteria:  
 
CSF Aβ42 ≤600 pg/mL, or  
 
A ratio of total tau to Aβ42 ≥ 0.39 
4. Mini-Mental State Exam (MMSE) ≥ 20 
5. Blood laboratories (LFTs, CBC, etc), UA, and EKG are WNL or deemed clinically not 
significant by the site investigator 
6. Stable medications (including approved AD therapies) for at least 4 weeks prior to 
baseline 
7. At least 6 years of education 
8. Able to swallow oral tablets 
9. Speaks English fluently 
10. Available qualified study partner (≥3 times per week in-person communication with the 
participant) 
 
10.1.2. Exclusion Criteria 
1. Active neurological or psychiatric diagnosis other than AD that may affect cognition 
and/or function. (Obstructive sleep apnea is permitted, if treated.) 
2. Any medical condition likely to significantly interfere with the evaluation of safety and 
efficacy of the study drug. 
3. Inability to undergo lumbar puncture, including use of Coumadin, novel oral 
anticoagulants, clopidogrel, or dipyridamole.  Use of aspirin <= 325mg daily is 
permitted. 
4. Hachinski ischemic scale > 4 
5. Magnetic Resonance Imaging (MRI) incompatibility 
6. MRI evidence of cortical stroke >1cm, superficial siderosis, or extensive white matter 
hyperintensity (Cardiovascular Health Study score 7-8+)35 
7. Diagnosis of cancer in the previous 3 years (with the exception of basal or squamous cell 
carcinoma) 
8. Geriatric Depression Scale (GDS) score >6 
9. History within the past 5 years of alcohol or substance use disorder (DSM-5) 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
14
10. Laboratory evidence of a clinically significant abnormality that may interfere with study 
assessments 
11. Active partial or total malabsorptive disease (e.g., celiac disease)  
12. Resides in a skilled nursing facility 
13. Use of concomitant medications likely to significantly interfere with the evaluation of 
safety and efficacy of the study drug. 
14. Participation in a clinical trial of a potential disease-modifying therapy for AD in 
previous 6-months (time between last investigational drug administration and baseline for 
the current study) 
15. Pregnant, lactating or of child bearing potential (that is, women must be 2 years post-
menopausal or surgically sterile to be considered not child bearing potential).   
16. Unwillingness to abstain from over-the-counter nicotinamide for the duration of the trial 
 
Subjects who do not meet all inclusion criteria, disease diagnostic criteria, or who meet any exclusion 
criteria may not be randomized into the study without prior approval from the Project Directors and 
Medical Monitor. 
 
10.1.3. Re-screens 
Unless otherwise approved by the Project Directors, only one re-screen is allowed per participant, should 
the original screen be a failure. The re-screen should typically occur at least 3 months after the original 
screen failure. Individuals who fail screening due to ineligible results from the CSF testing may not be re-
screened without permission from the Project Directors. 
 
10.2. Recruitment and Retention 
10.2.1. Recruitment rates and methods. The planned enrollment rate is 2 baselines/month/site for this trial. 
We plan a number of critical activities related to participant enrollment: 
1. We will enroll patients taking approved AD therapies and will reimburse participants for 
their time. The study will enroll participants with presumed underlying AD, including 
both patients with MCI and those with mild dementia. 
2. The two recruitment sites in this trial, UCI and UCLA, both have potential participant 
registries that will facilitate participant recruitment.36 These registries may enable rapid 
start-up of recruitment for the trial, by providing a bolus of participants who can be 
contacted about the study at initiation. 
4. We will leverage relationships with organizations such as the local chapters of the 
Alzheimer’s Association (California Southland and AAOC) and the newly formed 
independent organizations, Alzheimer’s Greater Los Angeles and Alzheimer’s Orange 
County. Community partners will be called upon to a) refer potentially eligible 
participants, b) share study materials with families and other advocates, and c) schedule 
and publicize community talks by investigators describing the study and encouraging 
participation.  
5. Participant education will be critical to recruitment, including dispelling myths about the 
lumbar puncture. Both sites have outstanding track records of community and participant 
education, stemming from a more than 20-year history (at both institutions) of being 
NIA-funded Alzheimer’s Disease Research Centers and California Department of Public 
Health Alzheimer’s Disease Centers. 
6. Both sites have outstanding media relations departments and a substantial track record of 
working with the ADCS Recruitment Core to secure local and national media stories 
covering new studies and participants in those studies. We will work with the ADCS 
Recruitment Core and the media relations offices at the two sites to generate local media 
stories on this trial.  
 
10.2.2. Participant engagement. Participant engagement will be critical to maximizing completion rates in 
this trial. To maximize participant retention, we will use a variety of methods to communicate 
investigator gratitude and the critical value of participant contributions.  


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
15
1. Telephone follow-ups. Study staff will call participants to complete safety assessments at 2, 
4, and 36-weeks. Calls will also serve to ensure participant satisfaction, remind 
participants about upcoming visits, and thank participants for their contribution.  
2. Thank you events. Each site holds annual Thank You Events (leveraging other sources of 
funding), honoring research participants in clinical studies. Events include faculty who 
deliver brief research updates. 
3. Cards and reminders. Each site will send annual Holiday and birthday cards and quarterly 
electronic newsletters (printed versions will be provided at study visits). We will use 
appointment reminder cards that, in addition to indicating the date of the next study visit, 
reiterate the value of participants’ contribution.  
4. Bi-annual newsletter. The principal investigator will generate a twice-annual newsletter 
that can be mailed or shared with participants at study visits. The newsletter will 
communicate the value of the study and the progress-to-date. The newsletter will also 
share personal stories from site or ADCS staff and testimonials from trial participants 
who are willing to forego confidentiality (with IRB approval). 
5. Compensation. Participants will be compensated for their time spent participating in the 
study. They will receive $250. This compensation value is below the annual minimum for 
reportable taxable income.    
 
 
11. TREATMENT 
11.1. Investigational product.  
Endurance Products Company, Tigard, OR, will provide the active therapy and matching placebo. 
Patients will be randomized to receive 1500 mg (two 750 mg tablets) BID. Participants and their study 
partners will receive 3-months supply of study medication at visit 1 and 2 and a 6-month supply at visit 3 
(see Appendix 1). 
 
The investigational product is produced by Innovite, Inc, and distributed by Endurance Products 
company. Innovite, Inc, specializes in the production of advanced tableting technology, including the 
development of effective controlled release delivery systems. Endurance Products Company is bulk 
provider of nutritional products that has operated since 1976. Innovite, Inc, and Endurance Products 
Company operate within the FDA guidelines for Good Manufacturing Practice. 
 
750 mg tablets 
The study treatment is a nutritional product, produced in bulk. The active treatment, niacinamide 
(nicotinamide; 99%) is produced in a 750 mg sustained release tablet that also includes: Vegetable Waxes 
(Rice Bran and/or Carnauba), Stearic acid (veg), Magnesium Stearate, and Silica. Tablets have a mottled, 
off-white appearance, measure with 0.365” x 0.770” with a thickness of 0.290”. The actual tablet weight 
is 1137 mg. Sustained release is anticipated at 5-7 hours (50±10% at hour 1; 70±10% at hour 2; 85±10% 
at hour 3.5; ≥90% at hour 5). 
 
Matching placebo 
Placebo tablets have a mottled, off-white appearance, measure with 0.365” x 0.770” with a thickness of 
0.295”. The actual tablet weight is 1124 mg. Ingredients include: Cellulose, Vegetable Waxes (Rice Bran 
and/or Carnauba), Stearic acid (veg), Magnesium Stearate, and Silica. 
 
