Conditions: Alzheimer's Disease Disruptive Behavior
Keywords: Dementia Agitation PEACE-AD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 35
Healthy volunteers: no

Brief summary:
The study evaluates the effects of Prazosin on agitation in adults with Alzheimer's disease.

Two thirds of the participants will participate in the medication portion, while one third will participate in the placebo portion

Detailed description:
Prazosin for Disruptive Agitation in Alzheimer's Disease (PEACE-AD) is a Phase IIb multicenter, randomized, double-blind, placebo-controlled trial of 12-weeks treatment with the brain active alpha-1 adrenoreceptor (AR) antagonist prazosin for disruptive agitation in 35 Alzheimer's disease (AD) residents in a long-term care (LTC) setting or living at home with full-time caregiving.

Distruptive agitation defined as having one or more of the following behaviors nearly daily during the previous week and at least intermittently for four weeks prior to screening: a) irritability, b) physically and/or verbally aggressive behavior, c) physically resistive to necessary care, d) and/or pressured motor activity (e.g., pressured pacing).

LTC is defined as assisted living or skilled nursing facility. Home dwelling participants require full-time caregiving defined as having continuous daily caregiving and a Study Partner who will assist in providing protocol specific information to the study team.

A previous single site pilot study addressing disruptive agitation in 22 predominantly LTC-residing AD participants demonstrated efficacy of prazosin on all three primary outcome measures.1 The current multicenter study is funded by the National Institute on Aging (NIA), and coordinated through the NIA-funded Alzheimer's Disease Cooperative Study (ADCS).

Arms:
arm 1: Eligible participants will be randomized using a 2:1 schedule to prazosin or placebo and stratified by site and gender, and will follow a fixed titration scheme for the first 15 days, followed by a flexible does titration from days 15-29, then a maintenance phase stable dose from days 29 to the end of the 12 weeks study period.

Prazosin Fixed titration dose schedule for Days 1 to 14 1 mg QHS for Days 1 to 3

1 mg QAM and 1 mg QHS for days 4 to 7

1. mg QAM and 2 mg QHS for days 8 to 10
2. mg QAM and 2 mg QHS for days 11 to 14

Prazosin Flexible titration dose schedule for Days 15 to 29. 3 mg QAM and 3 mg QHS on day 15, 4 mg QAM and 4 mg QHS on day 22, 4 mg QAH and 6 mg QHS on day 29,

Dose increases will be allowed only during the fixed and flexible dosing periods. arm 2: Placebo medication will be administered in a titration schedule mimicking the active comparator treatment.

Interventions: intervention 1: Prazosin intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Oral prazosin HCl capsules (or placebo) will be administered twice daily, with individualized doses up to a maximum of 4 mg QAM mid-morning and 6 mg at bedtime (QHS), or matching placebo capsules intervention 2: Placebo capsule matched to appearance of active drug.

Protocol document:
ICF_002.pdf: 
 
 
 
 
 
 
 
 
 
HOWARD FELDMAN, MDCM, FRCP(C)  
PROFESSOR, DEPARTMENT OF NEUROSCIENCES 
DIRECTOR, ALZHEIMER’S DISEASE COOPERATIVE STUDY (ADCS) 
DEAN, ALZHEIMER’S DISEASE AND NEURODEGENERATIVE RESEARCH 
9500 Gilman Drive     La Jolla, California 92037-0949     TEL: (858) 246-1347   FAX: (858) 246-1414 
 
 
 
Prazosin for Disruptive Agitation in Alzheimer’s Disease (AD) (PEACE-AD) 
Short Title: Prazosin for Agitation in AD 
Protocol Number: ADC-042-PRAZ 
 
NCT03710642 
 
 
Main Informed Consent Form (ICF) 
 
05 April 2021 
 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Informed Consent to Participate in a Research Study: 
 
Study Title: Prazosin for Disruptive Agitation in Alzheimer’s Disease-(AD) – PEACE-AD 
 
Project Directors: Elaine Peskind, MD and Murray Raskind, MD    
VA Puget Sound Health Care System  
1660 So. Columbian Way, S-116 MIRECC 
Seattle, WA 98108  
 
ADCS Coordinating Center Principal Investigator: Howard Feldman, MDCM, FRCP (C) ADCS Director 
UC San Diego 
Alzheimer’s Disease Cooperative Study 
9500 Gilman Drive, MC 0949 
La Jolla, CA 92093-0949 
 
