Conditions: Mild Cognitive Impairment
Keywords: Alzheimer's disease hypertension medication Mild Cognitive impairment Amyloid Beta
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 77
Healthy volunteers: no

Brief summary:
This study is intended to investigate the safety of candesartan, a blood pressure medication, in non-hypertensive individuals who have mild cognitive impairment (MCI) due to Alzheimer's disease and its effect on disease biomarkers.

Detailed description:
This is a double-blind placebo-control randomized clinical trial that compares candesartan to placebo in individuals with mild cognitive impairment (MCI) who also have positive Alzheimer's Disease (AD) biomarkers. The investigators will assess if blocking the effect of Ang II using angiotensin receptor blockers (ARBs) is safe in non hypertensive MCI individuals and whether the use of candesartan will be associated with changes in cerebrospinal fluid disease biomarkers.

Arms:
arm 1: Candesartan will be given orally once a day in a stepwise manner as follows: All participants will be initiated on 8 mg candesartan. The dose will be increased in 2 week increments to 16 mg and 32 mg as long as the systolic blood pressure (SBP) \>100 mm Hg, diastolic blood pressure (DBP) \>40 mm Hg and participant reports no symptoms of hypotension (dizziness or weakness). The highest achievable dose will be the Maximal Tolerated Dose (MTD) and the participant will receive this dose for the remaining duration of the study (participants will be treated for 1 year). arm 2: Participants will receive a matched placebo once a day orally for 12 months.

Interventions: intervention 1: Placebo intervention 2: Candesartan
Intervention descriptions: intervention 1: A matched placebo will be given once daily for 12 months. intervention 2: Candesartan will be started at 8 mg orally, once daily. The dose will be increased in 2 week increments to 16 mg and 32 mg orally, once a day, as long as SBP\>100 mm Hg, DBP\>40 mm Hg and there are no reported symptoms of hypotension (dizziness or weakness). Candesartan will be given for a total of 12 months.

Protocol document:
ICF_001.pdf: 
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CANDESARTAN’S EFFECTS ON ALZHEIMER’S DISEASE AND RELATED BIOMARKERS 
(CEDAR) 
NCT02646982 
Date: February 15, 2019 
IRB0008454


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You Are Being Asked to Be in a Research Study 
What Is a Research Study? 
The main purpose of research studies is to gain knowledge. This knowledge may be used to help others. 
Research studies are not intended to benefit you directly, though some might.   
Do I Have to Do This? 
No. Being in this study is entirely your choice.  If you decide to join this study, you can change your mind 
later on and withdraw from the research study.  
Taking part in a study is separate from medical care. The decision to join or not join the research study will not 
affect your status as a patient.   
What Is This Document? 
This form is an informed consent document. It will describe the study risks, procedures, and any costs to you. 
This form is also a HIPAA Authorization document. It will describe how your health information will be used 
and by whom. 
Signing this form indicates you are willing to take part in the study and allow your health information to be 
used. 
What Should I Do Next? 
1. Read this form, or have it read to you.
2. Make sure the study doctor or study staff explains the study to you.
3. Ask questions (e.g., time commitment, unfamiliar words, specific procedures, etc.)
4. If there will be medical treatment, know which parts are research and which are standard care.
5. Take time to consider this, and talk about it with your family and friends.


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Emory University 
Consent to be a Research Subject / HIPAA Authorization 
Title:  Effects of Candesartan on Alzheimer’s Disease and Related Biomarkers 
Principal Investigator:  Ihab Hajjar, MD 
Sponsors: Alzheimer’s Disease Drug Foundation (ADDF) and The National Institute of Health 
Introduction 
You are being asked to be in a medical research study. This form is designed to tell you everything you need to 
think about before you decide if you want to be a part of the study.  It is entirely your choice.  If you decide to 
take part, you can change your mind later on and withdraw from the research study. The decision to join or 
not join the research study will not cause you to lose any medical benefits.  If you decide not to take part in 
this study, your doctor will continue to treat you. 
Before making your decision: 
•
Please carefully read this form or have it read to you
•
Please listen to the study doctor or study staff explain the study to you
•
Please ask questions about anything that is not clear
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether you 
would like to participate. You may wish to discuss your decision with family or friends. Do not sign this consent 
form unless you have had a chance to ask questions and get answers that make sense to you.  By signing this 
form, you will not give up any legal rights. 
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 may search this Web site at any time. 
Study Overview 
What is the purpose of this study? 
This study is intended to investigate the effect of candesartan, a blood pressure medication, on cognitive 
function and thinking skills in those who have early or mild memory difficulties, also called mild cognitive 
impairment or MCI. This study also aims at studying the effect of candesartan on the build-up of specific 
proteins in the brain termed Amyloid and Tau. Amyloid and Tau protein build up may lead to Alzheimer’s 
disease.  
Who is eligible to participate? 
To be eligible for this study you need to: 
•
be 50 years and older;


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•
have early or mild memory difficulties, also called MCI. We will test your thinking skills when you come
to the study center;
•
have a blood pressure (BP) that is 110/40 mmHg or greater. You cannot have a diagnosis of
hypertension or be receiving blood pressure medications unless it is given to you for reasons other
than hypertension;
•
your kidney function, potassium level, platelet counts and bleeding tendency should be within a
normal range;
•
In addition, to be eligible we need to check if you have protein build-up in the brain. To do that, we will
obtain a sample of the fluid that surrounds the brain, also called cerebrospinal fluid or CSF for short.
CSF can be obtained using a routine procedure called lumbar puncture or spinal tap. If the CSF shows
signs of protein build-up, then you would qualify for the study. If it does not show signs of protein
build-up, then you will not qualify for the study.
Your doctor may have already performed this CSF analysis. In that case, we do not need to redo the spinal tap 
to check if you qualify for the study and we would like to obtain these results from your doctor to see if you 
are eligible. You will still need to have a spinal tap as part of the study at the baseline visit or if we could not 
obtain the CSF analysis from your doctor. 
If your blood pressure becomes elevated during the study period and your physician recommend starting a 
blood pressure medication, it is very important to notify us of this as soon as possible. For your safety it is 
important to let your physician know that you are possibly receiving candesartan before starting any blood 
pressure medicine.  
We ask you to call us before starting any new medication in order to ensure your safety. Some medications 
should not be used in combination with the study medicine, candesartan.  These include: angiotensin 
converting enzyme inhibitor (ACEI) such as Lisinopril, Captopril, Enalapril, Moexipril, Perindopril, Quinapril, 
Ramipril or Trandolapril; angiotensin receptor blockers (ARB) such as Losartan, Candesartan, Eprosartan, 
Irbesartan, Olmesartan, Telmisartan, and Valsartan; renin inhibitors such as Aliskiren; or Lithium. If your 
physician recommends any of these drugs and you wish to start on it, then we will need to withdraw you from 
the study to maintain your safety.  
We plan to enroll 72 individuals for this trial. Of those 72 participants, we will select a subgroup of participants 
to undergo specialized nuclear imaging also called PET scans. We will ask the same subgroup who complete 
the PET scans to undergo a retinal scan and eye tracking evaluation. 
What will I be asked to do? 
If you are eligible and you decide to take part in this study you will sign this informed consent form and you 
will be enrolled in this study for 1 year. You will need to take candesartan at 8, 16 or 32 mg once a day or a 
similar placebo. A placebo is an inactive medication. There is 50% chance you will receive candesartan or 
placebo. 
Your participation in the study involves coming to the study center for interviews, brain scans, a lumbar 
puncture (also called a spinal tap), blood pressure monitoring and blood tests. You will be asked to visit the 
study sites at least 8-11 times during that year. The following describes what happens at each visit: 


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Screening Visit: 
During the screening visit, we will ask you to sign this informed consent. We will measure your blood pressure, 
review the medications you are taking, and ask you a set of questions regarding your medical history. You will 
have memory and cognitive function tests and a blood sample will also be drawn to check on your eligibility 
for this study. A blood sample (2-3 Tablespoons) will also be drawn to measure the number of stem cells in the 
blood, the degree of inflammation and genetic profiles. You will also be asked to bring all of your prescribed 
medication bottles. 
During this visit we will also make sure that you understood the details of the study so you can make an 
informed decision to participate. If you are having trouble with the details of the study, we will ask for a 
surrogate and study informant to act on your behalf.  The surrogate may be your legal guardian, next of kin, or 
familial caregiver. If you do not need a surrogate or study informant to act on your behalf, we will still need a 
friend or family member to offer information about your memory for one of our questionnaires during the 
study. That person will also need to consent to the study. 
 If you qualify then a spinal tap or lumbar puncture will be performed. Lumbar punctures will be performed by 
a trained physician, nurse practitioner or physician assistant.  If a spinal tap has already been performed and 
the protein build-up has already been checked by your doctor, then we don’t need to repeat it at this visit. 
What is a lumbar puncture? 
A lumbar puncture, also called a spinal tap, is a procedure to obtain a sample of fluid (also called cerebrospinal 
fluid or CSF) that surrounds the brain. It will be performed twice during the study period. We will ask you not 
to eat or drink anything except water for at least 6 hours prior to having the spinal tap done. 
It is a routine procedure in many clinical and hospital settings. To obtain the fluid we need to insert a small 
needle to obtain the spinal fluid from the lower back. For this lumbar puncture, you will be asked to lie on 
your side with your knees drawn as close to the chest as possible or to sit with your arms and head resting on 
a table. Your lower back will be cleaned then numbed with local anesthetic, such as lidocaine. Lidocaine will 
help reduce pain sensations that may be caused by this procedure. A thin needle (typically 3.5 to 4 inches 
long) will be introduced into the back space between the backbones. About 2-3 teaspoons of spinal fluid will 
be removed and the needle withdrawn. If no spinal fluid is obtained on the first attempt, a second attempt will 
be made following the same steps. This lumbar puncture procedure will take approximately 20-40 minutes. 
After the lumbar puncture is completed, you will lie on your back for about 10-15 minutes. The spinal tap can 
be done on the same visit as your other study visits or on a separate visit. You should avoid any strenuous 
physical activity for the next 24 hours. This includes lifting, bending, doing housework and gardening, or doing 
exercise such as jogging or bicycle riding.  We will call you the day after the spinal tap to check on you.  
We will check the levels of proteins on the sample we obtained and if they show protein build-up then you 
qualify for this study and you will be scheduled for the baseline visit. This may take few weeks. 
Baseline Visit 
Once eligible, you will be asked to come in for the baseline visit. You can complete this visit on one day or 
divide it into 2 visits.  During this visit, we will measure your blood pressure and heart rate twice while you are 
seated and 1 and 3 minutes after standing. We will measure your weight and height. We will also perform 
tests to assess your thinking abilities, your mood, your balance and how fast you can walk. We may record 


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your voice for 5-10 minutes to assess certain patterns in your speech. This will be done during the memory 
tests or during a different time at one or more of your visits. We will also ask you to complete a few 
questionnaires regarding your physical and daily activities, levels of stress and health habits. Some of these 
will be mailed to you so you can review before your visit. A blood sample may also be drawn to measure the 
number of stem cells in the blood, the degree of inflammation and genetic profiles, if it was not performed 
during the screening visits. A spinal tap will also be performed if it was not performed during the screening 
visits. You may elect to have the spinal tap on a separate visit by itself. 
 