11.2. AE experiences across other trials. 
Vitamin B3 deficiency results in pellagra and is therefore recommended as part of the daily diet (0.3 
mg/kg/day). Alternatively, high dose nicotinamide has been investigated as a treatment or prevention for a 
number of health conditions.37 Because it is a vitamin, nicotinamide has not been subject to the same 
rigorous safety assessment as a new investigational drug would be. Nevertheless, the various clinical 
studies of high dose nicotinamide has resulted in a small literature related to potential adverse events.38 
 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
16
As noted in the Section 7, a previous pilot study supported the safe administration of high dose (1.5g 
BID) nicotinamide in mild-to-moderate AD. Similarly, a large (n=552) clinical trial to test 1.2g/m2 (up to 
3g/day) nicotinamide as a prevention for diabetes,24 and a large (n=386) trial of 500mg BID for recurrent 
basal and squamous cell carcinomas,25 revealed no differences in AE frequencies or profiles between 
those randomized to placebo and those randomized to nicotinamide. Similarly, no human study has 
revealed adverse growth, teratogenic, or oncogenic effects at these doses.38 
 
Alternatively, at doses greater than 3 g/day, nicotinamide may result in AEs. In a Phase I/II trial in ten 
Fragile X patients, each of the participants experienced nausea in the extended (8 week) treatment 
exposure phase with the individual participant’s MTD (2-8 g/day). The other most common AEs in this 
trial were headache (n=5), lightheadedness (n=6), vomiting (n=5) and diarrhea (n=4). Increases in 
abnormal results from liver function tests in three out of ten patients occurred when taking high doses—in 
two cases these effects were mild to moderate and self-limiting and in one case they were severe, but all 
resolved with reduction of the nicotinamide dose.39 A schizophrenic man developed acute hepatic toxicity 
after 9 g/day treatment. The toxicity resolved after treatment cessation, but resumed at re-challenge.40  
 
Thus, the tolerability and safety of nicotinamide at the doses that will be used in this clinical trial appear 
acceptable. At high doses, however, nicotinamide treatment may elicit adverse events. Ongoing safety 
monitoring, including assessment of compliance, will be important to ensure the safety of participants. 
 
Perhaps of note, the safety profiles of related but distinct treatments have been observed. High dose 
nicotinic acid, which can reduce serum cholesterol, frequently results in flushing.41 This is not an 
anticipated effect of nicotinamide treatment, which is not a vasodilator.42 In the ADCS trial of 
supplementation with Vitamin B6 and B12, higher occurrence of depression was observed in the active 
treatment, compared to the placebo arm.43 This difference was deemed marginal and inconsistent, because 
results with the Neuropsychiatric Inventory lacked a consistent effect.43 To our knowledge, no study has 
observed depression as an adverse event associated with nicotinamide treatment.  
 
11.3. Access to therapy and trial closure.  
There is no plan to offer open label access to nicotinamide at the closure of trial, regardless of the go/no-
go decision. Upon completion of the 48-week end of study visit, participants will be administered blinded 
treatment until such time as the go/no-go decision outcome has been determined. In the event of a no-go 
decision, participants will return for an additional visit to assess safety and collect study medication (no-
go).  
 
12. OUTCOME MEASURES 
 
12.1. Primary outcome measure 
The primary outcome of this 48-week go/no-go trial will be change in CSF p-tau231. As described in the 
Significance section of this proposal, CSF p-tau231 levels are elevated in AD dementia9, 10 and MCI due to 
AD.12 Preclinical data are supportive of this biomarker primary outcome, as nicotinamide treatment in 
3xTg mice decreased p-tau231 by 60% and this biomarker change was associated with improved 
microtubule stabilization and behavioral improvements.1 
 
12.2. Secondary outcomes measures 
12.2.1. CSF analyses 
1. CSF p-tau181. CSF p-tau181 is a well-replicated biomarker for AD and is used frequently in 
large AD natural history studies and clinical trials.34, 44 
2. CSF total tau. Increased total tau in the CSF is believed to be a marker of neuronal injury 
or degeneration, though this change is not necessarily unique to AD. Total tau may 
increase by 1.5-2 fold in AD, suggesting that treatment-related reduction in total tau would 
be strongly indicative of a disease modifying effect.34 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
17
3. CSF Aβ42. Reduced CSF Aβ42 is strongly associated with AD.34 Although preclinical work 
at our institution did not find an effect of nicotinamide treatment on brain Aβ42 levels, 
work from another laboratory, in which experiments involved longer exposure to 
nicotinamide did see treatment-induced amelioration of Aβ burden.2 
4. CSF Aβ40. We will also examine CSF levels of the shorter (40 amino acid) peptide 
fragment of Aβ. 
 
CSF biomarker and APOE genotype analyses. Analyses of p-tau231 levels will be performed by 
Quanterix (www.quanterix.com). Quanterix uses proprietary technology, called the Accelerator, and their 
Simoa Discovery kits to assay p-tau231 levels. Preliminary analyses reveal low variability among control 
samples, adequate differential between cases and controls, and strong correlation between this assay and 
p-tau181 (unpublished results), justifying selection of this assay.  
The ADCS Biomarker Core will perform the remaining CSF protein analyses. Validated assay 
platforms from Meso Scale Discovery (Rockville, MD) will be used to assess total tau, Aβ42 and Aβ40 
levels. Fujirebio INNOTEST® protein assay kits will be used to assess p-tau181 levels.  
Real-time PCR restriction fragment length polymorphism analysis will be performed to identify 
participant APOE genotypes. DNA will be extracted from blood using QIAamp DNA blood maxi kit 
(Qiagen, Venlo, Netherlands) and genotyping performed using Applied Biosystems (Foster City, CA) 
TaqMan SNP Genotyping Assay. The amplification reaction will contain 5 μL genomic DNA, 2.5 units of 
Taq DNA Polymerase (New England Biolabs, Inc, Ipswich, MA, USA), 1 × ThermoPol Reaction Buffer 
(New England Biolabs), 0.3 mmol/L dNTPs, 10% DMSO, and 0.3 μmol/L of each primer (forward 
primer: 5′-ACGCGGGCACGGCTGTCCAAGGA-3′; reverse primer: 5′-
GCGGGCCCCGGCCTGGTACAC-3′). The PCR cycling conditions will be: initial denaturation at 94°C 
for 3 minutes followed by 30 cycles of 94°C for 30 seconds and 72°C for 90 seconds with a final 
extension at 72°C for 4 minutes. The assays will be run on a Bio-Rad (Hercules, CA) CFX96. 
 
12.2.2. Clinical outcomes 
1. ADAS-cog13. The ADAS-Cog is the most commonly used cognitive outcome measure in 
AD trials. The 11-item version has a range of 0 to 70 and incorporates tests of memory, 
language, attention, and praxis.45 A 13-item version includes a delayed recall item and a 
number cancellation task, increasing the maximum score to 85, with higher scores 
indicating poorer performance.46 Extended versions of the ADAS-cog may increase 
sensitivity and statistical power in early AD.31, 47 
2. ADCS-ADL-MCI. The ADCS-ADL-MCI is a measure of patient functional performance 
in AD and MCI trials. The informant-based questionnaire assesses conduct of basic and 
instrumental ADLs. A total of 24 ADLs are evaluated. Scores range from 0 to 53, with 
higher scores representing more maintained function.48-50  
3. CDR-SB. The CDR uses patient and informant interviews to assess memory, orientation, 
judgment and problem solving, community affairs, home and hobbies, and self-care.51 The 
CDR can provide a global score of 0, 0.5, 1.0, 2.0, or 3.0 relating to not demented, very 
mild dementia, mild dementia, moderate dementia, and severe dementia, respectively. 
Alternatively, a sum of the boxes can be assessed, providing a wider range and greater 
sensitivity to change. 
4. MMSE. The MMSE52 evaluates orientation, memory, attention, concentration, naming, 
repetition, comprehension, and ability to create a sentence and to copy two intersecting 
pentagons. The range is 0-30, with lower scores indicating greater cognitive impairment. 
Participants must demonstrate MMSE scores >20 to be included in the study.  
5. Free and Cued Selective Reminding Task (FCSRT). The FCSRT53 is a 16-word list 
memory task that incorporates auditory and visual cueing. The FCSRT Total score is the 
sum of three trials – the total recall, the free recall, and the delayed recall of items across 
the 3 trials (Range: 0-48). The FCSRT will be used only as an inclusion criterion in this 
study and only for participants with MCI.  
6. C-SSRS: Consistent with FDA guidance, the C-SSRS will be implemented throughout the 
study. The C-SSRS captures the occurrence, severity, and frequency of suicide-related 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
18
thoughts and behaviors during the corresponding assessment period.  The scale includes 
suggested questions to elicit the type of information needed to determine if a suicide-
related thought or behavior occurred. The first time the scale is administered in this study, 
the C-SSRS “Screening/Baseline” version will be used, and the findings will constitute the 
baseline assessment.  The C-SSRS “Since Last Visit” scale will be used for all subsequent 
assessments. If a suicide-related thought or behavior is identified at any time during the 
study, a study physician will perform a thorough evaluation, and must immediately contact 
ADCS Medical Safety. Appropriate medical care will be provided. 
 