Funding Source:  National Institute on Aging  
 
Version Date: 05 Apr 2021 
Study Site: <<INSTITUTION NAME>> 
Principal Investigator: <<INVESTIGATOR NAME>> 
Contact info: <<INVESTIGATOR PHYSICAL ADDRESS, PHONE, FAX, EMAIL>> 
Central IRB Application Identifier: <<IRB Number>> 
 
This consent form describes a research study and your role as a research participant.  This document is 
intended to inform you about the possible risks and benefits of the research study, other options that may be 
available to you and your rights as a research participant.  Please read this consent form carefully and do not 
hesitate to ask the study doctor or study team any questions you may have about the study or the information 
provided below.  
 
Your participation in this study is entirely voluntary.  Please take as much time as you need to discuss the 
study with your doctors, family, and friends.  The decision to participate or not to participate is yours to make.  
If you choose to participate, you have the right to withdraw from the study at any time.  
 
If the person being asked to be in this research study is not able to give consent to be in the study, the 
person’s legally authorized representative (LAR) is being asked to give permission for this person to be in the 
study as his/her decision maker. In this consent form, referring to “you” may also refer to the loved one of the 
LAR. 
 
If you decide to participate in this study, you will need a Study Partner or legal representative. The Study 
Partner/legal representative will be able to remove you from this study if you become unable to say that you 
wish to remain in the study. Your study partner/legal representative will be asked to read and sign this 
Informed Consent.  
 


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A description of this clinical trial will be available on http://www.ClinicalTrials.gov.  This web site will not 
include information that can identify you.  The web site will only include a summary of the results when they 
become available.  You may access this web site at any time. 
 
PEACE-AD is being conducted by the Alzheimer’s Disease Cooperative Study (ADCS), through a grant from the 
National Institute on Aging (NIA). 
 
Why is this study being done?  
 
You are being invited to take part in a research study because you have Alzheimer’s disease (AD) and have 
also been having symptoms of disruptive agitation, such as irritability, anger outbursts, and pacing. The 
purpose of this study is to see if a drug called prazosin can help make these agitation symptoms better. 
 
Prazosin is a drug that is approved to treat people with high blood pressure. It has not been approved by the 
Food and Drug Administration (FDA) to treat agitation in people with AD and related disorders which is the 
purpose of this research study. Some people in this study will take placebo, which are capsules that look like 
the study drug but do not contain any active drug in them.   
 
How many people will take part in this study?  
 
This study is being done at multiple sites across the U.S. If you are eligible and agree to participate, you will be 
one of approximately 186 adults with AD and disruptive agitation who will be taking part in this study. 
Participants may either be residing in a Long-Term Care (LTC) facility/nursing home or living at home with a 
full-time caregiver. If you are living at home, your full-time caregiver will be assigned as your Study Partner.  
 
What will happen if I take part in this study? 
 
Neither you nor the study personnel will know whether you are receiving the active study drug or placebo. 
This study will last up to 16 weeks. All of the procedures during this study are research procedures. This 
study is not meant to replace visits with your regular doctor. You will continue to be seen by your regular 
doctor for ongoing medical care.  Depending on the safety recommendations and where you are living, the 
study staff will be able to perform your first visit either at the Long Term Care facility, the clinic, through a 
home visit, or by using remote technology (using telephone or video).  If you are living in a Long Term Care 
facility, the study staff may come to you in your care facility/nursing home for your first screening visit, or 
may visit you using remote technology (telephone and video).  If you are living at home, you and your Study 
Partner may be asked to come into the study clinic for your first screening visit, or a study team member will 
come to you for a home visit, or you may be visited using remote technology (telephone and video).  All 
remaining study visits may be conducted either in person or by remote visit (telephone or video).  
 
Please tell your study doctor or study staff if you would like to stop being in the study at any time. 
During this study, the local study team will be monitoring your condition.   
 


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Description of study visits 
 
The first part of the study is called the Screening period. This period will last up to 28 days. If you qualify and 
agree to participate in the study, there will be a study drug dose adjustment period during the first 29 days 
of the study drug regimen. From the time study drug is started, your participation will last up to 12 weeks. 
During this time, the study doctor will determine the best dose of drug for you to take and you will remain 
on this dose and be monitored throughout the study until the end, up to week 12. 
 