You will also have an assessment of the arteries in your neck, also called carotid artery. We will ask you not to 
eat for at least 2 hours before this test. We will use a sound wave machine or an ultrasound to see if you have 
hardening of the arteries. We will first apply gel on your neck and then use a small camera that touches your 
skin to take pictures of your carotid artery. There is no radiation during the ultrasound assessment. We will 
also measure the degree of hardening of the arteries in your finger and arm. To do so we will apply a small 
blood pressure cuff on your arm and inflate it for 5 minutes. We will then release the pressure from the cuff. 
We will measure the degree of change in the arteries before and after the cuff inflation.  
 
What is a brain MRI? 
You will also have a brain scan (MRI) at the baseline visit and at the final visit. MRI of the head will provide us 
with detailed information about your brain. The MRI does not use x-rays or radiation. These scans will take 
about 50-70 minutes. Before you have the scan, you will be asked to remove all metal objects (like earrings or 
watches) from your body. Throughout the exam, there will be loud thumping noises coming from the wall of 
the scanner. Earplugs will be provided to help reduce the noise. You may feel a warming sensation in your 
body during the MRI. You must lie still on a padded table during the scan. We will be continuously monitoring 
your comfort level during the scan procedure. We may also record the amount of carbon dioxide that you 
breathe out of your nose. During the scanning procedure, we may place a mask on your face and ask you to 
breathe a mixture of air including small amounts (5-8%) of carbon dioxide for about 2 minutes.  
 
PET scan 
In a subset of participants, we will also be performing Positron Emission Tomography (PET) scan. The scan 
allows doctors to detect presence amyloid and tau build up inside the brain of a living person. he PET scan in 
this study uses very small amounts of radioactive imaging agents, called Pittsburgh compound B (PiB) and 
T807, to make a picture showing how much amyloid and tau has been built-up in your brain.  It is possible that 
you will be asked to have one of the PET scans during the screening phase of the study (rather than the 
baseline visit) in order to see if you have protein build up.  
  
During the PET scan a catheter (hollow plastic tube) will be placed in a vein in your arm and you will undergo 
the infusion of the imaging agent. You will then be positioned on the scanner bed while the scanner takes 
pictures for 30-45 minutes.  During this time, you must hold your head as still as possible. 
 
Retinal Scan and Blood Sample 
This test is optional and will not affect your participation in this trial.  If you agree and are eligible to 
participate in the retinal scan, we will take digital images of your retina with dilation using a device very similar 
to that used during a visit to an eye doctor. This procedure lasts approximately 45-60 minutes. We may also 
ask you to provide 2 teaspoons (10mL tube) of blood that will be used for research purposes. These samples 
and images may be shared with other researchers. 


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Follow-up visits 
You will then be randomly prescribed either candesartan 8 mg once a day or placebo (inactive pill) once a day.  
You will then be seen every two weeks where the dose will be increased to 16 mg and 32 mg or matching 
placebo.  Once maximal dose is achieved, you will be seen every three months (total of 4 visits) until the study 
ends. During the last visit, we will repeat your MRI, spinal tap and PET scan if you were selected to have a PET 
scan. Blood samples will be drawn during each of these visits. 
 
During the follow-up visits, we may ask you questions regarding your social and functional history including 
your health habits, level of stress, and your ability to perform the activities of daily living. We may also ask you 
about your medical history, review the medications you are currently taking, measure your weight, height and 
blood pressure, and asses your balance, strength and walking speed. 
 
How will my medicine be provided?  
The medicine that you will take will be dispensed in a capsule format in a labelled bottle by the pharmacy and 
delivered to the principal investigator or study team member.  The medication will either be provided to you 
at your visit or mailed to you. If you have questions about the medicine you may call the study clinical 
personnel, the principal investigator or the pharmacy. The number for the pharmacy is included on your 
medicine package. Candesartan is an FDA-approved medication for treating hypertension but not for cognitive 
disorders. 
 
Who owns my study information and samples? 
If you join this study, you will be donating your samples and study information.  You will not receive any 
compensation if your samples or information are used to make a new product. If you withdraw from the 
study, data and samples that were already collected may be still be used for this study.   
 
Test results and incidental findings 
In general, we will not give you any individual results from the study of the samples you give us. If we find 
something of urgent medical importance to you, we will inform you, although we expect that this will be a 
very rare occurrence. All blood and CSF tests and vascular assessments are done for research purposes only.   
 
You will also be getting brain scans for research purposes only.  However, if the researchers have a question 
about something they see on the scan they will tell you and refer you to your primary care provider or another 
physician of your choosing for further clinical evaluation.  
 
What are the possible risks and discomforts? 
Cognitive testing assessment may be accompanied by anxiety, frustration and overall fatigue. The attachment 
and removal of a blood pressure cuff, cuffs for venous occlusion, and ultrasound probe on the neck may cause 
mild discomfort. Brain imaging requires you stay still and lie down for prolong time, which may cause 
boredom and minimal reversible back pain. Because of the closed space and noise, undergoing an MRI may be 
associated with anxiety or panic reactions. The potential side effects from CO2 inhalation may include a feeling 
of dizziness, faintness, or anxiety.  
 
The more common side effects from candesartan include: dizziness (4%), back pain (3%), upper respiratory 
tract infection (6%), pharyngitis/sore throat (2%), and runny nose (2%). 


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The less common risks (occurring around 1%) are: fatigue, leg edema, chest pain, headache, bronchitis, 
coughing, sinusitis, nausea, abdominal pain, diarrhea, vomiting, and joint pain.  
 
These adverse events have been reported in around 0.5% of participants: fever, vertigo, heartburn, rapid 
heartbeat/heart fluttering, kidney failure, increased potassium, muscle aches, swollen face, lip or tongue, rash, 
and shortness of breath. There may also be side effects from the study drug or procedures that are not known 
at this time. 
 
If you experience any adverse, call your doctor and the study personnel immediately.  
 
If you will be taking the study drug home, keep it out of the reach of children or anyone else who may not be 
able to read or understand the label.  Do not let anyone else take the study drug besides you. 
 
It is possible that the researchers will learn something new during the study about the risks of being in it.  If 
this happens, they will tell you about it. Then you can decide if you want to continue to be in this study or not.  
You may be asked to sign a new consent form that includes the new information if you decide to stay in the 
study. 
The most common complication of a spinal tap is a headache (5-10%). We use a thin spinal needle that 
decreases the risk of headaches to less than 10%. Please contact the study personnel or investigators if it 
persists beyond 3 days. Infection and bleeding are rare complication of a lumbar puncture, occurring in less 
than 1%.  
In very rare instances, a leak of CSF may occur. A leak means that your body did not heal the area where we 
obtained the CSF sample. If it persists this can be closed by a blood patch. A blood patch includes injecting a 
very small amount of your blood into that area where there is a leak. If the physician determines that a blood 
patch (applying a few drops of your blood on the site where the spinal tap was done) is necessary, you will not 
be billed for this procedure. 
If you were selected to have a PET scan, you will be exposed to radiation from nuclear medicine. The 
estimated radiation dose that you will receive is within limits acceptable to the Emory University Radiation 
Safety Committee. We have not encountered systemic toxic effects attributable to single dose T807 or PiB. 
Both ligands are rapidly cleared from the plasma and their binding to their target is temporary. Toxicity or 
allergies to PiB or T807 remain a possibility and you will be monitored for such events during the scan and at 
follow-up.  Infection, bleeding and transient discomfort may be encountered from the intravenous catheter 
introduced in your arm vein during this scan. 
Principal Investigators shall immediately (within 24 hours of the event) report to the Radioactive Drug 
Research Committee all adverse effects associated with the use of the radioactive drug in the research study. 
All adverse reactions probably attributable to the use of the radioactive drug in the research study shall be 
immediately reported (within 24 hours of receiving the initial report) by the RDRC to the Food and Drug 
Administration, Center for Drug Evaluation and Research. 
If you were selected to have retinal imaging performed, adverse reactions to dilation of the eyes may include 
discomfort, irritation, or other reactions similar to pupillary dilation experienced during a visit to the eye 
doctor. Increased sensitivity to bright lights is commonly experienced, and we will provide disposable 
sunglasses to counteract these effects. You will be monitored for adverse effects. 


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Will I benefit directly from the study?  
This study is not designed to benefit you directly.  Your thinking skills may or may not improve while you are in 
this study, and they may even get worse.  This study is designed to learn more about the effect of candesartan 
on the protein buildup in the brain. The study results may be used to help others in the future. 
Will I be compensated for my time and effort? 
Compensation for your participation in these study visit will be in the form of gift cards. You will be 
compensated for your effort and time at the following schedule: 
 
• Screen Visit: $25 + $100 (for lumbar puncture procedure) 
• Baseline Visits: $100 (for visit + MRI) + $75 for each PET scan (optional) 
• Titration Visits (2): $10 
• 3 & 9 Month Follow Up Visits: $25 
• 6 Month Follow Up Visit: $50 (cognitive testing, blood draw) 
• 12 Month Follow Up Visits: $100 (for visit + MRI) + $75 for each PET scan (optional) + $100 (for lumbar 
puncture procedure) 
• Return Visit for blood redraw: $20 and LP $100 (as needed) 
• Retinal Imaging: $25 
• 
Transportation: Up to $30 for gas reimbursement and up to $50 for taxi or shuttle service to the study site  
You may be asked to fill out a tax form, including your Social Security or Taxpayer Identification Number, in 
order to be reimbursed, depending on the amount and method of payment. Some payment methods involve 
mail coming to your house, which may be seen by others in your household. You can decline payment if you 
are concerned about confidentiality, or you can talk to the study team to see if there are other payment 
options.   
What are my other options? 
If you decide not to enter this study, there is care available to you outside of this research study. [List the 
major standard care options and/or possibility of other studies; if the study compares two standard care 
treatments, state which one the subject would be most likely to get outside of the study, if applicable]. The 
study doctor will discuss these with you.  You do not have to be in this study to be treated for your memory 
symptoms. 
 
Taking part in this study, however, will make you unable to participate in other research studies.  You should 
discuss this with the study personnel if you have concerns. You may wish to research other study options at 
websites like clinicaltrials.gov and ResearchMatch.org. 
 