12.3. Exploratory outcomes 
12.3.1. Neuroimaging. The ADCS Imaging Core will oversee all MRI procedures. MRI will be performed 
on a 1.5T or 3.0T scanner. Each site’s scanner will have an identifying number, which will be appended 
to the image header of all MRI data. Each scanner will be subjected to a qualifying process that includes 
an evaluation for excessive vibration or other image artifact revealed through submitted MR images 
obtained through a standard protocol of an American College of Radiology phantom. In addition, 3D T1 
MPRAGE or IR-FSPGR images of a human brain obtained through a standardized imaging protocol of a 
volunteer at each site will be submitted to the ADCS Imaging Core for automated segmentation, and the 
resulting segmentations will be examined by ADCS Imaging Core for anatomical accuracy. Once the 
phantom and volunteer scan passes quality control by the ADCS Imaging Core, the scanner will be 
considered certified for the study. Local reads will be used at screening to confirm participant eligibility. 
MRI will be performed only on participants deemed eligible based on CSF criteria. Because longitudinal 
analysis of brain volumetry will be used in this study, sites will use the same scanner for both scans 
(screening, 48-weeks) of a particular participant.  
Volumetric analyses. The ADCS Imaging Core will analyze MRI data and secondary outcomes 
will assess changes in hippocampal volume, total brain volume, and lateral ventricular volume.  
Volumetric measures will be made using 3D T1-weighted sequences analyzed longitudinally. Methods 
based on FreeSurfer will be used to segment images, and Quarc, an inverse-consistent nonlinear 
registration method54 will be used to assess regional deformation between screening and 48-weeks within 
regions of interest. 
 
12.3.2. In order to bank tissue (including blood and CSF) for future experiments and analyses to be 
determined, participants will need to provide consent for specimen banking to the study investigators. 
 
 
13. SAFETY ASSESSMENTS 
 
13.1. Definition of adverse event (AE) 
Any untoward medical occurrence associated with the use of an intervention in humans, whether or not 
considered intervention-related . Included in this definition is the worsening of a preexisting medical 
condition. AEs will be collected for the period beginning with the signing of informed consent through 
the end of the study follow-up period.  
 
13.1.1. Adverse events will be categorized based on the following taxonomy: 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.   
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning.   
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment.  
 
13.1.2. The site investigator will assign each adverse event as being: 
• 
Related to therapy. There is a reasonable possibility that the study agent caused the AE, or there 
is a temporal relationship between the study agent and event. Reasonable possibility means that 
there is evidence to suggest a causal relationship between the study agent and the AE.   


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
19
• 
Not related to therapy. There is not a reasonable possibility that the administration of the study 
agent caused the event, there is no temporal relationship between the study agent and event onset, 
or an alternate etiology has been established.   
 
13.2. Definition of serious adverse event (SAE) 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
 
13.3. AE and SAE collection and reporting 
 
13.3.1. AE and SAE collection. Adverse event information will be collected at every planned and 
unplanned in-person and telephone visit until 7 (for non-serious AEs) or 30 days (for SAEs) after the last 
day of study participation. At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit. Events will be documented using an AE log eCRF (EDC entry) and 
followed for outcome information until resolution or stabilization. 
 
13.3.2. AE and SAE reporting. All AEs will be recorded in the eCRF. SAEs must be reported on a SAE 
report form and on the AE pages in the eCRF. All SAEs must be reported immediately by the site 
investigator, within one calendar day (24 hours) from time of awareness by email to the Project Director 
and the ADCS.  
All safety related information will be collected and processed promptly, to comply with 
regulatory requirements. An adverse event or suspected adverse reaction is considered “unexpected” if 
specificity or severity exceeds what that has been observed in previous studies. “Unexpected,” as used in 
this definition, also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation.  
Suspected Unexpected Serious Adverse Events (SUSARs) will be reported to the FDA and IRB 
in an expedited manner as follows: fatal or life-threatening SUSARs – as soon as possible but no later 
than 7 calendar days after the sponsor’s initial receipt of the information: non-fatal and non-life 
threatening SUSARs—as soon as possible but no later than 15 calendar days after the sponsor determines 
that the information qualifies for reporting. Relevant follow-up information for fatal or life-threatening 
SUSARs will be provided to the FDA and IRB.  
The UC Irvine regulatory team will report events meeting reporting criteria to the UCI IRB (IRB 
of record) within 5 business days. Once the SAE is reported, the ADCS DSMB liaison will communicate 
the information to the DSMB.  In the event that the Project Director, ADCS, DSMB, or the IRB 
determine that the safety information related to the study has changed, site investigators and the 
remaining parties will be notified as soon as possible, but in no case later than 15 calendar days from said 
determination.  
 
13.3.3. Data Safety Monitoring Board (DSMB). This trial will utilize the ADCS DSMB. The DSMB will 
be provided with regular safety reports approximately every 3 months (see DSMB Charter). Life-
threatening events and deaths will be reported to the DSMB immediately. In addition the DSMB will be 
notified of unexpected significant new safety data on an ad hoc basis as deemed necessary by the Project 
Director and the ADCS. 
 
14. SAMPLE SIZE AND STATISTICAL METHODS 
14.1. Overview of the statistical design 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
20
The study will implement a seamless phase 2a-2b sequential design with a go/no-go futility analysis 
occurring after one year of follow-up.  While the primary efficacy endpoint for the first phase of the study 
is p-tau231, the futility analysis occurring at the end of phase 2a will be based upon change in p-tau231 or p-
tau181.  Regardless of the decision to continue onto phase 2b, unadjusted inference for the change in p-
tau231 comparing treatment to control will be reported at the end of phase 2a.  In the event that the trial 
does continue on to phase 2b, final inference will be adjusted for the futility analysis based on p-tau231 and 
p-tau181.   
 
14.2. Analysis of the primary outcome 
The primary analysis of phase 2a will focus on the change in p-tau231.  The primary analysis will be based 
on the Intention-to-Treat population, defined as all participants who were randomized to study drug or 
treatment.  We will model the change in p-tau231, using an analysis of covariance model (ANCOVA).  
That is, 48-week p-tau231 will be regressed upon baseline p-tau231 and an indicator for treatment vs. 
placebo.  The Huber-White robust variance estimator will be used to estimate the variance of the 
estimated difference in the mean change in p-tau231 comparing treatment to placebo.  Along with the 
estimated difference in mean change in p-tau231, a Wald-based 95% confidence interval and 
corresponding p-value will be computed and presented. 
 
14.3. Implementation of the futility boundary 
At the conclusion of phase 2a, a futility decision of whether to continue follow-up of patients for an 
additional year will be based upon either the change in p-tau231 or p-tau181 after 48-weeks. The decision 
boundary for continuing to an additional 48-weeks of follow-up will be based upon the observed mean 
differences in p-tau231 or p-tau181 after 48-weeks of treatment.  Specifically, the trial will continue to the 
second phase if the observed relative reduction in change in p-tau231 or p-tau181 is greater than 0.5 pg/ml, 
corresponding to a 10% reduction based upon an anticipated change of 5.1 pg/ml in the control arm (a 
similar distribution is expected for the change in or p-tau231 and p-tau181).44 Individually, this boundary 
decision corresponds to a Pocock futility boundary at 50% of the maximal statistical information, 
maintaining level 0.025 for a one-sided hypothesis test.55, 56 While implementation of the futility boundary 
will not affect inference for the primary outcome in phase 2a, it will need to be accounted for in the 
inference corresponding to the outcomes of phase 2b.  In the event that the trial does proceed to phase 2b, 
final inference will account for the futility decision by utilizing a Benjamini-Hotchberg adjustment57 for 
multiplicity bias stemming from the use of two biomarkers in the decision to continue the trial.  In this 
case, simulation will be used to adjust the final inference at phase 2b in order to maintain an overall 
familywise type I error rate of .05. 
 