You or your legally authorized representative (LAR) must sign this consent form before beginning the 
screening process.  
 
Screening (Visit 1) 
 
 
During your Screening appointment, we will determine your eligibility to enroll in PEACE-AD, and if this study 
is right for you.  The screening period may take up to 28 days, and may occur over two visits. The study staff 
will explain these procedures and answer any questions you and your LAR may have.  
 
During this screening visit, the following things will happen:  
 We will ask you about your general medical and psychiatric history.  We may request additional 
records if we have questions about your medical history.  We will ask you to sign a release of 
information form to get these medical records, if needed. 
 We will ask you questions about your behavior and mood.  We will ask you if you are feeling irritable or 
angry, restless, depressed or sad, if you have had problems sleeping, or any strange or unusual 
experiences.  Some questions may make you feel uncomfortable, and you are free not to answer those 
questions. We will also ask your nurse and LAR or your Study Partner if you are living at home some of 
the same questions about your behavior and mood. 
 We will review and update (if needed) your risk of having a fall. We will discuss with you any added 
risks of having a fall while on this trial and a care plan to prevent falls from occurring.  
 We will review and record your current medications. 
 When possible, you will have a brief physical and neurological exam.  If your screening is done as a 
remote visit, a combination of telephone and video conference will be used.  The study doctor will ask 
you to move your arms and legs and walk if it is safe to walk.  If conducting screening as a remote visit, 
a combination of telephone and video conference can be used; at a minimum, the observational 
elements of the Physical and Neurological Exam including visual assessment of participant gait should 
be done via video conference. 
 We will measure your blood pressure and heart rate while you are lying down and again when you 
are standing up (or sitting up if you cannot stand up).  Your blood pressure may be taken several 
times over a 7 to 14 day period to see if you may continue in the study. 
 
 
 


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 If your blood pressure is too low, and you are given medicines to keep it low, the study doctor will 
contact your regular doctor (primary care physician) to talk about adjusting your blood pressure 
medicines.  The study doctor and your regular doctor will work together to decide if it is safe for you 
to continue in the study.  You may have an electrocardiogram (ECG—tracing that measures the 
electrical signals of your heart) if you have not one within 12 months of this visit.  
 If you have not had routine laboratory tests (complete blood count and blood chemistries) done within 
12 months of this visit, we  may collect about between 10 to 20 ml (a little more than 1 tablespoon) of 
blood from your arm. This is to make sure you have no medical conditions that prevent your 
participation in this study.  
 We may collect a urine sample from you if the study doctor determines that it needs to be collected.   
 
Baseline (Visit 2) 
 
Baseline procedures will be completed within 28 days of your screening visit, and before you can be assigned 
to one of the 2 study groups. Baseline procedures include:  
 
 We will measure your blood pressure and heart rate while you are lying down and again when you 
are standing up (or sitting up if you cannot stand up).  
 We will ask you if you have had any illnesses or changes in your health since your last visit.   
 We will update the list of any medications that you are currently taking. 
 We will ask some questions about your behavior and your daily functioning. We will ask you if you 
are depressed or sad, if you have had problems sleeping or feelings of worthlessness. We will also 
ask you questions such as if you get angry a lot, have trouble sitting still, or have changes in your 
appetite. Some questions may make you feel uncomfortable, and you are free not to answer those 
questions. 
 
We will also ask your nurse, other care facility/nursing home staff, and LAR some of the same 
questions about your behavior like the ones we asked you.  If you are living at home with full-time 
caregiving, we will ask your Study Partner some of the same questions about your behavior like the 
ones we asked you. We will also ask questions about your daily functioning and your ability to do 
things such as dressing yourself.  
 
At the end of this visit, you will be randomly assigned (like flipping a coin) to one of two groups. Group 1 will 
take prazosin capsules, and Group 2 will take capsules that do not contain any active medication (placebo). Since 
two-thirds of the subjects will receive the active drug, there is a greater chance that you will receive prazosin 
rather than the placebo.  Neither you nor the study staff will know which group you are in, although that 
information will be available if there is an emergency. 
 