How will you protect my private information that you collect in this study? 
Whenever possible, a study number, rather than your name, will be used on study records.  Your name and 
other identifying information will not appear when we present or publish the study results. 
 
Study records can be opened by court order.  They also may be provided in response to a subpoena or a 
request for the production of documents.  


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Storing and Sharing your Information 
Your samples, study data and health information will be stored and shared with other researchers. The 
samples and information will be available for any research question, such as research to understand what 
causes certain diseases (for example heart disease, cancer, or psychiatric disorders), development of new 
scientific methods, or the study of where different groups of people may have come from. 
 
Medical Record 
If you have been an Emory Healthcare patient before, then you already have an Emory Healthcare medical 
record.  If you have never been an Emory Healthcare patient, you do not have one.   An Emory Healthcare 
medical record will be made for you if an Emory provider or facility gives you any services or procedures for 
this study.   
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory Healthcare medical 
record you have now or any time during the study.   
 
Emory Healthcare may create study information about you that can help with your care.  For example, the 
results of study tests or procedures.  These study results will be put in your Emory Healthcare medical record. 
Anyone who has access to your medical records will be able to have access to all the study information placed 
there.  The confidentiality of the study information in your medical record will be protected by laws like the 
HIPAA privacy rule.  State and federal laws may not protect the research information from disclosure.  
 
Tests and procedures done at non-Emory facilities may not become part of your Emory medical record. Also, if 
you decide to be in this study, it is up to you to let your other health providers know.  
 
How is my Genetic Information Protected? What are the Risks? 
The Genetic Information Nondiscrimination Act (GINA) is a federal law that generally makes it illegal for health 
insurance companies, group health plans, and most employers to discriminate against you based on your 
genetic information. This law generally will protect you in the following ways:  
• 
Health insurance companies and group health plans may not request your genetic information that we 
get from this research. 
• 
Health insurance companies and group health plans may not use your genetic information when 
making decisions regarding your eligibility or premiums.  
• 
Employers with 15 or more employees may not use your genetic information that we get from this 
research when making a decision to hire, promote, or fire you or when setting the terms of your employment. 
 
Be aware that GINA does not protect you against genetic discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance, and does not apply to employers with less than 15 
employees. 
 
In addition to GINA, the State of Georgia has laws that prohibit insurers from using genetic testing information 
for any non-treatment purpose.  However, like GINA, this state law protection has exclusions: life insurance 
policies, disability income policies, accidental death or dismemberment policies, Medicare supplement 
policies, long-term care insurance policies, credit insurance policies, specified disease policies, hospital 
indemnity policies, blanket accident and sickness policies, franchise policies issued on an insurance policy 


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written as a part of workers’ compensation equivalent coverage, or other similar limited accident and sickness 
policies. 
 
Privilege  
In the State of Georgia, your genetic information has special legal protections called “privilege,” which means 
that the information cannot be used as evidence in a court.  By signing this form and allowing us to use and 
disclose your genetic information for the purposes described in this consent, you waive any privilege with 
regard to that genetic information, meaning that the information loses this legal protection.   
 
Genomic studies, including genome-wide association studies (GWAS), examine genetic differences in the 
entire human genome (the complete set of human genes) and the association between these genetic 
differences and health conditions.   
 
In Case of Injury 
If you get ill or injured from being in the study, Emory will help you get medical treatment.   Emory and the 
sponsor have not, however, set aside any money to pay you or to pay for this medical treatment. The only 
exception is if it is proven that your injury or illness is directly caused by the negligence of an Emory or sponsor 
employee.  “Negligence” is the failure to follow a standard duty of care.  
If you become ill or injured from being in this study, your insurer will be billed for your treatment costs.  If you 
do not have insurance, or if your insurer does not pay, then you will have to pay these costs.   
If you believe you have become ill or injured from this research, you should contact Dr. Ihab Hajjar at 
 
 You should also let any health care provider who treats you know that you 
are in a research study.  
Costs 
There will be no costs to you for participating in this study, other than basic expenses like transportation. You 
will not be charged for any of the research activities. 
 
Withdrawal from the Study 
You have the right to leave a study at any time without penalty.   
 
For your safety, however, you should consider the study doctor’s advice about how to go off the study 
treatment.  If you leave the study before the final planned study visit, the researchers may ask you to have 
some of the final steps done.   
 
The researchers also have the right to stop your participation in this study without your consent for any reason, 
especially if they believe it is in your best interest or if you were to object to any future changes that may be made 
in the study plan. 
 
Authorization to Use and Disclose Protected Health Information 
 
The privacy of your health information is important to us.  We call your health information that identifies you, 
your “protected health information” or “PHI.”  To protect your PHI, we will follow federal and state privacy 


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laws, including the Health Insurance Portability and Accountability Act and regulations (HIPAA).  We refer to all 
of these laws as the “Privacy Rules.”  Here we let you know how we will use and disclose your PHI for the main 
study and for any optional studies in which you may choose to participate. 
 
PHI that will be Used/Disclosed:   
The PHI that we will use or share for the main research study includes: 
• Medical information about you including your medical history and present/past medications. 
• Results of exams, procedures and tests you have before and during the study. 
• Laboratory test results. 
 
Purposes for Which Your PHI Will be Used/Disclosed: 
We will use and share your PHI for the conduct and oversight of the research study.  We will use and share 
your PHI to provide you with study related treatment and for payment for such treatment.  We will also use 
and share your PHI to conduct normal business operations.  We may share your PHI with other people and 
places that help us conduct or carry out the study, such as laboratories, data management centers, data 
monitors, contract research organizations, Institutional Review Boards (IRBs) and other study sites. If you 
leave the study, we may use your PHI to determine your health, vital status, eligibility or contact information. 
We will use and disclose your PHI for the administration and payment of any costs relating to subject injury 
from the study. 
 
Use and Disclosure of Your Information That is Required by Law:   
We will use and disclose your PHI when we are required to do so by law. This includes laws that require us to 
report child abuse or abuse of elderly or disabled adults. We will also comply with legal requests or orders that 
require us to disclose your PHI. These include subpoenas or court orders.   
 
Authorization to Use PHI is Required to Participate: 
By signing this form, you give us permission to use and share your PHI as described in this document. You do 
not have to sign this form to authorize the use and disclosure of your PHI.  If you do not sign this form, then 
you may not participate in the research study or receive research-related treatment.  You may still receive 
non-research related treatment.   
 
People who will Use/Disclose Your PHI: 
The following people and groups will use and disclose your PHI in connection with the research study: 
 
• The Principal Investigator and the research staff will use and disclose your PHI to conduct the study and 
give you study related treatment. 
• Emory may use and disclose your PHI to get payment for study related treatment and to run normal 
business operations.  
• The Principal Investigator and research staff will share your PHI with other people and groups to help 
conduct the study or to provide oversight for the study. 
• The research team may use and disclose your PHI, including disclosure to insurance carriers to 
administer payment for subject injury.   
• The following people and groups will use your PHI to make sure the research is done correctly and safely: 


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o Emory offices that are part of the Human Research Participant Protection Program and those that 
are involved in study administration and billing.  These include the Emory IRB, the Emory Research 
and Healthcare Compliance Offices, and the Emory Office for Clinical Research.  
o Government agencies that regulate the research including:  Office for Human Research Protections 
and the Food and Drug Administration. 
o Public health agencies. 
o Research monitors and reviewer. 
o Accreditation agencies. 
• Sometimes a Principal Investigator or other researcher moves to a different institution. If this happens, 
your PHI may be shared with that new institution and their oversight offices. PHI will be shared securely 
and under a legal agreement to ensure it continues to be used under the terms of this consent and 
HIPAA authorization. 
 
Expiration of Your Authorization 
Your PHI will be used until this research study ends. 
 
Revoking Your Authorization 
If you sign this form, at any time later you may revoke (take back) your permission to use your information.  If 
you want to do this, you must contact the study team at 
: 
 
At that point, the researchers would not collect any more of your PHI.  But they may use or disclose the 
information you already gave them so they can follow the law, protect your safety, or make sure that the 
study was done properly and the data is correct.  If you revoke your authorization you will not be able to stay 
in the study.  
 
Other Items You Should Know about Your Privacy 
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care providers, 
health care payers, and health care clearinghouses.  If we disclose your information to people who are not 
covered by the Privacy Rules, including HIPAA, then your information won’t be protected by the Privacy Rules.  
People who do not have to follow the Privacy rules can use or disclose your information with others without 
your permission if they are allowed to do so by the laws that cover them.   
 
To maintain the integrity of this research study, you generally will not have access to your PHI related to this 
research until the study is complete.  When the study ends, and at your request, you generally will have access 
to your PHI that we maintain in a designated record set.  A designated record set is data that includes medical 
information or billing records that your health care providers use to make decisions about you. If it is 
necessary for your health care, your health information will be provided to your doctor.  
 
We may remove identifying information from your PHI.  Once we do this, the remaining information will not 
be subject to the Privacy Rules.  Information without identifiers may be used or disclosed with other people or 
organizations for purposes besides this study.   
 
Contact Information 
 
• if you have any questions about this study or your part in it,   


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• if you feel you have had a research-related injury or a bad reaction to the study drug, or 
• if you have questions, concerns or complaints about the research 
 
Contact the Emory Institutional Review Board 
 
• if you have questions about your rights as a research participant. 
• if you have questions, concerns or complaints about the research. 
• You may also let the IRB know about your experience as a research participant through our Research 
Participant Survey at http://www.surveymonkey.com/s/6ZDMW75. 
 