14.4. Statistical power for phase 2a.  
Based upon prior reported data, it is expected that the change in p-tau231 over one year will be 
approximately 5.1 pg/ml with a standard deviation of 1.5.44 With a sample size of 48 participants, a 1:1 
randomization scheme, and a 10% per year loss-to-follow-up rate, the proposed study will attain 
approximately 80% power for detecting a true absolute difference in mean within-subject change in p-
tau231 of 1.26 pg/ml (24.5% relative reduction).  Further, the probability of successfully passing the 
“go/no-go” decision for a second year of clinical follow-up is 80% if the true absolute difference in the 
within subject change in either CSF p-tau231 or p-tau231 1.06 pg/ml (20.9% relative reduction). 
 
14.5. Handling of missing data 
In primary analyses, outcome values will not be imputed. Further sensitivity analyses for the impact of 
potential missing data will be conducted following study completion. These will include a multiple 
imputation analysis and a pattern mixture model analysis considering various departures from the 
estimated treatment effect using completely observed data.58 
 
14.6. Analysis of secondary outcomes 
Mean differences in the within subject change in CSF p-tau181, CSF total tau, CSF Aβ40, CSF Aβ42, ADAS-
cog13, ADCS-ADL, CDR-SB will be tested between treatment arms.  To control the familywise type I 
error rate at level 0.05 (two-sided), the Benjamini-Hotchberg closed testing procedure will be utilized.57 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
21
 
14.6.1. Additional exploratory analyses.  To assess sensitivity to patient compliance, the primary outcome 
will also be analyzed using only data on study completers and with adjustment for protocol compliance.  
In addition, we will examine for association between blood levels of nicotinamide and change in CSF p-
tau231, quantified via linear regression. Descriptive analyses of safety and efficacy data will be presented 
by site, diagnostic category (MCI or dementia), and APOE genotype (ε4 carriers, ε4 non-carriers). The 
primary efficacy endpoint, as well as all secondary efficacy endpoints and safety outcomes will be 
presented by site, diagnostic category (MCI or dementia), and APOE genotype (ε4 carriers, ε4 non-
carriers). As these analyses will be for descriptive purposes, no adjustment for multiple comparisons will 
be made when presenting subgroup analyses. 
 
14.6.2. Analysis of safety outcomes. Safety analyses will be conducted on the Full Analysis Population, 
defined as all subjects who were randomized into the study and received study intervention. Summaries of 
the number and percent of subjects with at least one AE/SAE will be provided.  Comparisons of the 
proportion of subjects experiencing AEs/SAEs will be made between treatment arms.   Summaries of the 
number or percent of AEs will be provided for each treatment arm. 
 
14.6.3 Randomization. The ADCS Safety Biostatistics group will oversee the randomization scheme, 
which will be administered through the EDC. Randomization will incorporate blocking to maintain 
temporal balance between arms and will be stratified to ensure balance across likely correlates of the 
study outcome. Specifically, randomization will be stratified by site, diagnostic category (MCI or 
dementia), and APOE genotype (ε4 carriers, ε4 non-carriers). The ADCS Biostatistics Core will perform 
analyses. Both enrollment sites have a long history of completing trials using the ADCS Electronic Data 
Capture (EDC) system, which will make the initiation and conduct of data entry and upload for this trial 
seamless. 
 
 
15. ETHICS 
 
15.1. Ethical Conduct of Study 
This study will be conducted according to Good Clinical Practice, the Declaration of Helsinki,59 the 
Belmont Report, and US 21 CRF Part 50 – Protection of Human Subjects – and Part 56 – Institutional 
Review Boards.  
 
15.2. Institutional Review Board (IRB) 
All materials will be submitted, reviewed, and approved by the UC Irvine Institutional Review Board. 
UCLA will utilize the reliance agreement available through the UC BRAID/UC Reliance Services 
mechanism to achieve approval for this multisite trial using a single IRB mechanism.  
 
15.3. Human subject protection 
The substantial clinical experience with nicotinamide in a variety of therapeutic areas, including doses 
higher than that proposed in this study, suggest that the overall risk for this study is low. We will 
nevertheless utilize the ADCS DSMB to ensure that the study has appropriate monitoring for safety. The 
DSMB will be notified immediately of any life-threating events or deaths. The DSMB will receive 
blinded reports of adverse events and serious adverse events on a quarterly basis and will be convened 
telephonically for the purpose of assessing trial continuation. At any time, the DSMB will be able to 
request additional data, including unblinded data, for the purpose of safety review. The DSMB may 
recommend halting of the study prior to conclusion or modification to the protocol at any time. 
 
15.4. Informed Consent Document 
The principles of informed consent in the current edition of the Declaration of Helsinki will be 
implemented before any protocol-specified procedures are carried out. Informed consent will be obtained 
in accordance with US 21 CFR 50.25 and requires approval from the UCI IRB. Consent forms must be in 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
22
a language fully comprehensible to the prospective participant and the dated signature of the participant 
will document consent.  
 
Informed consent will be performed in the private research setting by the site PI or study coordinator. The 
capacity to provide informed consent will be assessed using the University of California Post-Consent 
Assessment Instrument. Individuals lacking the capacity to provide informed consent may be enrolled 
provided that 1) a legally authorized representative (LAR) is able to give surrogate consent, and 2) the 
participant provides assent. The LAR must be certified as appropriate using the “Self-Certification of 
Surrogate Decision Makers for Potential Subject’s Participation in University of California Research.” 
 
Each participant must have a qualified study partner (see section 10.1.1) and this individual must also 
provide written informed consent to participate.  
 
15.4. Participant Confidentiality 
All participants have a right to protection against invasion of privacy. After completion of the informed 
consent process, participants will be assigned a study identification number.   Throughout this study, data 
will be identified in the Case Report Forms by the subject identification number only.  
 
 
16. DATA HANLDLING AND RECORDING 
 
16.1. Data collection and management responsibilities 
Case report forms (CRFs) will be provided for use as source documents and used for primary data 
collection at the sites. These will be maintained for each participant enrolled in the study. The investigator 
is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. All 
source documents must be completed in a neat, legible manner to ensure accurate interpretation of data. 
Black ink is required. When making changes or corrections, cross out the original entry with a single line, 
and initial and date the change.   
 
Participant visit data will be entered into the ADCS Electronic Data Capture (EDC) system within 72 
hours of visit completion. EDC entry will include manual entering of data and the scanning and uploading 
of some specific CRFs (see procedures manual). Data reported in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained and 
captured in a progress note and maintained in the participant’s official electronic study record. Clinical 
data (including AEs, concomitant medications, and adverse reactions data) and clinical laboratory data 
will be entered into the EDC. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents.  
 
16.2. Study records retention  
Study documents should be retained for a minimum of 2 years after the investigation is discontinued and 
FDA notified. No records will be destroyed without the written consent of the sponsor, if applicable. It is 
the responsibility of the sponsor to inform the investigator when these documents no longer need to be 
retained.   
 
16.3. Protocol deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or GCP requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations within 5 
working days of identification of the protocol deviation, or within 5 working days of the scheduled 
protocol-required activity. All deviations must be addressed in study source documents and reported in 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
23
the ADCS EDC system. Protocol deviations must be sent to the IRB of record, per IRB reporting 
guidelines.  
 