 
 
 
 


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Dose adjustment (Days 1-29) 
 
The dose adjustment period will happen after all the baseline procedures are done. During the dose 
adjustment period, we will determine what the best dose of study drug is for you. The nursing home staff or 
your Study Partner will be asked to help you in taking your study drug. Your starting dose will be 1 mg of 
prazosin (or placebo) per day (one capsule of study drug to be taken at bedtime). After the first day of taking 
the study drug, we will ask you if you are having any side effects. If you are not having any side effects, you 
will keep taking this dose for 2 more days. On day 4 and for the rest of the 12-week study, you will take the 
study drug twice a day, at approximately at 10:00AM and at bedtime. 
 
We will ask if you have been having any side effects and will ask some questions about your symptoms of 
agitation. If your agitation has not markedly improved and if you are not having any side effects, we will 
increase your dose of prazosin (or placebo). We will continue increasing your dose until your agitation gets 
better, or until the maximum dose of 10 mg per day of prazosin (or placebo) is reached.  
 
The care facility/nursing home staff or your Study Partner at home will measure your blood pressure and 
heart rate while you are lying down and again while you are standing up (or sitting if you cannot stand) 
every day while your dose is being adjusted and through the following week.  Care facility/nursing home 
staff or your Study Partner may measure your blood pressure more than once a day if needed to more 
closely monitor any changes observed in blood pressure measurements during the dose adjustment period.  
 
If you have intolerable side effects during the dose adjustment period, the dose will be reduced to the last 
tolerated dose, until the side effect resolves. When the side effect resolves, the study doctor may recommend 
you take a higher dose of the study drug again during this adjustment period. For safety purposes, the dose may 
be decreased any time throughout the study. 
 
Study Weeks 5, 6, 8, 10, 12 
 
At each of these visits, we will ask you whether you have been having any side effects, if there has been any 
change in your medications (including over-the-counter medications and supplements), and whether you 
have been sick or had any other adverse events since your last visit. We will measure your vital signs (blood 
pressure and heart rate while lying down and standing up) every day until Day 35, and then every 3 days for 
the rest of the study.   
 
At Weeks 8 and 12, we will also ask questions about your mood, behavior, and ability to do daily tasks. You 
will be asked the same questions we asked you at your baseline visit. You are free not to answer any questions 
you do not wish to answer. 
 
After your Week 12 visit, you will be done with the study. We will discuss with you, your family, and the care 
facility staff or Study Partner whether you would like to continue taking active drug. If you would like to 
continue taking prazosin, we will work with your regular doctor to set up a dosing schedule. 
 


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You will be asked to report any side effects or adverse events that happen to you during the study and for 30 
days after you leave the study. 
 
Early Discontinuation  
 
Participation in this research study is entirely voluntary.  You can stop participating at any time without losing 
or changing your current medical care. If you choose to stop being in the study for any reason, you will be 
asked to have a final study visit. This visit will include all of the procedures normally performed at Week 12. It 
is important for your health and safety to have these final procedures completed.   
 
Your participation in the study may be stopped by the study doctor or sponsor if you experience a medical 
condition that makes it unsafe for you to continue your participation in the study.  You may also be removed 
from the study if the study is cancelled or for other reasons we do not know at this time.  
 
Potential Study Risks 
 
Participation in this study may involve some added risks or discomforts, which are described below: 
 
Risks of the Study Drug 
 
The most common side effects of prazosin (seen in up to 10% of people) include:  
 Dizziness 
 Nausea 
 Drowsiness 
 Lack of energy 
 Lightheadedness 
 Weakness 
 Headache 
 Palpitations (abnormal heartbeat) 
Other side effects (less than 4% of people) include: 
 Vomiting 
 Nervousness 
 Diarrhea 
 Rash 
 Constipation 
 Increased urinary frequency 
 Drop in blood pressure when standing 
 Indigestion 
 Fainting 
 Vertigo 
 Shortness of breath 
 Depression 
 Blurred vision 
 Reddened eyes 
 Dry mouth 
 Nasal congestion 
 Nosebleeds 
 Edema (swelling) 
 
Dizziness or lightheadedness may occur after the first dose of the study drug. Your first dose of study drug 
will be taken right before you go to bed for the night.  Dizziness, lightheadedness, or fainting may occur, 
especially when getting up from a lying or sitting position. Getting up slowly may help lessen the problem. 
Your nurse or your Study Partner will check up on you after you take your first dose to make sure you are 
tolerating the study drug.  Also, use extra care if standing for long periods. Check with one of the study 


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doctors if you have any questions.  
 