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TO BE FILLED OUT BY SUBJECT ONLY 
Please print your name, sign, and date below if you agree to be in the study. By signing this consent and 
authorization form, you will not give up any of your legal rights. We will give you a copy of the signed form to 
keep. 
Name of Subject 
Signature of Subject (18 or older and able to consent) 
Date 
 Time 
Signature of Legally Authorized Representative with authority for 
Date 
 Time 
research decisions 
Authority of Legally Authorized Representative or Relationship to Subject 
TO BE FILLED OUT BY STUDY TEAM ONLY 
__________________________________________________________ 
Name of Person Conducting Informed Consent Discussion 
Signature of Person Conducting Informed Consent Discussion 
Date 
 Time 


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STUDY PARTNER INFORMATION & CONSENT 
STUDY PARTNER INFORMATION AND CONSENT 
As the participant’s study partner, you have the important tasks of providing important 
assistance to the enrolled participant to complete the study accurately.   
These responsibilities include providing information about the participant’s physical and 
thinking abilities and informing the study personnel about any significant changes in these 
abilities. You also agree to come with the study participant for his or her exams and evaluations. 
If you cannot come to the study center, then you agree to be available by phone to discuss with 
the study personnel the participant’s physical and thinking abilities. 
If for some reason you become unable to carry out these responsibilities, please tell the study 
coordinator immediately.  You may be asked, if possible, to select a substitute who can take 
over your duties. 
AGREEMENT: 
I have read (or someone has read to me) all the preceding information which describes both the 
participant’s involvement in the study and my involvement as the participant’s study partner.  I 
have been given a chance to ask questions. All my questions have been answered. By signing 
this form, I am agreeing to take part in this study.   
______ 
Name of Study Partner (print) 
Signature  
  Date 
I have personally explained the research to the research participant and answered all questions. I 
believe that he/she understands the information described in this informed consent and freely 
consents to participate.  
Name of Investigator/Person 
Obtaining Informed Consent (print) 
Signature 
Date 

Prot_SAP_002.pdf: 
CEDAR-V14.0: 3/23/2020 
CANDESARTAN’S EFFECTS ON ALZHEIMER’S DISEASE AND RELATED BIOMARKERS 
(CEDAR) 
NCT02646982 
Date: March 23, 2020 
IRB00084574 


1 
CEDAR-V14.0: 3/23/2020 
PROTOCOL 
Candesartan’s Effects on Alzheimer’s Disease 
And Related Biomarkers 
(CEDAR) 
VERSION 14; 3/23/2020 
Principal Investigator: 
Ihab Hajjar, MD 
Emory University 


2 
CEDAR-V14.0: 3/23/2020 
TABLE OF CONTENTS 
STUDY TEAM ROSTER ........................................................................................................................................................................ 1 
PARTICIPATING STUDY SITES ............................................................................................................................................................. 3 
PRÉCIS ............................................................................................................................................................................................... 4 
SCHEDULE OF PROCEDURES FOR THE DURTAION OF THE STUDY ...................................................................................................... 5 
1. STUDY OBJECTIVES ........................................................................................................................................................................ 7
2. BACKGROUND AND RATIONALE .................................................................................................................................................... 7
2.1. DISEASE TARGETS FOR ARBS IN AD ....................................................................................................................................................... 7 
2.2. SAFETY OF ARBS IN NON-HYPERTENSIVE INDIVIDUALS ................................................................................................................................ 7 
2.3. STUDY RATIONALE ............................................................................................................................................................................... 8 
3. STUDY DESIGN ............................................................................................................................................................................... 8
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ......................................................................................................................... 8
4.1. INCLUSION CRITERIA ............................................................................................................................................................................ 8 
4.2. EXCLUSION CRITERIA ............................................................................................................................................................................ 9 
4.3. STUDY RECRUITMENT ........................................................................................................................................................................... 9 
5. STUDY INTERVENTIONS ............................................................................................................................................................... 10
5.1. INTERVENTIONS, ADMINISTRATION, AND DURATION ................................................................................................................................ 10 
5.2. HANDLING OF STUDY INTERVENTIONS ................................................................................................................................................... 10 
5.3. CONCOMITANT INTERVENTION ............................................................................................................................................................. 10 
5.3.1. Allowed Interventions ........................................................................................................................................................... 10 
5.3.2. Prohibited Interventions ....................................................................................................................................................... 10 
5.4. ADHERENCE ASSESSMENT ................................................................................................................................................................... 10 
6. STUDY PROCEDURES AND MEASURES ......................................................................................................................................... 10
6.1. QUESTIONNAIRES, LIFESTYLE AND ANTHROPOMETRIC MEASURES ................................................................................................................ 11 
6.2. BLOOD PRESSURE MEASUREMENT ......................................................................................................................................................... 11 
6.3. NEUROPSYCHOLOGICAL ASSESSMENT: ................................................................................................................................................... 11 
6.4. CEREBROSPINAL FLUID (CSF) COLLECTION ............................................................................................................................................. 12 
6.5. BRAIN MRI AND PET IMAGING PROTOCOLS ........................................................................................................................................... 12 
6.6. VASCULAR MEASURES......................................................................................................................................................................... 13 
6.7. PROTEOMICS AND INFLAMMATORY MARKERS .......................................................................................................................................... 13 
6.8. RENIN ANGIOTENSIN SYSTEM ACTIVITY .................................................................................................................................................. 13 
6.9. BLOOD CHEMISTRIES, BLOOD COUNT, AND APO-E ................................................................................................................................... 13 
6.10. BLOOD WILL BE DRAWN AT VARIOUS VISITS. PLEASE REFER TO THE TABLE FOR SPECIFIC TESTS DONE AT EACH VISIT. BLOOD AND CSF BANKING ........ 13 
6.11. SCHEDULE OF EVLAUATIONS .............................................................................................................................................................. 14 
6.11.1. Screening ............................................................................................................................................................................ 14 
6.11.2. Enrollment, baseline, and follow-up ................................................................................................................................... 14 
7. SAFETY ASSESSMENTS ................................................................................................................................................................. 14
7.1. SPECIFICATION OF SAFETY PARAMETERS ................................................................................................................................................ 14 
7.2. METHODS FOR ASSESSING AND RECORDING SAFETY PARAMETERS ............................................................................................................... 15 
7.3. REPORTING ADVERSE EVENTS AND DEATH ............................................................................................................................................ 15 
7.4. FOLLOW-UP FOR ADVERSE EVENTS ....................................................................................................................................................... 16 
7.5. INCIDENTAL FINDINGS ......................................................................................................................................................................... 16 
8. INTERVENTION DISCONTINUATION ............................................................................................................................................. 16
9. STATISTICAL CONSIDERATIONS ................................................................................................................................................... 17
9.1. GENERAL DESIGN .............................................................................................................................................................................. 17 
9.2. RANDOMIZATION .............................................................................................................................................................................. 17 
9.3. DATA ANALYSIS ................................................................................................................................................................................. 17 


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CEDAR-V14.0: 3/23/2020 
10. DATA COLLECTION AND QUALITY ASSURANCE .......................................................................................................................... 17
10.1. DATA COLLECTION FORMS ................................................................................................................................................................ 17 
10.2. DATA MANAGEMENT ....................................................................................................................................................................... 17 
10.3. QUALITY ASSURANCE ....................................................................................................................................................................... 18 
10.3.1. Training .............................................................................................................................................................................. 18 
10.3.2. Quality Control ................................................................................................................................................................... 18 
10.3.3. Protocol Deviations............................................................................................................................................................. 18 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY............................................................................................................................ 18
11.1. INSTITUTIONAL REVIEW BOARD (IRB) REVIEW ...................................................................................................................................... 18 
11.2. CONSENTING PROCEDURE , INFORMED CONSENT FORMS, AND STUDY INFORMANTS..................................................................................... 18 
11.3. PARTICIPANT CONFIDENTIALITY .......................................................................................................................................................... 19 
11.4. PARTICIPANT COMPENSATION............................................................................................................................................................ 19 
11.5. STUDY DISCONTINUATION ................................................................................................................................................................. 20 
12. PUBLICATION OF RESEARCH FINDINGS ...................................................................................................................................... 20
13. REFERENCES .............................................................................................................................................................................. 21


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CEDAR-V14.0: 3/23/2020 
 
STUDY TEAM ROSTER 
 
Ihab Hajjar, MD, MS (Principal Investigator) 
Section of Geriatrics and Gerontology 
 
 
 
 
Allan Levey, MD, PhD (Co-investigator, Neurologist) 
Department of Neurology 
 
 
 
Arshed Ali Quyyumi, MD (Co-investigator, Cardiology) 
Division of Cardiology 
Department of Medicine 
 
 
 
Deqiang Qiu, PhD (Co-investigator, MRI expert) 
Division of Magnetic Resonance Research 
Department of Radiology 
 
 
 
Felicia Goldstein, PhD (Co-investigator, Neuropsychologist) 
 
 
Department of Neurology 
 
 
 
Jonathan Nye, PhD (co-investigator, Medical Physicist) 
Department of Radiology 
 


2 
CEDAR-V14.0: 3/23/2020 
 
 
 
Mark M. Goodman, PhD (co-investigator, Radiochemist) 
Department of Radiology 
 
 
 
John Hanfelt, PhD (Co-investigator; Statistician) 
Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, 
 
 
 
Nicholas T. Seyfried (Co-investigator, Neuroproteomics) 
Director, Emory NINDS-Neuroscience Proteomics Core Facility 
 
 
 
 


3 
CEDAR-V14.0: 3/23/2020 
 
PARTICIPATING STUDY SITES 
 
Wesley Woods Health Center 
 
Emory University Hospital Clinical Research Network 
 
Executive Park Medical Campus 
 


4 
CEDAR-V14.0: 3/23/2020 
 
PRÉCIS 
Study Title 
Candesartan’s Effects on Alzheimer’s Disease And Related Biomarkers 
Acronym 
CEDAR 
Objectives  
Our Primary objective is to determine the safety and dose-response for target engagement of the treatment 
with escalating doses of candesartan in those with mild cognitive impairment (MCI) and Alzheimer’s disease 
(AD) based on cerebrospinal fluid levels of amyloid and tau.  
Our secondary objectives are to assess the efficacy of 1 year treatment of candesartan on biomarkers of vascular 
function, neurodegeneration, and neuro-inflammation; to assess the efficacy of 1 year treatment with 
candesartan on amyloid imaging; and to estimate the effect size of candesartan on cognitive and functional 
measures in MCI and AD.   
Design and Outcomes  
 This is a double-blind placebo-control randomized clinical trial that compares candesartan to placebo in 
individuals with MCI who also have positive AD biomarkers. Our measures include cognitive function, cerebral 
perfusion and reserve, markers of vascular brain damage, atherosclerosis, arterial stiffness, vascular 
inflammation and endothelial function. Amyloid and Tau PET imaging will be collected on a subgroup of this 
trial. 
Interventions and Duration  
The intervention includes candesartan (8, 16, or 32 mg) or placebo. The duration of the study is 1 year.  
 Sample Size and Population  
Our target population includes subjects who are 50 years or older who are not receiving antihypertensive 
medications with MCI and AD. Our sample size is 72 for this trial. All 72 subjects will be invited to participate in 
the additional PET study. 
 