16.4. Publication and data sharing  
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a 
clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any 
research project that prospectively assigns human subjects to intervention or concurrent comparison or 
control groups to study the cause-and-effect relationship between a medical intervention and a health 
outcome. Medical interventions include drugs, surgical procedures, devices, behavioral treatments, 
process-of-care changes, and the like. Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events. The ICMJE 
policy, and the Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that 
all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by 
the National Library of Medicine. This trial will be registered through ClinicalTrials.gov 
(NCT03061474). 
 
At a minimum, electronic item-level data from this trial will be made publicly available through the 
ADCS Data Sharing Process, one year after publication of the primary outcome results, in accord with the 
data-sharing policy of this NIH-funded trial organization. 


Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
24
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Nicotinamide as an Early AD Treatment (NEAT) Trial – 28December2017 
 
27
APPENDIX 1.  
 
Table 1. Study schedule of events. 
Week 
* 
* 
* 
0 
2 
4 
12 
24 
36 
48 (or early 
termination) 
Visit 
SC v1 
SC v2 
SC v3 
V1 
@ 
@ 
V2 
V3 
@ 
V4^ 
ICF/HIPAA 
X 
 
 
 
 
 
 
 
 
 
Demographics/medical 
history 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Physical/neurological 
exams 
X 
 
 
X 
 
 
X 
X 
 
X 
Vital signs 
X 
 
 
X 
 
 
X 
X 
 
X 
MMSE 
X 
 
 
X 
 
 
 
X 
 
X 
CDR-SB 
X 
 
 
 
 
 
 
X 
 
X 
Wechsler Logical 
Memory II 
X 
 
 
 
 
 
 
 
 
 
Free and cued selective 
reminding task (FCSRT) 
X 
 
 
 
 
 
 
 
 
 
Assessment of 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Blood draw (safety 
laboratories) 
X 
 
 
X 
 
 
 
X 
 
X 
Fasting blood draw 
(future biomarkers) 
 
X 
 
 
 
 
X 
X 
 
X 
Blood draw (drug levels) 
 
 
 
 
 
 
X 
X 
 
X 
Urinalysis 
X 
 
 
X 
 
 
 
X 
 
X 
Electrocardiogram 
(EKG) 
X 
 
 
 
 
 
 
X 
 
X 
Blood draw (APOE 
genotyping) 
X 
 
 
 
 
 
 
 
 
 
GDS 
X 
 
 
X 
 
 
 
X 
 
X 
Lumbar puncture 
 
X# 
 
 
 
 
 
 
 
X 
MRI 
 
 
X 
 
 
 
 
 
 
X 
ADAS-cog 
 
 
 
X 
 
 
 
X 
 
X 
ADCS-ADL-MCI 
 
 
 
X 
 
 
 
X 
 
X 
C-SSRS 
 
 
 
X 
 
 
 
X 
 
X 
Dispense study drug 
 
 
 
X 
 
 
X 
X 
 
Xπ 
Distribute study 
medication diaries 
 
 
 
X 
 
 
X 
X 
 
 
Collect completed study 
medication diaries 
 
 
 
 
 
 
X 
X 
 
X 
Assess treatment 
assignment blindness 
 
 
 
 
 
 
 
 
 
X 
 
* 60 days are allotted to complete the screening assessments 
# Must be performed within 30 days of platelet level and coagulation parameters (SC v1 blood panel). In the event of inability to procure 
adequate sample, may be performed under guided fluoroscopy, which may require additional visits.  
@ Telephone visits will assess safety and adverse events 
^ In the event of early termination due to participant withdrawal of consent or removal by investigator, the end of study visit should be 
completed. 
π Participants will be administered blinded study drug at the end of study visit as part of an extension study, until the go/no-go analyses 
are complete. If a go decision is achieved, participants will be enrolled in an extension study. 
 

SAP_001.pdf: 
1 
NEAT SAP V. 1.1 30Nov2022 
UC Reliance # 2016-10797 
A Phase 2, Proof-of-Concept, Double-Blind-Randomized, Placebo-Controlled Adaptive Design 
Trial of Nicotinamide in MCI due to AD and Mild AD Dementia (NEAT) 
Statistical Analysis Plan 
Version: 1.1 
Date: 30Nov2022 


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NEAT SAP V. 1.1 30Nov2022 
SIGNATURE PAGE 
Protocol Title: 
A Phase 2, Proof-of-Concept, Double-Blind-
Randomized, Placebo-Controlled Adaptive Design Trial 
of Nicotinamide in MCI due to AD and Mild AD 
Dementia (NEAT) 
Sponsor: 
UC Irvine Institute for Memory Impairments and 
Neurological Disorders 
Protocol Number: 
 
Document Version/Date: 
V1.1 November 30, 2022 
Author:                    
Daniel L. Gillen, Ph.D.,  
Professor and Chair, Department of Statistics 
Institute for Memory Impairments and Neurological 
Disorders 
Alzheimer’s Disease Research Center 
University of California, Irvine  
Signature:____________________________________ 
Date:________________________________________ 
 
 
Contributing Authors:   
Karen Messer, PhD 
Jing Zhang 
Shelia Jin, MD 
 
 
Investigator Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol.  
 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author.  
 
I also understand that any subsequent changes to the planned statistical analyses, as 
described herein, will be updated within any publications related to the study.  
 
07-Dec-2022




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NEAT SAP V. 1.1 30Nov2022 
 
 
TABLE OF CONTENTS 
SIGNATURE PAGE ....................................................................................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
ABBREVIATIONS ......................................................................................................................................... 6 
1 
Introduction ....................................................................................................................................... 7 
 Introduction .................................................................................................................................... 7 
 Randomization Methodology ......................................................................................................... 7 
 Power and Sample Size Determination ........................................................................................... 7 
2 
Objectives and outcomes of Statistical Analysis ................................................................................. 7 
 Primary Objectives and Outcomes ................................................................................................. 7 
 Secondary Objectives and Outcomes ............................................................................................. 8 
 Exploratory Objectives and Outcomes ............................................................................................ 8 
3 
Study Design ...................................................................................................................................... 9 
 Synopsis of Study Design ................................................................................................................ 9 
4 
Participant Populations ...................................................................................................................... 9 
 Population Definitions .................................................................................................................... 9 
5 
Statistical Methods .......................................................................................................................... 10 
 Primary Efficacy Analysis .............................................................................................................. 10 
An exploratory sensitivity analysis will investigate compare within-patient change in pTau231 in the 
per-protocol population.  Sensitivity analyses for the impact of potential missing data will be 
conducted for the primary outcome as described in Section 5.8. .................................................... 10 
 Analysis of Safety Outcomes ......................................................................................................... 10 
5.2.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................................ 11 
 Analysis of Secondary Efficacy Outcomes ..................................................................................... 11 
5.3.1 
Secondary Objective 1 ....................................................................................................... 11 
5.3.2 
Secondary Objective 2 Determine if daily treatment with high-dose nicotinamide in 
individuals with mild AD dementia or MCI due to AD reduces the rate of cognitive decline, as 
assessed by ADAS-Cog 13 ................................................................................................................. 12 
5.3.3 
Secondary Objective 3 ....................................................................................................... 12 
Alzheimer’s Disease Cooperative Study-Activities of Daily Living - MCI (ADCS-ADL-MCI) ................ 12 
CDR-Sum of Boxes ............................................................................................................................ 12 
 Analysis of Exploratory Outcomes ................................................................................................ 13 


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NEAT SAP V. 1.1 30Nov2022 
5.4.1 
Exploratory Objective 1 ..................................................................................................... 13 
MRI QUARC ...................................................................................................................................... 13 
5.4.2 
Exploratory Objective 2 Determine the effect size of daily treatment with high dose 
nicotinamide over 48 weeks in individuals with mild AD dementia or MCI due to AD on 
phosphorylated tau (p-tau181) .......................................................................................................... 13 
5.4.3 
Exploratory Objective 3: Estimate the association between blood levels of nicotinamide 
and change in CSF p-tau231. .............................................................................................................. 14 
5.4.4 
Exploratory Objective 4: Describe efficacy data by the stratification subgroups of MCI or 
dementia, and APOE genotype (ε4 carriers, ε4 non-carriers) .......................................................... 14 
 Enrollment and Participant Flow .................................................................................................. 14 
5.5.1 
Study Accrual Tables and Figures ....................................................................................... 14 
5.5.2 
Early Termination ............................................................................................................... 14 
 Demographics and Baseline Characteristics ................................................................................. 14 
 Protocol Deviations ...................................................................................................................... 15 
 Handling of missing data .............................................................................................................. 15 
 Data Handling ............................................................................................................................... 15 
 
Coding of AEs and Concomitant Medications ....................................................................... 15 
 
Adjustments for Covariates and Stratification ...................................................................... 16 
 
Randomization ...................................................................................................................... 16 
 
Software................................................................................................................................ 16 
6 
References ....................................................................................................................................... 16 
1. White H. A heteroskedasticity-consistent covariance matrix estimator and a direct test for 
heteroskedasticity. Econometrica: journal of the Econometric Society. 1980 May 1:817-38. ............ Error! 
Bookmark not defined. 
 