Other side effects (less than 1% of people) include: 
 Abdominal discomfort or pain 
 Heart beating faster than usual 
 Tingling sensation (pins and needles) 
 Hallucinations 
 Severe itching in the skin 
 Unable to control going to the bathroom 
 Not able to achieve erection (men) 
 Pain in the penis when there is an erection 
 
If your doctor thinks you need additional medication for your agitation, he will order for you to take a 
medication called lorazepam, which risks include:  
 
Increased drowsiness  
 
Physical and mental fatigue 
 
Increased anxiety 
 
Confusion and disorientation 
 
Memory loss 
 
Learning difficulties 
 
Slow, shallow breathing 
 
Pale or bluish skin 
 
Procedure Risks  
 
All of the study procedures will cause some inconvenience to you. Having your blood drawn may cause 
temporary discomfort or in some cases, a bruise may form where the needle enters the vein. Rarely, an 
infection may develop. The total amount of blood drawn during this study is between 10 and 20 mls (a little 
more than 1 tablespoon). 
 
During the interviews, you may feel uncomfortable talking about your behavior and mood. We will make 
these interviews as stress-free as possible. 
 
Although there is no pain or discomfort during the electrocardiogram (ECG), which is a test that records the 
electrical activity of your heart, removing the pads that are placed in your skin may cause some irritation.  
 
Some people taking prazosin, or other drugs related to prazosin, had a side effect when they had cataract 
surgery. This effect is called Intraoperative Floppy Iris Syndrome (IFIS). If you are planning any eye surgery or 
ever need cataract surgery in the future, your eye surgeon needs to know if you ever took prazosin in order 
to reduce the risk of IFIS. If you ever need cataract surgery, be sure to tell your eye surgeon that you may 
have taken prazosin in a research study. 


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Women who are pregnant, breastfeeding, or of childbearing potential may not participate in this study.  
 
It is very important during the study that you tell us before you start taking any new medications 
(prescriptions, herbal, or over-the-counter medications or supplements) or change the dose of medications 
you already take. It is also very important that you tell us of any changes in your health. 
For your safety, the study doctor may need to do extra visits. This would mean you may have extra blood 
samples taken, physical exams, or your vital signs taken more often. 
 
In addition to the side effects already described, the study drug and the study procedures may have other 
unknown risks.  As with any new medicine, there is a risk of rare or previously unknown side effects.  You must 
tell your study doctor if you experience any side effects.   
 
There is also a potential risk for loss of confidentiality.  
 
What are the benefits of taking part in this study? 
 
Your participation in this study may help the investigators learn more about the safety and benefits of 
prazosin in disruptive agitation for Alzheimer’s disease to help other people who have a similar medical 
problem in the future. 
 
Participation in this study may help to improve your condition, but it is also possible that your condition may 
not improve or worsen. There is no guarantee that you will personally benefit by participating in this research 
study. 
 
What other choices do I have if I do not take part in this study?  
 
Currently there are no FDA-approved treatments for disruptive agitation in Alzheimer’s disease.  There are 
five FDA-approved treatments for people with Alzheimer’s disease. These are donepezil (Aricept®), 
rivastigmine (Exelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®). If you are 
currently taking any of these medications, you will be able to continue to take them while you are 
participating in this study. The research staff can inform you about any other investigational drugs that are 
being studied for treatment of Alzheimer’s disease and related disorders.  
 
Will My Medical Information Be Kept Private/Confidential?  
 
Research records will be kept as confidential as possible within the limitations of state and federal law.  The 
study staff and sponsors will handle your personal health information in a confidential manner. 
 


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Federal Privacy Regulations require that you authorize the release of any health information that may reveal 
your identity.  This includes information in your existing medical records needed for this study and new 
information created or collected during the study.  
 
The persons and entities that you are authorizing to access your personal health information may include: 
 
 The study team members 
 The institution where this research is conducted 
 The institution’s Institutional Review Board (IRB) 
 Johns Hopkins Single Institutional Review Board (sIRB) 
 The Alzheimer’s Disease Cooperative Study (ADCS)  
 The National Institute on Aging (NIA), the study sponsor 
 
In order to analyze the data collected during this research study, all of the health information generated about 
you during this study may be inspected by the Department of Health and Human Services (DHHS) agencies or 
ethics committees like the Institutional Review Board (IRB). 
 