 


5 
CEDAR-V14.0: 3/23/2020 
 
SCHEDULE OF PROCEDURES FOR THE DURTAION OF THE STUDY 
 
Phase:  SCREEN 
BASELINE 
RANDOMIZATION 
TITRATION 
FOLLOW-UP 
Number of visits 
1-2 
1-3 
2 
4 
Months 
-1 
0 
1-2 
3 
6 
9 
12 
Informed Consent  
X 
Cognitive screening 
X 
 
 
 
 
 
 
Screening labs  
X* 
 
 
 
 
 
 
 Amyloid Positivity to assess 
eligibility 
X** 
CSF for molecular analysis  
X*** 
X*** 
 
 
 
 
X 
Weight/Height 
X 
X 
X 
X 
X 
X 
Blood Pressure 
X 
X 
X 
X 
X 
X 
X 
Safety labs  
  
X# 
X# 
X^ 
X# 
X^ 
Brain MRI 
 
X 
 
 
 
 
X 
In-vivo Aβ and Tau PET scan 
X** 
X** 
 
 
 
 
X 
Vascular function measures 
X 
X 
Cognitive Battery 
X 
X 
X 
Functional battery (IADL, SPPB) 
 
X 
 
 
 
 
X 
RAS biomarkers (blood and CSF) 
 
X 
 
 
X 
 
X 
APOE genotype 
 
X 
 
 
 
 
 
Retinal scan and blood 
draw**** 
 
 
 
 
 
 
 
Inflammatory/molecular  
biomarkers (proteomics 
/metabolomics) 
X$ 
X$ 
X 
Time (in minutes) 
60-120 
150-210 
30 
30 
75 
30 150-210 
*: Screening labs include: CBC, CMP (BUN, CR, electrolytes, liver function), B12, TSH and PT/INR 
**: Amyloid positivity can be assessed by either LP (CSF levels of amyloid) or PIB-PET. We will routinely use LP 
as the default method to determine Amyloid positivity however, in some instances e.g. a failed LP or delayed 
CSF results due to lab issues then we will use a screening PIB-PET instead. If a PIB-PET was done at screening, it 
WILL NOT be repeated at baseline. Subjects will only have Tau-Pet at baseline. 
***: If subject has had an LP within the 6 months prior to their screening/baseline visit and samples are 
available for assessing eligibility and for measuring CSF outcomes then no LP will be done at screening. If CSF is 
only available for eligibility assessment (e.g. from PIB-PET/ clinical LP/assessment/ another research study and 
subject willing to share these samples) then an LP will be done to obtain CSF for the outcome measures (such 


6 
CEDAR-V14.0: 3/23/2020 
 
as molecular analysis). This LP can be done at baseline instead of screening (since eligibility would have been 
already established). 
****: Retinal scan +/- 10 cc blood draw are optional and can be done at any visit or after the completion of 
the study. 
#: Safety labs at titration, 3 and 9 months include BMP (BUN, CR, electrolytes)  
^: Safety labs at 6 months and 12 months include BMP (BUN, CR, electrolytes) + CBC. If subject started taking 
any blood thinners during the study, PT/INR will be repeated before LP at 12 months.   
$: Samples for inflammatory/molecular biomarkers will be drawn either at screening or at baseline visits. 


7 
CEDAR-V14.0: 3/23/2020 
 
1. STUDY OBJECTIVES 
Our Primary objective is to determine the safety and dose-response of target engagement for treatment with 
escalating doses of candesartan in those with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). 
Our secondary objectives are to assess the efficacy of 1 year treatment of candesartan on biomarkers of vascular 
function, neurodegeneration, and neuro-inflammation; to assess the efficacy of 1 year treatment with 
candesartan on amyloid imaging; and to estimate the effect size of Candesartan on cognitive and functional 
measures in MCI and AD.   
2. BACKGROUND AND RATIONALE  
Available treatments for AD do not address novel neurovascular and inflammatory pathways. Prior research has 
documented that the antihypertensive angiotensin receptor blockers (ARBs), in general, and candesartan, in 
particular, may have a positive effect on both AD biomarkers and clinical manifestations.   
2.1. DISEASE TARGETS FOR ARBS IN AD 
AD is a multifactorial and a multisystem disease.  ARBs target vascular, inflammatory, and amyloid pathways 
involved in AD initiation or progression shown in Figure 1. At the neurovascular level, ARBs improve cerebral 
perfusion and restore neurovascular coupling and microvascular function.1-3 Both MCI and AD individuals exhibit 
significant microvascular dysfunction as reflected by declines in vasodilator response to CO2 (Vasoreactivity).4 
Our work suggests that in MCI, RAS activation leads to lower vasoreactivity, and ARBs may improve this measure 
which translates into improved cognition.1,5 Peripheral vascular markers including increased  arterial stiffness 
(which correlates with amyloid deposition in the 
brain6,7)  and decreased microvascular  regeneration 
capacity reflected by  circulating endothelial-related 
progenitor cells (EPC)8 are both observed in AD. EPC’s 
have a potential role in repairing the blood brain 
barrier (BBB) endothelium9,10  by differentiating into 
BBB 
like-cells11,12 
and 
improving 
neurovascular 
healing.13  EPC are decreased in AD patients 8 and 
correlate positively with cognitive function.8 Ang II (via 
AT1) leads to smooth muscle hypertrophy14 and 
release 
of 
endothelial-related 
inflammatory 
mediators,15 resulting in increased stiffness.16  Aβ17 and 
Ang II18 reduce EPC counts and function leading to 
apoptosis, and ARBs may inhibit these effects in animal 
models.19 ARBs also inhibit Aβ induced neurovascular 
impairments, independently of BP.20-22 Aβ is transported back from the blood to the brain by receptors for 
advanced glycation end products (RAGE) on the endothelium.23 Ang II up-regulates RAGE and increases BBB 
permeability by increasing oxidative stress24 and disrupting tight junctions.25,26 ARBs inhibit the expression of 
RAGE27 and restore BBB integrity by “healing” its endothelium. Ang II also increases and ARBs inhibit glycogen 
synthase kinase 3β (GSK3β) activity.28 GSK3β increases tau phosphorylation and synaptic defects and is initiated 
in the earliest stages of clinical AD.29-31 ARBs hence may decrease p-tau levels as suggested by a recent rat 
experiment. 32  This multi-target characteristic of ARBs increases the likelihood of producing a disease-modifying 
effect, rather than a symptomatic effect as provided by currently approved medications. 
2.2. SAFETY OF ARBS IN NON-HYPERTENSIVE INDIVIDUALS 


8 
CEDAR-V14.0: 3/23/2020 
 
Prior studies in non-hypertensive individuals with normal cognition have shown that it has a good safety profile 
with respect to adverse events and 
hypotension.   In a non-hypertensive 
sample, 
 
Losartan 
(at 
equipotent 
candesartan 
doses; 
n=142 
non-
hypertension) had similar BP declines 
(4.7/3 mm Hg) compared to placebo.33 
(Table-1) In the Diabetic Retinopathy 
Candesartan Trial Program [n=3,326, follow-up=5 years, pretreatment BP: 115-118/70-75 mm Hg], systolic 
blood pressure (SBP) reductions were in the range of 2.6-3.6 mm Hg in the candesartan arm and 2.5-2.7 in the 
placebo arm with no diastolic blood pressure (DBP) changes. 34   These declines were not associated with 
hypotensive symptoms.  
2.3. STUDY RATIONALE 
In the brain, Angiotensin II (Ang II) binds AT1 and AT2 receptors. AT1 activation increases oxidative stress,35 
endothelial dysfunction, vasoconstriction and hypoperfusion, cholinergic depletion, neuro-degeneration, and 
memory loss.36-39 AT2 improves endothelial function, increases cerebral perfusion,40 decreases superoxide 
production,40 promotes neuronal cell differentiation,41-48 and facilitates memory functions.49,50 Blocking the 
effect of Ang II, a crucial mediator of neuro-vascular injury, using ARBs may address shortcomings of current 
treatments. ARBs affect multiple systems involved in AD: vascular function, blood pressure (BP), inflammation, 
and the amyloid cycle.[see review51] 
3. STUDY DESIGN   
This is a PHASE II 1-year double-blind placebo-controlled randomized clinical trial where participants will be 
treated with candesartan (escalating doses: 8, 16 to 32 mg) or matched placebo.  
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1. INCLUSION CRITERIA 
(1) Age: 50 years or older;  
(2) MCI will be defined as:  
(i) Subjective memory concern;  
(ii) Abnormal memory function documented using the Logical Memory subscale (Delayed 
Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale-Revised (the maximum 
score is 25):  [<11 for 16 or more years of education; <9 for 8-15 years of education; <6 for <7 
years of education];  
(iii) Montreal Cognitive Assessment (MoCA) < 26; 
(iv) Clinical Dementia Rating scale /Memory sum Box score=0.5.  
(v) General functional performance sufficiently preserved (Functional Assessment 
Questionnaire<9); 
(3) Amyloid positivity: This will be determined by measuring the amyloid content in the brain. This can 
be determined by either CSF amyloid level or an amyloid scan (PIB-PET). We will plan to use CSF levels 
of amyloid as our default method. However, if we are not able to determine eligibility using CSF levels 
then a PIB-Pet will be performed to assess amyloid positivity. 


9 
CEDAR-V14.0: 3/23/2020 
 
 
 
In instances where the diagnosis of MCI is not clear, a review of the subject cognitive and non-cognitive 
data will be performed by the study physicians or neuropsychologists and a diagnosis of MCI will be 
based on the clinical judgment of the study physicians or neuropsychologists. 
4.2. EXCLUSION CRITERIA 
(1) Intolerance to ARBs;  
(2) Current use of ARBs or ACEI (use of antihypertensive medications other than ACEI or ARBs for other 
indications is allowed); 
(3) Current diagnosis of hypertension or current use of antihypertensive medication that is prescribed 
specifically for hypertensive therapy;  
(4) SBP less than 110 or DBP less than 40 mm Hg;  
(5) Renal disease (Creatinine >2.0 mg/dl), hyperkalemia (K>5.5 meq/dl), platelets<50,000/μl, or INR>1.9;  
(6) Active medical or psychiatric diseases that in the judgment of the investigator would affect the safety of the 
subject or scientific integrity of the study e.g. if the patient has hypothyroidism or low vitamin B12 that is 
contributing to the subject’s cognitive impairment;  
(7) Uncontrolled congestive heart failure reflected by poor exercise tolerance and shortness of breath;  
(8) History of stroke in the past 3 years;  
(9) Inability to have MRI (eg metal implants or cardiac pacemaker) with an exception for those who cannot have 
an MRI, if all other parts of the study are obtained successfully they may still be enrolled in the study, or cognitive 
assessment or inability to assess amyloid positivity (no LP and no amyloid scan);  
(10) History of increased intracranial pressure (ICP) or bleeding diathesis (from disease states or from use of 
anticoagulants such as warfarin, heparin and related products, Rivaroxaban or Xarelto, Apixaban or Eliquis, 
Edoxaban or Savaysa, Dabigatraban or Pradaxa);  
(11) Women of childbearing potential (non-menopausal);  
(12) In those who are unable to demonstrate that they understood the details of the study (ie lack of decisional-
capacity to consent), a study partner/surrogate who can sign on their behalf will be required, otherwise they 
will be excluded;  
(13) Current use of Lithium, as Candesartan may increase lithium concentration to toxic levels. 
4.3. STUDY RECRUITMENT 
Potential participants will be identified through community activities, health fairs, and patient referrals. Below 
we describe our recruitment venues: 
(1) The Emory Alzheimer's Disease Research Center (ADRC) Clinical Core registry of research participants will be 
utilized for recruitment.  Participants have agreed to be referred to other studies. 
(2) Community-based recruitment: Community education sessions in local neighborhoods e.g. churches or 
barbershops will be conducted and attendees will be invited to participate in this study.   
(3) MindMate App recruitment: MindMate users have the opportunity to first express their interest in clinical 
studies within the ‘Research’ section of the app. MindMate can also reach out to users once they have 
consistently utilized the app, usually after 3-4 weeks, & ask the user if they would like to receive further 