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NEAT SAP V. 1.1 30Nov2022 
ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
BQL 
Below limit of quantification 
BUN 
Blood urine nitrogen  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CI 
Confidence interval 
CPK 
Creatine phosphokinase  
CRF 
Case Report Form 
CSR 
Clinical study report 
DILI 
Drug induced liver injury 
ECG 
Electrocardiogram 
HDL 
High-density lipoprotein  
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measures 
MMSE 
Mini Mental State Exam 
PID 
Participant Identification Number 
PK 
Pharmacokinetic 
PP 
Per protocol set 
PT 
Preferred term 
QD 
Quaque die (once daily) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
ULN 
Upper limit of normal  
WHO Drug 
World Health Organization drug reference dictionary 
 
 
 


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NEAT SAP V. 1.1 30Nov2022 
1 INTRODUCTION 
 
 
Introduction 
 
This document presents the statistical analysis plan (SAP) for the protocol titled: A Phase 2, Proof-of-
Concept, Double-Blind-Randomized, Placebo-Controlled Adaptive Design Trial of Nicotinamide in MCI 
due to AD and Mild AD Dementia (NEAT). This study is a multisite, randomized, double-blind, placebo-
controlled Phase 2 trial comparing efficacy and safety of nicotinamide versus placebo in patients with 
MCI due to AD and Mild AD Dementia. 
This SAP is based on Version 4.0, Amendment 3, of the NEAT Protocol dated 28Dec2017. It contains the 
analysis details and methodology to answer the study objectives, including planned summary tables, by-
subject listings, and figures, which will provide the basis for the results section of the clinical study 
report (CSR). Operational aspects related to collection and timing of planned clinical assessments are 
not repeated in this SAP unless relevant to the planned analyses. 
 
Randomization Methodology 
 
The ADCS Safety Biostatistics group oversaw the randomization scheme, which was administered 
through the EDC. Randomization incorporated blocking to maintain temporal balance between arms 
and was stratified to ensure balance across likely correlates of the study outcome. Specifically, 
randomization was stratified by site, diagnostic category (MCI or dementia), and APOE genotype (ε4 
carriers, ε4 non-carriers). 
 
Power and Sample Size Determination 
 
Based upon prior reported data, it is expected that the change in p-tau231 over one year will be 
approximately 5.1 pg/ml with a standard deviation of 1.5. With a sample size of 48 participants, a 1:1 
randomization scheme, and a 10% per year loss-to-follow-up rate, the proposed study will attain 
approximately 80% power for detecting a true absolute difference in mean within-subject change in p-
tau231 of 1.26 pg/ml (24.5% relative reduction).  
2 OBJECTIVES AND OUTCOMES OF STATISTICAL ANALYSIS 
 
 
Primary Objectives and Outcomes 
 
• 
Primary Objective 1: Determine if daily treatment with high dose nicotinamide reduces 
levels of phosphorylated tau (p-tau231) over 48 weeks in individuals with MCI due to AD and 
mild probable AD dementia  
 
• 
Primary Objective 2: Assess the safety and tolerability of high-dose nicotinamide treatment 
in individuals with MCI due to AD and mild probable AD dementia, as assessed by: 
 Vital signs,  


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NEAT SAP V. 1.1 30Nov2022 
 Treatment emergent adverse events,  
 Serious adverse events 
 Suicidality rating scale scores,  
 ECG abnormalities.  
 
Secondary Objectives and Outcomes 
 
• 
Secondary Objective 1: Determine if daily treatment with high-dose nicotinamide in 
individuals with MCI due to AD and mild AD dementia can affect CSF levels of: 
 amyloid beta (Aβ42) 
 amyloid beta (Aβ40)  
 phosphorylated tau (p-tau181) 
 total tau (t-tau) 
 the ratio of total tau/Aβ40 
 the ratio of total tau/ Aβ42 
 
• 
Secondary Objective 2: Determine if daily treatment with high-dose nicotinamide in 
individuals with MCI due to AD and mild AD dementia reduces the rate of cognitive decline, 
as assessed by:  
 ADAS-Cog 13 
 
• 
Secondary Objective 3: Determine if daily treatment with high dose nicotinamide in 
individuals with mild AD dementia or MCI due to AD reduces the rate of functional decline 
and everyday activities as assessed by:  
 ADCS-ADL-MCI  
 CDR-SB 
 
Exploratory Objectives and Outcomes 
 
• 
Exploratory Objective 1: Determine if daily treatment with high-dose nicotinamide reduces 
rate of brain volumetric changes atrophy in individuals with MCI due to AD and mild AD 
dementia, as assessed by: 
 whole brain volume,  
 ventricular volume,  
 hippocampal volume,  
 and cortical thickness 
 
• 
Exploratory Objective 2: Determine the effect size of daily treatment with high dose 
nicotinamide over 48 weeks in individuals with mild AD dementia or MCI due to AD on: 
  phosphorylated tau (p-tau181) 
 
• 
Exploratory Objective 3: Estimate the association between blood levels of nicotinamide and 
change in CSF p-tau231. 


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NEAT SAP V. 1.1 30Nov2022 
 
• 
Exploratory Objective 4: Describe efficacy data by the randomization factors of diagnostic 
category (MCI or dementia), and APOE genotype (ε4 carriers, ε4 non-carriers) 
 
3 STUDY DESIGN 
 
 
Synopsis of Study Design 
 
Forty-seven participants were randomized to 1500 mg BID nicotinamide or matched placebo at a 1:1 
ratio, stratified by site, diagnostic category (MCI or dementia), and APOE genotype (ε4 carriers, ε4 non-
carriers). 
There was a screening period of up to 60 days, during which each participant completed 3 screening 
visits. 
The ADAS-Cog 13, ADCS-ADL-MCI and CDR-SB were collected at 3 timepoints: baseline, week 24, and 
week 48. The MMSE was collected at screening visit 1, baseline, week 24, and week 48. the Free and 
Cued Selective Reminding Task (FCSRT) was only done at screening visit 1.  
Lumbar punctures and MRI scans were performed at screening and week 48. Safety measures including 
the C-SSRS, EKG, and safety laboratories were collected at screening or baseline, week 24, and week 48. 
Vital signs, blood collection for biomarker banking, physical exams, and neurological exams were done 
at screening or baseline, week 24, week 36, and week 48. Concomitant medications and adverse events 
were collected at every visit.   
4 PARTICIPANT POPULATIONS 
 
 
Population Definitions 
 
The following populations will be evaluated and used for presentation and analysis of the data: 
• 
Enrolled Participants: Participants who signed an informed consent form and were assigned 
a Participant Identification number (PID) 
• 
Intent to Treat (ITT) Population: All enrolled participants who received a randomized 
treatment assignment.  
• 
Safety Population: Enrolled and randomized participants who received at least 1 dose of 
blinded study therapy (nicotinamide or placebo). This will be the primary analysis population 
used for the safety analyses. 
• 
Modified Intent-to-Treat (mITT) population: All randomized participants who have a 
baseline assessment of the endpoint, and who have at least one evaluation of the endpoint 
following baseline.  