Because of the need to release information to these parties, absolute confidentiality cannot be guaranteed.  
Once your personal health information is released it may be re-disclosed, at which point your health 
information will no longer be protected by federal privacy regulations.  
 
The purpose of this access is to review the study and make sure that it meets all legal, compliance, and 
administrative requirements.  If a review of this study takes place, your records may be examined. The 
reviewers will protect your privacy. 
 
Your data for this study will be kept indefinitely.  All the information collected for the study will be labeled 
with a study code number and will not have any identifying information on it. The link between your name 
and study code number will be stored separately from the data in a password-protected computer file and 
will also be kept indefinitely. The study data will be kept in locked offices that only the study staff will have 
keys to. Only the study investigators listed on this consent form and their staff will have access to identifying 
data. 
 
All of the information you provide will be confidential.  However, if we learn that you intend to harm 
yourself or others, we must report that to appropriate authorities. 
 
At any point during the study if we find any medical conditions of concern, we will discuss this information 
with you and refer you to your personal doctor for follow-up. 
 
There may be publications about this study in the future.  If so, your identity will be held confidential.  No 
personal information will be given in a publication without your approval in writing.  
 


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Your study information will be used only for research purposes and will not be sold.   
 
What Are The Costs Of Taking Part In This Research Study?  
 
There will be no costs to you for participation in this study. 
 
Will I Be Paid For Taking Part In This Research Study?  
 
You will not be paid for your participation in this study.   At the completion of your week 12 visit, you will 
receive a hand-crafted quilt, donated by the Quilt Guild for study participants, as a gift, not as compensation 
for your participation.  
 
Should you not have your own access to remote video visit technology, an  electronic tablet  can be provided 
to your Study Partner to help with video tele-conferencing. The electronic tablet will allow your Study Partner 
easy to use access to video conferencing for remote visits that occur during the study. Your Study Partner will 
receive training on how to use the electronic tablet.  The device (approximately $200.00 value) will be 
provided at no cost to you. The electronic tablet will not be returned at the end of the study.  Any internet-link 
between the study team and you will be removed from the electronic tablet. You will be responsible for 
internet connectivity, device maintenance or technical upkeep.   
 
No research data will be collected or stored on this electronic tablet.   
 
Study Partner Stipend 
 
A stipend of $50.00 for each visit completed up to a total of 10 completed visits (up to $500 ) will be paid to 
your Study Partner for time and effort needed for learning to use the electronic tablet, the Omron blood 
pressure machine, taking and documenting participant blood pressure, administering study drug and 
participating in remote study visits.  
 
What Happens If I Experience An Injury Or Illness As A Result Of Participating In This Study? 
 
All forms of medical findings and treatments – whether routine or experimental – involve some risk of injury.  
In spite of all safety measures, you might develop medical problems from participating in this study. 
  
You must report any suspected illness or injury to the study doctor immediately.  If such problems take place, 
the [SITE INVESTIGATOR’S INSTITUTION] will provide emergency medical treatment and will assist you in 
getting proper follow-up medical treatment.  Neither financial compensation nor reimbursement for such 
things as pre-existing conditions, illness or disease unrelated to study participation, lost wages, property 
damage, disability, or discomfort is available.  
 


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The National Institute on Aging and the Alzheimer’s Disease Cooperative Study do not provide compensation 
for research-related injury.  [SITES TO ADD INSTITUTION’S SUBJECT INJURY CLAUSE HERE (you will / will not 
pay for subject injury, etc)]   
 
By signing this consent form you do not give up any of your legal rights. 
 
What if there is a Certificate of Confidentiality for this study? 
 
Your study information is protected by a Certificate of Confidentiality.  This Certificate allows us, in some 
cases, to refuse to give out your information even if requested using legal means.  
 
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases.  The Certificate does not prevent us from disclosing your information if we learn of possible harm to 
yourself or others, or if you need medical help.  
 
Disclosures that you consent to in this document are not protected. This includes putting research data in the 
medical record or sharing research data for this study or future research. Disclosures that you make yourself 
are also not protected.  
 
Who Do I Contact If I Have Questions Or Concerns About This Research?   
 