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information when a matching clinical study is available in their area. All users that are interested in participating 
in a clinical study must then go through a multi-stage opt-in & consent process. After MindMate matches a user 
to an open clinical trial, they automatically ask if they’re happy to be contacted by a researcher to learn more 
about an open study they might qualify for. 
(4) Physician recruitment: Local physicians (primary care or specialty physicians) will be informed of the study 
and its criteria and provided information about referral to the study personnel. In addition, flyers for the study 
will be posted at outpatient areas in the local medical facilities.  
5. STUDY INTERVENTIONS 
5.1. INTERVENTIONS, ADMINISTRATION, AND DURATION 
Participants will be randomized to either candesartan or placebo in a 1:1 fashion. All participants will be initiated 
on 8 mg. The dose will be increased in 2 week increments to 16 mg and 32 mg as long as:  SBP>110 mm Hg, 
DBP>40 mm Hg and participant reports no symptoms of hypotension (dizziness or weakness).  The highest 
achievable dose will be the Maximal Tolerated Dose (MDT) and will be prescribed for the duration of the study. 
The cut-off of 110 mm Hg for SBP is based on the evidence that a decrease of ≤5 mm Hg in SBP is expected in 
non-hypertensive individuals. Hence, a cutoff of 110 mm Hg in SBP decreases the risk of developing hypotension 
(defined as <100 mm Hg in SBP). Treatment will be provided in similar capsules format to be taken once a day 
orally. Investigators, study personnel and participants will be blinded for drug assignment. Participants will be 
treated for 1 year.  
5.2. HANDLING OF STUDY INTERVENTIONS 
 The drugs will be stored in the medication room in the Investigational Drug Service (IDS) Pharmacy. The location 
of the IDS pharmacy is The Emory Clinic Bldg. A, Suite 1200, 1365 Clifton Road, NE, Atlanta, Georgia 30322. 
Access to the med room is limited to the IDS Pharmacists via a badge swipe. Accountability records are 
maintained for all investigational product (IP). A courier will deliver prescriptions to study location to be given 
to subjects or study staff will be able to pick up prescriptions.  
5.3. CONCOMITANT INTERVENTION 
5.3.1. ALLOWED INTERVENTIONS 
Participants will continue to receive their usual care from their regular primary care physicians. In the event a 
participant becomes hypertensive during the trial, the participant will be referred to the primary care provider 
for further hypertension management. Participants will be allowed to use any class of antihypertensive 
medication except another ARB, an ACEI, or a renin inhibitor. The PMD will be notified of the potential that the 
subject might be receiving candesartan to avoid this overlap. 
5.3.2. PROHIBITED INTERVENTIONS 
Additions of an ARB, ACEI, or renin inhibitors are prohibited during the study period. Participating in another 
clinical trial or study is prohibited. 
5.4. ADHERENCE ASSESSMENT 
 Participants will be asked to bring their study medication bottles to the study center at each visit. Medication 
compliance will be assessed using pill count during the titration and follow up periods. We will define a 
compliance rate for a time period, t, as the ratio of: (the used number of pill prescribed for the number of days 
t - number of pills remaining or unused for the time t / number of pills prescribed for time t) multiplied by 100. 
6. STUDY PROCEDURES AND MEASURES  


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6.1. QUESTIONNAIRES, LIFESTYLE AND ANTHROPOMETRIC MEASURES 
Study interviews will be conducted in English and include the following: 
(1) Demographic, social, stress, physical activity data and medical history data, as well as a medication inventory 
will be collected. All participants are asked to bring all their prescribed medication bottles.  
(2) Instrumental activities of daily living (IADL) scale .52  
(3) Weight and height (stadiometer to measure height with the subjects standing and balance beam scale to 
measure weight without shoes). 
(4) Short Physical Performance Battery [SPPB: ability to stand with the feet side-by-side, semi-tandem, and 
tandem, time to walk 8 feet (measured twice), and time to rise from a chair and return to the seated position 5 
times).53  
6.2. BLOOD PRESSURE MEASUREMENT 
Office blood pressure will be measured according to the American Heart Association guidelines: sitting position, 
rested for 5 minutes, appropriate cuff size (covering 60% of upper arm length and 80% of arm circumference), 
correct cuff placement (1-2 inches above brachial pulse on bare arm). Measurement will be done manually using 
the bell of the stethoscope or using a validated and calibrated automatic machine. Blood pressure will be 
measured in both arms. The arm with the higher blood pressure will be used throughout the study. We will 
obtain 2 seated readings followed by 2 standing blood pressure measurements at 1 and 3 minutes during each 
visit. 
6.3. NEUROPSYCHOLOGICAL ASSESSMENT:  
(i) Clinical Dementia Rating- (CDR).  The CDR rates each of the six general domains (or boxes) involving memory, 
orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care, and a 
global rating is then generated, ranging from 0-no impairment to 3-severe impairment. A Study informant or 
study partner will be questioned either by phone or in person to assist with the CDR. 
(ii) EXecutive Abilities Measures and Instruments for Neurobehavioral Evaluation and Research or 
“EXAMINER”54:  This is a test battery that reliably and validly assesses executive function in clinical trials: working 
memory, inhibition, set shifting, and fluency. The EXAMINER battery has excellent psychometric properties with 
test-retest reliability of over 0.9 and correlates by over 0.60 with an informant-based measure of day-to-day 
executive functioning, the Frontal Systems Behavior Scale.  The parts of EXAMINER that we selected include:  
1) Flanker task (inhibition) which involves responding to a central stimulus while ignoring flanking stimuli 
that are either compatible or incompatible with the central stimulus.55  
2) Set-shifting, a measure of mental flexibility assessing the subject's ability to attend to the specific 
attributes of compound stimuli, and to shift that attention when required.56  
3) Spatial 1-Back test assesses spatial working memory and  
4) Dot Counting test assesses verbal working memory.57  
5) Verbal Fluency will be tested using a List Generation test which require the participant to generate 
words beginning with a specific letter, and category fluency in which the participant generates words 
from a specified category (e.g., animals, fruits).58   
(iii) To assess additional cognitive domains/mood, we will use these tests included in the National Alzheimer’s 
Coordinating Center Uniform Data Set.59,60  


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1) Hopkins Verbal Learning Test will be used to assess memory domains.61  
2) Digit Span Test (DST) is a brief task that assesses attention.62,63  
3) Boston Naming Test assesses language by measuring ability of naming a visual confrontation drawing 
(15 items).64,65  
4) Trail Making Test: will be used as an additional measure of executive function. 
5) Center for Epidemiologic Studies Depression Scale (CESD),66 and consists of 20 items, each scored from 
0 to 3 points and higher scores indicate greater depressive symptoms.  
(iv) Voice recording to assess speech changes related to cognitive function may be collected at one or more 
visits. These will include a recording of the cognitive tests, free speech, speech in response to questions, and 
speech in response to specific cognitive tasks such as counting, fluency and/or a picture description. All voice 
recording files will not contain personal identifiers or PHI. They will be saved under the subject deidentified 
study number. 
6.4. CEREBROSPINAL FLUID (CSF) COLLECTION 
Participant will have CSF acquired via lumbar puncture (LP). In some instances, subjects would have had an LP 
as part of clinical evaluations or other research studies. If we are able to determine eligibility from the prior LP 
(within 6 months of the screening visit) and samples are available for the molecular analysis, then screening LP 
will not be necessary. Otherwise an LP will be done at screening. All CSF samples will be collected after at least 
6-hour fast from the last meal. CSF will be collected using a 24-g Sprotte atraumatic spinal needles. This needle 
decreases the frequency of post LP headaches to < 1%.67   All CSF collection is completed according to guidelines 
put forth in the “Biospecimens Best Practice Guidelines for the ADCs” published by the National Alzheimer's 
Coordinating Center (NACC) and available on their website. Approximately 30-45 ml of CSF will be collected 
using sterile polypropylene collection tubes. The samples will be immediately divided into aliquots and 
transferred for storage in a freezer for future assays. In addition to routine assessment (cells, proteins, albumin, 
glucose), Aβ1-42, t-tau, and p-tau181p will be measured using the multiplex xMAP Luminex platform (Luminex 
Corp, Austin, TX) with Innogenetics (INNO-BIA AlzBio3; Ghent, Belgium; for research use–only reagents) 
immunoassay kit–based reagents68 at the local ADRC core laboratory.  
6.5. BRAIN MRI AND PET IMAGING PROTOCOLS 
MRI protocols are performed in 50-70 minutes and will be conducted at The Center for Systems Imaging (CSI). 
The MRI protocol includes: 
(i) Structural MRI and WMH: High-resolution anatomical images will be acquired using a 3D-Fast Spoiled 
Gradient Recalled Echo (FSPGR) Sequence. WMH regions will be identified by a 3D T2 Fluid Attenuated Inversion 
Recovery (FLAIR) Fast Spin Echo sequence.  
(ii) ASL-MRI: ASL images will be acquired using a custom 3D stack of interleaved spirals fast spin echo sequence 
and will be averaged in order to improve the signal-to-noise ratio. In addition to resting perfusion, scans will be 
taken during normocapnia (2 minute scan) and hypercapnia (breathe a mixture of 8% CO2 for 2 minute scan). 
The following metrics will be calculated: resting perfusion, Vasoreactivity (VR)=slope of the regression between 
cerebral perfusion and end-tidal CO2, in ml/100g/min per mm of Hg during normal and hypercapnia. 
(iii) Diffusion tensor imaging: DTI is highly sensitive to detect structural changes over a short time, less than 1 
year, as compared to traditional MRI.69  
(iv) Resting state functional MRI (rs-fMRI): Resting state fMRI will be used to assess  "functional connectivity" 
between brain regions.70 Functional connectivity has a key role in important complex cognitive processes.70  It 