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NEAT SAP V. 1.1 30Nov2022 
• 
Per-protocol population: All randomized participants who completed trial activity through 
week 48  including lumbar puncture. 
5 STATISTICAL METHODS 
 
 
Primary Efficacy Analysis 
 
The primary outcome measure of phase 2a is the within-participant change in p-tau231 from baseline to 
week 48. The primary analysis will be conducted on the ITT population. No missing data will be imputed 
The change in p-tau231 will be modeled using an analysis of covariance model (ANCOVA). That is, 48-
week p-tau231 will be regressed upon baseline p-tau231 and an indicator for treatment vs. placebo using 
a linear regression model of the form: 
𝐸𝐸ൣ𝑝𝑝𝑝𝑝𝑝𝑝𝑢𝑢231,𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝൧= 𝛽𝛽0 + 𝛽𝛽1𝐼𝐼𝑁𝑁𝑁𝑁𝑁𝑁+ 𝛽𝛽2𝑝𝑝𝑝𝑝𝑝𝑝𝑢𝑢231,𝑝𝑝𝑝𝑝𝑝𝑝. 
𝛽𝛽1represents the parameter of interest. The Huber-White robust variance estimator1 will be used to 
estimate the variance of the estimated difference in the mean change in p-tau231 comparing treatment 
to placebo. Specifically, the variance estimator for the estimated treatment effect will be the (2,2) 
element of  
(𝑋𝑋𝑇𝑇𝑋𝑋)−1𝑋𝑋𝑇𝑇Σ෠X(𝑋𝑋𝑇𝑇𝑋𝑋)−1,   
where 𝑋𝑋 denotes the 𝑛𝑛× 3 design matrix from regression model, Σ෠ is the 𝑛𝑛× 𝑛𝑛 diagonal matrix with 
the squared model residuals on the diagonal and 0 on the off-diagonal, and 𝑛𝑛 the number of 
observations included in the analysis. Along with the estimated difference in mean change in p-tau231, a 
Wald-based 95% confidence interval and corresponding p-value will be computed and presented.  
Sensitivity analyses for the primary outcome 
An exploratory sensitivity analysis will investigate compare within-patient change in pTau231 in the per-
protocol population.  Sensitivity analyses for the impact of potential missing data will be conducted for 
the primary outcome as described in Section 5.8.  
 
 
Analysis of Safety Outcomes 
 
Safety analyses will be conducted on the Safety Population.  
The safety and tolerability of high-dose nicotinamide treatment in individuals with MCI due to AD or 
mild AD dementia will be assessed by the following, for each arm separately: 
• Treatment emergent Adverse Events (TEAEs) summarized: 
o Overall and by number of subjects with an AE 
o By severity and relation to investigational product 


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NEAT SAP V. 1.1 30Nov2022 
o By number of events and by subjects with an event by System Organ Class (SOC) 
o By Preferred Term (PT) within SOC 
• Serious adverse events (SAEs) including deaths summarized as for TEAEs  
• Vital signs (weight, BMI, blood pressure, pulse) will be presented with means and standard 
errors at each study visit 
• Descriptive statistics for ECG interval data will also be reported across visits including baseline, 
week 24 and week 48 or early termination. 
o Proportion of subjects with at least 1 abnormal ECG by treatment arm  
o Proportion of subjects with at least 1 abnormal QTC by treatment arm  
 The QTC will be computed using the Friderica formula. Abnormal will be defined 
as above 460 for men and above 470 for women. 
o Average within subject change in QTC by treatment arm (baseline to latest available) 
• Adverse events (AEs) leading to discontinuation 
5.2.1 Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors 
during the corresponding assessment period. The scale includes suggested questions to elicit the type of 
information needed to determine if a suicide-related thought or behavior occurred. The first time the 
scale is administered in this study, the C-SSRS “Screening/Baseline” version will be used, and the 
findings will constitute the baseline assessment.  The C-SSRS “Since Last Visit” scale will be used for all 
subsequent assessments.  
The number and proportion of subjects with treatment emergent Suicidal ideation or behavior will be 
reported overall and by study arm. 
Treatment emergent suicidal ideation or behavior is defined as a “yes” answer at any time during 
treatment to any one of the questions in the ten suicidal ideation and behavior categories (Categories 1-
10) on the C-SSRS2. Self-injurious behavior without suicidal intent, while assessed on the C-SSRS, does 
not form part of this outcome. 
 
Analysis of Secondary Efficacy Outcomes 
Mean differences in the within subject change in CSF p-tau181, CSF total tau, CSF Aβ40, CSF Aβ42, 
ADAS-cog13, ADCS-ADL-MCI, and CDR-SB will be tested between treatment arms, as described below.  
To control the familywise type I error rate at level 0.05 (two-sided) within each objective, the Holm-
Bonferroni closed testing procedure will be utilized. Secondary analyses will be conducted on the mITT 
population. 
5.3.1 Secondary Objective 1 
The efficacy of nicotinamide will be assessed by the mean within-participant changes from baseline to 
week 48, compared between the treatment group and the placebo group, on the following CSF 
biomarker measures: 
 amyloid beta (Aβ42),  


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NEAT SAP V. 1.1 30Nov2022 
 amyloid beta (Aβ40),  
 phosphorylated tau (p-tau181),  
 total tau (t-tau),  
 the ratio of total tau/Aβ40,  
 the ratio of total tau/ Aβ42 
Analyses will be the same as the primary efficacy outcome analysis.  The Holm-Bonferroni closed testing 
procedure will be utilized to control the family-wise error rate at the 5% level across the 6 hypothesis 
tests. 
5.3.2 Secondary Objective 2 Determine if daily treatment with high-dose nicotinamide in individuals 
with mild AD dementia or MCI due to AD reduces the rate of cognitive decline, as assessed by 
ADAS-Cog 13 
5.3.3 Secondary Objective 3 
Alzheimer’s Disease Cooperative Study-Activities of Daily Living - MCI (ADCS-ADL-MCI)  
The ADCS-ADL-MCI is a measure of patient functional performance in AD and MCI trials. The informant-
based questionnaire assesses conduct of basic and instrumental ADLs. A total of 24 ADLs are evaluated. 
Scores range from 0 to 53, with higher scores representing more maintained function. 
CDR-Sum of Boxes 
 
The CDR uses patient and informant interviews to assess memory, orientation, judgment and problem 
solving, community affairs, home and hobbies, and self-care. The CDR can provide a global score of 0, 
0.5, 1.0, 2.0, or 3.0 relating to not demented, very mild dementia, mild dementia, moderate dementia, 
and severe dementia, respectively. Alternatively, a sum of the boxes can be assessed, providing a wider 
range and greater sensitivity to change. 
The within-participant change in each of these three measures (ADAS-Cog 13 ADCS-ADL-MCI and CDR) 
will be evaluated with a longitudinal mixed effects model with repeated measures. Terms in the model 
will be: age, baseline score, treatment, time defined categorically as visit, and time by treatment 
interaction.   
A random effect will be included for participant. The within-participant covariance matrix will be 
unstructured. If the model does not converge a compound symmetry covariance matrix will be used. If 
the model still does not converge, the ANCOVA approach of the primary analysis will be used, using the 
last available measurement for each subject.  Each endpoint will be tested using model-adjusted least 
squares means at the week 48 visit. A point estimate, standard error and two-sided 95% Wald 
confidence interval and a p-value will be presented for the difference between arms at 48 weeks. The 
Holm-Bonferroni closed testing procedure will be utilized to control the family-wise error rate at the 5% 
level across the 3 hypothesis tests. 
Point estimates, standard errors and two-sided 95% confidence intervals for the mean within patient 
change at each time point will be presented by arm, as descriptive statistics unadjusted for multiple 
confidence intervals.   