If you have any questions regarding this research or if you believe that you may have experienced a research 
related injury, you should contact Dr. [Insert Site PI Name] (study doctor) at [TELEPHONE] to report this or 
other research-related problems.  The Johns Hopkins Medicine IRB will serve as the central IRB for this 
study.  The IRB reviews human research studies. It protects the rights and welfare of the people taking part in 
those studies.  You may contact the IRB if you have questions about your rights as a participant or if you think 
you have not been treated fairly.  The IRB office number is 410-955-3008. You may also call this number for 
other questions, concerns or complaints about the research. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Do not use this form for consenting research participants. 
 
 
ADCS Main ICF  05 Apr 2021 
ADC-042-PRAZ
 
Page 12 of 12 
 
STATEMENT OF CONSENT 
You have read (or have had read to you) the description of PEACE-AD study.  You have been informed of the 
risks and benefits involved, and all of your questions have been answered to your satisfaction.  By signing this 
form, you voluntarily consent to participate in the research study and you authorize the use of your data for 
the research described above. 
 
Unless you authorize the use and disclosure of your personal health information, you cannot participate in 
PEACE-AD.  If you refuse to give your authorization, your medical care will not be affected.      
 
You will receive a copy of this consent form. 
 
 
 
  
Participant’s Name (print) 
 
 
Signature 
 
Date 
Person Obtaining Consent (print) 
 
Signature 
 
Date 
 
Legally Authorized Representative Consent  
I, as the legally authorized representative of the participant, give consent for his/her participation in this 
study. 
You have read all the preceding information that describes the participant’s involvement in PEACE-AD.  The 
study has been explained to you in detail, and all of your questions have been answered to your satisfaction.  
 
 
 
 
 
 
Legally Authorized Representative 
Name (print) 
 
 
Signature 
 
Date 
Person Obtaining Consent (print) 
 
Signature 
 
Date 
 
 
California Site Only: Insert the Experimental Bill of Rights 

Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
HOWARD FELDMAN, MDCM, FRCP(C)  
PROFESSOR, DEPARTMENT OF NEUROSCIENCES 
DIRECTOR, ALZHEIMER’S DISEASE COOPERATIVE STUDY (ADCS) 
DEAN, ALZHEIMER’S DISEASE AND NEURODEGENERATIVE RESEARCH 
9500 Gilman Drive     La Jolla, California 92037-0949     TEL: (858) 246-1347   FAX: (858) 246-1414 
 
 
 
Prazosin for Disruptive Agitation in Alzheimer’s Disease (AD) (PEACE-AD) 
Short Title: Prazosin for Agitation in AD 
Protocol Number: ADC-042-PRAZ 
 
NCT03710642 
 
Protocol Version 11.0 
06 DEC 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Number: ADC-042-PRAZ 
 
Page 1 of 60 
 
 
Version: 11.0 06DEC2021  
 
 
 
 
Prazosin for Disruptive Agitation in 
Alzheimer’s Disease (AD) (PEACE-AD) 
 
 
Short Title: Prazosin for Agitation in AD 
 
 
Protocol Number: ADC-042-PRAZ 
 
Sponsor: Alzheimer’s Disease Cooperative Study  
at University of California, San Diego, 
 
Protocol Version 11.0 
06 DEC2021 
 
 
 
 
 
Confidentiality Statement 
The information in this document is privileged or confidential and may not be disclosed unless 
such disclosure is required by applicable laws and regulations.  It is the property of ADCS and 
should not be copied by or distributed to persons not involved in the study.  Persons to whom 
the information is disclosed must be informed that the information is privileged or confidential 
and may not be further disclosed by them. These restrictions on disclosure will apply equally to 
all future information supplied to you, which is indicated as privileged or confidential. Any 
unauthorized review, use, disclosure, copying or distribution is strictly prohibited. 
 