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focuses on spontaneous, rather than task-induced, low frequency (<0.1 Hz) fluctuations in the blood 
oxygenation level-dependent (BOLD) signals. 
(v) In-vivo Aβ- and Tau PET imaging: This will be performed on the original sample (n=72). Participants will be 
selected consecutively for the original study until up to a total sample of 72 complete the PET studies (36 per 
group). In-vivo amyloid imaging will be conducted using N-methyl-[11C] 2-(4’-methylaminophenyl)-6-
hydroxybenzothiazole also termed [11C] Pittsburgh Compound B (PiB),71 following ADNI protocol.72 PET images 
(20 minutes; 4 × 5 minute frames) will be acquired approximately 50 minutes after intravenous administration 
of 15±1.5 mCi of [11C] PiB. Images will be analyzed as recently recommended.73 In certain cases (see eligibility 
section) PiB Pet can be performed at screening to determine amyloid positivity. In-vivo Tau-PET imaging will be 
conducted using  18F-labeled benzimidazole pyrimidine, 7-(6-[18F]fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole 
([18F]T807) which has been shown to have selectively high affinity to Tau;  and T807 PET scans are now available 
to measure in-vivo Tau content in patients with MCI and AD.74-78  
6.6. VASCULAR MEASURES 
Arterial stiffness and microvascular function: Indices of arterial stiffness and wave reflections will be estimated 
in the supine position using the Sphygmocor device (Atcor Medical, Australia), which records sequential high‐
quality pressure waveforms at peripheral pulse sites using a high‐fidelity tonometer. Pulse‐wave velocity (PWV) 
measured between carotid and femoral arteries is a regional assessment of aortic stiffness and is the gold 
standard index of arterial stiffness. Digital pulse amplitude tonometry (PAT) will be used to measure pulse 
volume amplitude (PVA) in the tip of the index finger, with participants resting in the supine position in a quiet, 
temperature‐controlled environment and during reactive hyperemia, which will be elicited by the release of an 
upper arm blood pressure cuff inflated to supra-systolic pressure for 5 minutes. The Endo‐PAT (Itamar‐Medical, 
Israel) will be used to measure PAT. The reactive hyperemia index (RHI) is a marker of endothelial function. 
Blood pressure and Ultrasound: A brachial BP will be measured twice while seated and after 1 and 3 minutes 
standing according to the AHA guidelines.94 High-resolution B-mode ultrasound of the right common carotid 
artery using a 7.5-MHz linear-array will be performed to measure carotid intima-media thickness (IMT).95 
6.7. PROTEOMICS AND INFLAMMATORY MARKERS 
We will conduct proteomic and metabolomics studies of the CSF and blood samples (screening/baseline & 12 
months) at the Emory Neuroscience NINDS Core Facilities (ENNCF) and the Emory Metabolomics core. We will 
use a targeted proteomic approach with selected reaction monitoring (SRM).82 Our set of proteins in the 
targeted proteomic analysis are enriched with the inflammatory/oxidative stress pathways: adhesion 
molecule,83 cytokines (see Hu et al84 for full list), oxidative stress (F2-isoprostanes),85,86 and BBB integrity 
proteins (astrocytic protein S100β, neuron-specific enolase (NSE) and RAGE).87-89 
6.8. RENIN ANGIOTENSIN SYSTEM ACTIVITY 
RAS activity will be assessed using a comprehensive analysis of different angiotensin peptides measured 
simultaneously in a single sample by a highly selective and sensitive mass spectrometry method described 
previously.90 We will use this to assess the degree of blockade of AT1 and activation of AT2. 
6.9. BLOOD CHEMISTRIES, BLOOD COUNT, AND APO-E  
Blood will be drawn at various visits. Please refer to the table for specific tests done at each visit. 
6.10. BLOOD AND CSF BANKING 
We will collect blood and CSF samples for future research. Vials containing blood samples will be labeled with 
subject ID numbers, name of the study, date collected and barcoded and stored at the cryogenic storage facility 


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until time of processing. The label will include the study name, study visit number, contents of each collection 
vial, and the date of collection. The samples will be kept until the samples are exhausted. Future study results 
obtained from these samples may not be reported to subjects. For those who agree to have their retina scanned, 
an additional (10 cc) of blood will be drawn during or close to the retinal scan visit.  
6.11. RETINAL AMYLOID SCAN 
We will perform retinal imaging on the study subjects to test the utility and suitability of retina imaging for 
detecting AD markers. This is a non-invasive procedure that requires dilation of the eyes and obtaining 
photographs of the retina. Retinal scans can be done during or after the participant has completed the study. 
Those already completed will be re-contacted for this procedure.  
 
6.12. SCHEDULE OF EVALUATIONS 
6.12.1. SCREENING 
Individuals who express an interest will have a 2-tier screening process. Individuals meeting criteria of a clinical 
diagnosis of MCI will undergo further screening.  Those who are eligible, i.e. have MCI will undergo a clinical 
evaluation (clinician interview, review of prior imaging, review of prior CSF analysis). If no clinical data is available 
to confirm AD biomarkers in the CSF within the last 24 months, an LP will be performed. This will be scheduled 
on a separate visit or on the same day if safety labs are available on that day.   
6.12.2. ENROLLMENT, BASELINE, AND FOLLOW-UP 
Once eligible, baseline evaluation will be completed. An LP will be done if not done during the screening visit. 
Once baseline data are collected, participants will be randomized into candesartan or placebo and seen every 
two weeks where study dose will be increased to 16 mg and 32 mg until MDT is achieved. They will be seen 
afterwards every three months until the study ends. All visits will have a +/- three week window except during 
medication escalation visits where the window will be +/- 5 days. An optional modified phone/virtual visit will 
be completed as needed for any visit to collect data that can be reasonably collected by phone. This change is 
in response to the COVID-19 stay home orders and in-person research activities will resume when normal 
business operations resume. Study procedures are shown in the Table above.  
7. SAFETY ASSESSMENTS  
7.1. SPECIFICATION OF SAFETY PARAMETERS 
(i) The following safety parameters are related to the use of Candesartan: rash, dizziness, cough, weakness, 
fatigue, headaches, lower extremity edema, constipation, back pain, sore throat, upper respiratory tract 
infection, rhinitis, pharyngitis and hoarseness. Angioedema, renal failure (Cr>2.5), hyperkalemia (K>5.9 meq/dl), 
and fainting are also potential complications of candesartan.  
(ii) The following safety parameters are related to the conduct of the study procedures: Neuropsychological 
assessment may be accompanied by anxiety, frustration and overall fatigue. The attachment and removal of a 
blood pressure cuff, cuffs for venous occlusion, and ultrasound probe on the neck may cause mild discomfort. 
Brain imaging requires the participant to stay still and lie down for 50-70 minutes, which may cause boredom 
and minimal reversible back pain. Because of the closed space and noise, undergoing an MRI may be associated 
with anxiety or panic reactions. We will ask participants to breathe via a mask air richer in CO2 than normal 
atmospheric air (5-8%) during the brain MRI procedure. The reported potential side effects may include a feeling 
of dizziness, faintness, or anxiety during CO2 inhalation. CO2 administration will be promptly terminated if any 
of the aforementioned conditions occur. The vascular ultrasound is safe and only mildly uncomfortable due to 


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tightness in the arm when the cuff is inflated. We will use ultrasound to painlessly bounce sound beams off of 
the carotid artery using a pencil-like sensor. 
(iii) The following safety parameters are related to the LP procedure: The most common complication of a 
lumbar puncture is post-LP headache. We use a smaller 24-gauge Sprotte spinal needle. All subjects will be 
counseled on the signs and symptoms of post-LP headaches and given information on management 
(acetaminophen, caffeine, rest). Bacterial meningitis and a CSF leak are very rare complications of lumbar 
punctures. A blood patch is rarely needed to heal CSF leaks. All subjects will be instructed to promptly contact 
us if the headache persists beyond 3 days and if a blood patch is required, the cost of the patch will be covered 
by the funds supporting this project.  
(iv) Potential risks of the study PET imaging are as follows: There may be discomfort, bruising, bleeding or 
infection at the site of the intravenous puncture.  The radiation exposure is within limits acceptable to the Emory 
University Radioactive Drug Research Committee.  Systemic toxic effects attributable to single dose T807 or PiB 
have not been encountered. Both ligands are rapidly cleared from the plasma and their binding to their target 
is reversible. Toxicity remains a possibility and patients will be monitored for such events during the scan and 
at follow-up.   
(v) Potential risks of the retinal amyloid scan are as follows: Adverse reactions to dilation of the eyes may include 
discomfort, irritation, or other reactions similar to pupillary dilation experienced during a visit to the eye doctor. 
Increased sensitivity to bright lights may be experienced. We will provide disposable sunglasses to counteract 
these effects.  Participants will be monitored for adverse effects. 
7.2. METHODS FOR ASSESSING AND RECORDING SAFETY PARAMETERS  
During the course of the study, any problem reported by the participants will be recorded in the participant’s 
chart (adverse event log), along with the start and stop dates. The problem may be related to the research 
participation or the drug used in the study (drug reaction).  All Adverse events will be rated on the following 
characteristics: 
(i) Serious (YES/NO): A serious adverse event (SAE) is defined using the Code of Federal Regulations Title 21 
definition as any event that 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.  
(ii) Related to the research: All adverse events will be judged regarding their relationship to the research 
participation or the study drug as related, possibly related, probably related, unrelated, or unknown. 
(iii) Severity: The severity of the AE will be rated on the following scale mild, moderate, severe, life-threatening, 
or death. 
(iv) Anticipated or unanticipated: We use the Emory IRB definition of an unanticipated event as any event that 
is “unexpected, not described in the study documents, or if described before, it is now presenting with increased 
severity, duration, or frequency”.   
7.3. REPORTING ADVERSE EVENTS AND DEATH 
Principal Investigators shall immediately (within 24 hours of the event) report to the Radioactive Drug Research 
Committee all adverse effects associated with the use of the radioactive drug in the research study. All adverse 
reactions probably attributable to the use of the radioactive drug in the research study shall be immediately 
reported (within 24 hours of receiving the initial report) by the RDRC to the Food and Drug Administration, 
Center for Drug Evaluation and Research. 