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NEAT SAP V. 1.1 30Nov2022 
 
Analysis of Exploratory Outcomes 
 
The efficacy and safety of nicotinamide will be further assessed for treatment effects between the 
treatment group and the placebo group, through the following exploratory analyses. As these analyses 
will be for descriptive purposes, no adjustment for multiple comparisons will be made when presenting 
subgroup analyses. 
5.4.1 Exploratory Objective 1 
MRI QUARC  
 
Whole brain volume, ventricular volume, hippocampal volume, and cortical thickness will be measured 
as volumetric MRI. MRI imaging of the brain will be performed in order to measure brain atrophy over 
time. Results from vMRI studies suggest that the patterns of atrophy in AD can reliably be detected and 
tracked across time. Atrophy of the medial temporal lobe, including hippocampus and entorhinal 
cortex, has long been described in vMRI studies of AD. Hippocampal volume derived from MRI 
correlates with histological hippocampal volume and degree of neuronal loss and AD pathology, and 
entorhinal cortical thickness change appears to be an early and sensitive indicator of 
neurodegeneration associated with AD. Longitudinal MRI measures of regional and whole brain 
volumetric change provide a valuable complement to cognitive measures in that they are not influenced 
by temporary symptomatic improvements, and they provide an early index of the study drug’s ability to 
reach the target organ and have an effect on AD-related atrophy.  
The analysis of structural change will be performed through QUARC nonlinear registration comparing 
each participant’s follow-up scan to the initial baseline scan. The procedure provides percent 
deformation within regions of interest (ROIs) obtained through segmentation of the baseline scan. The 
registration of serially-acquired brain volumes yields a deformation field that represents the volumetric 
shift of internal structure required for optimal overlaying of the two scans. The anatomically-based 
segmentation is overlaid on the smoothed voxel-wise deformation field and an average percent 
deformation is created for each ROI. Visual QC of registration is performed and values from scans 
passing QC are returned to the statistical team for analysis.  
The mean difference in QUARC change will be compared for each volumetric measure between the 
nicotinamide and placebo groups. Analyses will be the same as the primary efficacy outcome analysis.  
The Holm-Bonferroni closed testing procedure will be utilized to control the family-wise error rate at 
the 5% level across the 4 hypothesis tests. 
The number of images which are not quantifiable due to scan alignment failure will be summarized by 
study arm. 
5.4.2 Exploratory Objective 2 Determine the effect size of daily treatment with high dose 
nicotinamide over 48 weeks in individuals with mild AD dementia or MCI due to AD on 
phosphorylated tau (p-tau181) 
 
This will be conducted in the same manner as the primary analysis. 


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NEAT SAP V. 1.1 30Nov2022 
5.4.3 Exploratory Objective 3: Estimate the association between blood levels of nicotinamide and 
change in CSF p-tau231.  
 
A linear regression model will be used to assess the association between blood levels of 
nicotinamide, as measured in the lab of Dr. Greg Brewer, and within-patient change in CSF p-
tau231.   
5.4.4 Exploratory Objective 4: Describe efficacy data by the stratification subgroups of MCI or 
dementia, and APOE genotype (ε4 carriers, ε4 non-carriers) 
 
Means and standard deviations will be presented by arm for the 48 weeks within subject change 
on each primary and secondary endpoint, separately for these two subgroup categories.  
 
Enrollment and Participant Flow 
5.5.1 Study Accrual Tables and Figures 
 
Tables will summarize accrual by study site, and figures will summarize the overall rate of accrual 
over calendar time.  
Participant Disposition 
A description of participant flow per the CONSORT guidelines and checklist will be provided. The 
diagram will describe study status from screening to the end of the study and will include the following 
information: 
• 
Number of participants enrolled and signed informed consent form 
• 
Number of enrolled participants excluded from the study prior to randomization and reason 
for exclusion 
• 
Number of participants randomized  
• 
Number of participants treated  
• 
Number of participants who completed a lumbar puncture  
• 
Number of participants who prematurely withdrew from the study and reasons for 
withdrawal 
The CONSORT diagram is separated by study arm after the randomization step. 
5.5.2 Early Termination 
 
Early termination from the study includes participants who leave the study and/or discontinue 
treatment prior to completing the week 48 visit. Proportions of participants who prematurely 
discontinued the study prior to the week 48 visit will be compared between the study arms. 
 
Demographics and Baseline Characteristics 
Tabulations of demographic and baseline characteristics will be made for all randomized participants.  


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NEAT SAP V. 1.1 30Nov2022 
Descriptive statistics will be presented as N, mean, standard deviation, minimum, 25th quartile, median 
75th quartile and maximum for continuous variables, and frequency tables (row, column percentages) 
for categorical variables. Statistical comparisons will be performed between randomized arms using 
Wilcoxon Rank Sum Test (for continuous variables) or Fisher's exact test (for categorical variables). 
The following variables will be reported: 
• 
Baseline Demographics:  
• 
Baseline Vital Signs: All variables collected in the Vital Signs Form 
 
Protocol Deviations 
 
Any significant event that does not comply with the inclusion/exclusion criteria, study conduct (e.g., 
inadequate informed consent, unreported SAEs), or study procedures (e.g., use of prohibited 
medications as defined by the protocol; improper breaking of the blind) will be documented as a 
protocol deviation.  
All protocol deviations will be presented in a tabulation  
 
Handling of missing data 
 
No imputation of missing data will be performed in the primary analysis of the primary, secondary, or 
exploratory endpoints. Sensitivity analyses for the impact of potential missing data will be conducted 
for the primary outcome and the secondary clinical outcome measures, including CDR-SB, ADAS-Cog 13, 
and ADCS-ADL-MCI. In each case a multiple imputation analysis will be performed and compared to the 
non-imputed analysis results.  
 
Data Handling 
 
Tabulations will be produced by randomized treatment group and overall, unless otherwise specified.  
Descriptive statistics will be presented as N, mean, standard deviation, minimum, 25th quartile, median 
75th quartile and maximum for continuous variables, and frequency tables (row, column percentages) 
for categorical variables.  
Change from baseline is calculated by subtracting the baseline value from the observed post-baseline 
value at any subsequent visit. Baseline will be defined as last available assessment on or before the 1st 
day the participant receives study medication for that phase. 
Tabulations of the following endpoints will present the number of unique participants with an event: 
protocol deviations; non-study medications; AEs; and laboratory abnormalities. Thus, for these 
endpoints, multiple occurrences of the same event are counted only once per participant. 
Unique Participant ID’s take the form “NEATsite#participant#”.  
 Coding of AEs and Concomitant Medications 


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NEAT SAP V. 1.1 30Nov2022 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, Version 21.1.) 
Concomitant medications will be coded with WHO Drug (Global March 2019) using the WHO Drug 
Insight tool.  
 Adjustments for Covariates and Stratification 
No additional covariate adjustment or stratification will be made in the primary analysis. 
 Randomization 
The ADCS Safety Biostatistics group has overseen the randomization scheme, which has been 
administered through the study EDC. Randomization has incorporated blocking to maintain temporal 
balance between arms with stratification to ensure balance across likely correlates of the study 
outcome. Specifically, randomization has been stratified by site, diagnostic category (MCI due to AD or 
mild AD dementia), and APOE genotype (ε4 carriers, ε4 non-carriers). The ADCS Biostatistics Core will 
perform analyses. Both enrollment sites have a long history of completing trials using the ADCS 
Electronic Data Capture (EDC) system, which will make the initiation and conduct of data entry and 
upload for this trial seamless. 
 Software 
Statistical software R (version 4.1.2) will be used http://www.r-project.org. 
6 REFERENCES 
 
1. 
White H. A Heteroskedasticity-Consistent Covariance Matrix Estimator and a Direct Test for 
Heteroskedasticity. JSTOR. 1980;48:817-838. 
2. 
Nilsson ME, Suryawanshi S, Gassmann-Mayer C, Dubrava S, McSorley P, Jiang K. Columbia–
Suicide Severity Rating Scale Scoring and Data Analysis Guide. https://cssrs.columbia.edu/2013.