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All other adverse events will be assessed for the need for prompt reporting. We follow the guidelines set-forth 
by the Emory IRB for reporting AE’s. Any event that fulfills the following criteria being unanticipated (as defined 
in section 7.2), probably or possibly related to study participation (drug effect or as a consequence of a study 
procedure), and involving risk for participants or others is considered an unanticipated problem and will be 
reported to the Emory IRB within 10 days. If an event could be explained by the underlying medical condition, 
it is not considered related and hence not reportable. Any SAE as defined in section 7.2 that does not fit all the 
criteria of being an unanticipated problem will be reported during continuing review. Deaths of participants 
during the study will be promptly reported to the IRB if related to study participation and reported during 
continuing if they are not related to study participation. A yearly summary of AE/SAE/Deaths will be presented 
to the DSMB by the study biostatistician. 
7.4. FOLLOW-UP FOR ADVERSE EVENTS 
All AE/SAE’s will be recorded in the participant chart with start/stop date. The study physician may perform 
additional evaluations, visits, phone communication, repeat blood testing, or refer to the emergency room or 
the participant healthcare provider for medical care if necessary. If the event results in intervention 
discontinuation and/or study withdrawal, the participant will be followed for 2 months post-withdrawal with a 
monthly phone call. They will also be invited to perform the final visit evaluation including all study procedures 
planned for that visit if the participant has been in the study more than 5 month post baseline evaluation. 
Follow-up on reported symptoms of hypotension or a BP<100/40 mm Hg: When a subject notifies the study team 
that they have either symptoms suggestive of hypotension (dizziness, weakness, near syncope, or syncope) or 
that their blood pressure is less than 100/40 mm Hg, the study physician will review the incident and determine 
if the subject is safe to continue in the study. The physician may discontinue the study medication immediately, 
elect to lower the dose of the study medication, ask subject to present to the study center for a safety 
evaluation, and/or monitor the subject blood pressure. The subject may continue in the study if blood pressure 
is >100/40 mm Hg on the lower dose of the study medication and had resolution of symptoms. In those on 16 
mg and 32 mg, the doses will be decreased to the next lower dose. Those on 8 mg of candesartan, a trial of 
every other day 8 mg of candesartan will be attempted prior to discontinuation. 
7.5. INCIDENTAL FINDINGS 
Incidental findings (lab testing, neuroimaging or vascular testing) identified during the conduct of the study that 
do not require immediate medical care will be reported to the subject with instructions to seek medical care 
from the participant’s healthcare provider. Those with incidental findings requiring urgent care will be referred 
to an emergency room in a facility of their choosing. 
8. INTERVENTION DISCONTINUATION  
A subject may choose to withdraw from the study for any reason. The investigators may also request that the 
subject withdraw from the study, for safety or other reasons. The criteria for discontinuing a subject’s 
participation include: 
(1) the subject’s request,  
(2) adverse events that requires un-blinding or necessitate stopping the study drugs, 
(3) persistent (>2 episodes on 2 separate days) of symptomatic hypotension or a blood pressure <100/40 mm 
Hg on 2 separate occasions despite adjusting study medication to the lowest dose (see section on follow-up on 
AE 7.4).(4) new clinically evident stroke or myocardial infarction or other event that limits ability to complete 
the study procedures 
(4) inability to participate due to relocation or other personal reasons, 


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(5) renal failure (increase in serum Creatinine above 2.5 mg/dl) or hyperkalemia (greater than 5.9 meq) 
9. STATISTICAL CONSIDERATIONS  
9.1. GENERAL DESIGN 
The study is a 2-arm double-blinded RCT. The statistical analysis will follow the intention-to-treat approach. 
Intention-to-treat (ITT) and per-protocol analyses will be performed. 
9.2. RANDOMIZATION 
The study blinded biostatistician will provide oversight of randomization fidelity and blinding. Randomization 
will be stratified by use of cholinesterase inhibitors or Memantine (yes vs no) using a computerized random 
number generator (SAS, V9.4).  Only the pharmacy will have access to the randomization lists.  As the pharmacist 
is notified that an individual subject is eligible for randomization, the pharmacist prepares the appropriate 
blinded study product.  The pharmacist will enter the subject ID, date of product randomization, and the unique 
allocation sequence number on a web-based data form.   
9.3. DATA ANALYSIS 
Table 2 provides a list of main outcomes.  
Table 2: Independent, main outcome and other variables to be used in the analyses 
Independent:   
 Group (Candesartan vs placebo) 
Safety outcome:  
hypotensive episodes, symptoms (dizziness, weakness, cough) , creatinine >2.5 mg/dl , 
K>5.9 mEq/dl, number of  discontinuations of candesartan, AE, SAE, Deaths 
CSF outcomes:  
 CSF tau, inflammatory proteins 
Vascular outcomes: 
 PWV, augmentation index 
Imaging outcomes: 
 Perfusion, hippocampal volume, vasoreactivity, Global SUVR (PiB and T807) 
Cognitive outcomes: 
CDR, EXAMINER, HVLT, TMT (B and B-A)  
  
Baseline characteristics including demographic, APOe, social and cognitive measures will be compared between 
the 2 groups to assess randomization fidelity. The list of the main variables is shown in Table 3.  We will compare 
the change in our outcomes over the study period between the treatment and placebo arms using Mixed 
Models. For the dose response analysis, the dose vs RAS activity will be plotted to explore the degree of 
modulation for each Ang peptide at the various doses.  
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1. DATA COLLECTION FORMS 
Data collected during interviews and exams will be documented on trial-specific data forms. Neuroimaging and 
ultrasound data will be saved in digital formats on a HIPAA-compliant server. 
10.2. DATA MANAGEMENT 
Once a subject is enrolled into the study, he/she will be assigned a unique identifier number and be referred to 
by initials and the study number only.  Only research team members will have access to the files.   Data will be 
entered on a web-based secure trial data system; the trial database will include for all variables an electronic 
data audit of data edits (who, when, and why).  A data query report (including missing, out of range, and logic 


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checks) will be generated by the trial statistician. The investigators will keep subjects’ medical records private 
as far as the law allows. The IRB and officials of the sponsor/funding agency will have access to these records as 
needed within legal guidelines.  If study results are published in journals or presented at meetings, we will not 
use the subjects’ names.   
10.3. QUALITY ASSURANCE  
10.3.1. TRAINING 
Research personnel will be trained by the PI and co-investigators. The process of training on data forms 
completion, neuropsychological assessment and subject evaluation will be documented in a training log for each 
study personnel.  
10.3.2. QUALITY CONTROL 
To assess protocol compliance and quality of data collected, the PI along with another investigator will randomly 
and on intervals review data obtained. In addition, assessment of personnel competencies in obtaining data will 
be performed.  
10.3.3. PROTOCOL DEVIATIONS 
Every attempt will be exercised to maintain compliance with the approved study protocol. In the event when a 
deviation is noted, the Emory IRB will be notified as required by IRB Policies & Procedures only if the deviation 
affects the rights or welfare of subjects, the safety of subjects,  the willingness of subjects to continue with study 
participation, or the integrity of the research data. The PI or designated personnel will conduct an investigation 
about the setting, reasons, and potential remedies that need to be instituted to rectify the deviation and prevent 
future similar instances. 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1. INSTITUTIONAL REVIEW BOARD (IRB) REVIEW 
This protocol and the informed consent document and any subsequent modifications will be submitted and 
reviewed by the Emory IRB. 
11.2. CONSENTING PROCEDURE, INFORMED CONSENT FORMS, AND STUDY INFORMANTS 
A signed consent form will be obtained from each participant or the participant’s legally authorized 
representative. A single informed consent form will describe both the screening and study procedures.   The 
consent form will describe the purpose of the study, the procedures to be followed, and the risks and benefits 
of participation. A copy will be given to each participant and this fact will be documented in the participant’s 
study record.  
During the consenting process, an assessment for decisional capacity to participate in clinical research will be 
performed. This is conducted by asking the subject a set of study-specific questions. A validated brief instrument 
for decisional capacity assessment will be administered:91 The University of California, San Diego Brief 
Assessment of Capacity to Consent (UBACC) instrument is a 10 item questionnaire that asks the participant 
about key areas of the informed consent. A score greater than 14.5 correlates with a score of greater than 16 
on the MacArthur Competency Assessment Tool for Clinical Research (MacCAT-CR).91 MacCAT-CR is the most 
validated instrument in assessing decisional capacity in clinical research92 and a score greater than 16 has been 
traditionally considered adequate in prior NIH studies.93  
Participants who are unable to answer the capacity assessment questions correctly (UBACC score <14.5) may 
still qualify for the study but will need to have a surrogate and a study informant. The definition of the surrogate 


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will be consistent with the intent of the Common Rule (45 CFR 46, Subpart A).The following are, in order, possible 
surrogates: 
(1) The person's agent designated by an advance health care directive. 
(2) The conservator or guardian of the person having the authority to make healthcare decisions for the person. 
(3) The spouse of the person. 
(4) The domestic partner of the person as defined in Section 297 of the Family Code 
(5) An adult son or daughter of the person. 
(6) A custodial parent of the person. 
(7) Any adult brother or sister of the person. 
(8) Any adult grandchild of the person. 
(9) An available adult relative with the closest degree of kinship to the person. 
When there are two or more available persons who are in different orders of priority pursuant to subdivision 
(c), refusal to consent by a person who is a higher priority surrogate shall not be superseded by the consent of 
a person who is a lower priority surrogate. That surrogate will need to consent to the study. If either party 
refuses, we do not enroll the subject. To ensure both the participant and the proxy understand the study 
protocol, we will ask subjects or legal next of kin to explain in their own words the nature of the study and the 
procedures involved.  
The proxy will be considered the study informant if there is contact at least once a month.  In some instances 
such as the lack of adequate contact by the surrogate or the surrogate’s inability to complete the tasks of the 
study informant, the study informant may be a different individual as long as he/she is willing to provide 
information about the participant, and have contact with the participant for at least once a month (in person or 
telephone). The study informant will sign the study informed consent. If they are not available in person, the 
study staff will contact the informant to obtain needed information about the subject cognitive symptoms. In 
that case, a verbal consent will be obtained.  
11.3. PARTICIPANT CONFIDENTIALITY 
Only the investigators will have access to information about a particular subject. The subject’s primary care 
physician will only be notified if the subject agrees. To maintain confidentiality, subject data will be referenced 
by number and stored in locked computer files and cabinets. Identifying information about a subject will not be 
used during the discussion, presentation, or publication of any research data. Only research team members will 
have access to the files.  Data recorded and stored on the computer will be backed up to a disc and stored with 
the paper files.  Participants will not be given any results of the research procedures unless there is a medical 
necessity. This will be clearly stated in the informed consent process. 
11.4. PARTICIPANT COMPENSATION 
Subjects will be compensated with gift cards for their effort and time at the following schedule: 
 
• Screen Visit: $25 + $100 (for lumbar puncture procedure) 
• Baseline Visits: $100 (for visit + MRI) + $75 for each PET scan (optional) 
• Titration Visits (2): $10 
• 3 & 9 Month Follow Up Visits: $25 
• 6 Month Follow Up Visit: $50 (cognitive testing, blood draw) 


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• 12 Month Follow Up Visits: $100 (for visit + MRI) + $75 for each PET scan (optional) + $100 (for lumbar 
puncture procedure) 
• Return Visit for blood redraw: $20 and LP $100 (as needed) 
• Retinal Imaging: $25Transportation: Up to $30 for gas reimbursement and up to $50 for taxi or shuttle 
service to the study site  
11.5. STUDY DISCONTINUATION 
The study may be discontinued at any time by the investigators, the Emory IRB, the OHRP or other government 
agencies as part of their duties to ensure that research participants are protected.   
12. PUBLICATION OF RESEARCH FINDINGS  
Publication of the results of this trial will be governed by the policies and procedures of the NIA and Emory.   
 
 


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