 


Protocol Number: ADC-042-PRAZ 
 
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Version: 11.0 06DEC2021  
PROJECT DIRECTORS 
FUNDING AGENCY 
Elaine Peskind, MD 
Murray Raskind, MD 
VA Puget Sound Health Care System 
1660 S Columbian Way 
S-116 MIRECC 
Seattle, WA 98108 
 
peskind@uw.edu 
Tel: (206) 277-3965 
murray.raskind@va.gov 
Tel: (206) 277-3797 
National Institute on Aging 
7201 Wisconsin Avenue, Suite 350 
Bethesda, MD 20892-9205 
 
Kristina McLinden, PhD 
Kristina.mclinden@nih.gov  
Tel: (301) 496-9350 
 
SPONSOR, COORDINATION & DATA 
MANAGEMENT CENTER 
ADCS MEDICAL MONITOR 
Howard Feldman, MDCM, FRCP(C) 
ADCS Director 
 
UC San Diego 
Alzheimer’s Disease Cooperative Study 
9500 Gilman Drive, MC 0949 
La Jolla, CA 92093-0949 
 
howardfeldman@health.ucsd.edu  
Tel: (858) 246-1347 
Gabriel Leger, MD 
 
 
UC San Diego 
Alzheimer’s Disease Cooperative Study 
9500 Gilman Drive, MC 0949 
La Jolla, CA 92093-0949  
 
gleger@health.ucsd.edu  
Tel: (858) 246-2539 
PROTOCOL VERSION 
VERSION DATE 
Protocol Version 11.0 
06DEC2021 
 
 


Protocol Number: ADC-042-PRAZ 
 
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Version: 11.0 06DEC2021  
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ......................................................................................................... 7 
PROTOCOL AGREEMENT .......................................................................................................... 9 
1 
PROTOCOL SYNOPSIS .................................................................................................... 10 
2 
INTRODUCTION ................................................................................................................. 13 
2.1 Overview ........................................................................................................................... 13 
2.1.1 Rationale for Studying Prazosin ................................................................................. 13 
2.1.2 Rationale for Study Design ........................................................................................ 14 
2.1.3 Rationale for the Dose ............................................................................................... 14 
2.1.4 Rationale for Length of Trial ....................................................................................... 14 
2.1.5 Rationale for Actigraphy Sub-Study ........................................................................... 14 
2.2 Background and Significance ........................................................................................... 15 
3 
PRELIMINARY STUDIES ................................................................................................... 15 
3.1 Neurobiologic Rationale for the Alpha-1 AR Antagonist, Prazosin, as a Potential 
Therapeutic for Disruptive Agitation in AD .............................................................................. 15 
3.2 Placebo-Controlled Pilot Study of Prazosin for Disruptive Agitation in AD ....................... 16 
3.3 Safety and Compliance ..................................................................................................... 16 
4 
SPECIFIC AIMS .................................................................................................................. 17 
5 
STUDY DESIGN ................................................................................................................. 18 
5.1 Study Population ............................................................................................................... 18 
5.2 Participating Sites ............................................................................................................. 19 
5.3 Inclusion Criteria ............................................................................................................... 19 
5.4 Exclusion Criteria .............................................................................................................. 19 
5.5 End of Study/Participant Withdrawal/Early Study Termination ......................................... 21 
5.5.1 Reasons for Early Termination ................................................................................... 21 
6 
STUDY DRUG AND COMPARATOR ................................................................................ 21 
6.1 Name and Description of Investigational Product (IP) and Comparator ........................... 21 
6.1.1 Formulation Packaging and Labeling ......................................................................... 22 
6.1.2 Mode of Administration .............................................................................................. 22 
6.1.3 Shipping, Storage and Handling of IP ........................................................................ 22 
6.1.4 Replacement Procedures for IP ................................................................................. 23 
6.1.5 Study Drug Dispensing .............................................................................................. 23 
6.1.6 Accountability and Return of IP .................................................................................. 23 


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6.2 Dosing Administration and Schedule ................................................................................ 24 
6.2.1 Study Drug Dose Escalation ...................................................................................... 24 
6.2.1.1 Fixed Dose Titration ................................................................................................ 25 
6.2.1.2 Flexible Dose Titration ............................................................................................ 25 
6.2.2 Dose Reductions and Re-Challenges ........................................................................ 25 
6.2.3 Overdose .................................................................................................................... 26 
6.2.4 Study Drug Orders ..................................................................................................... 27 
7 
METHODS OF ASSIGNING PARTICIPANTS TO TREATMENT GROUPS ...................... 28 
7.1 Randomization .................................................................................................................. 28 
7.2 Blinding/Masking ............................................................................................................... 28 
7.2.1 Blinding at the Study Site ........................................................................................... 28 
7.2.2 Premature Unblinding of Study Participants in the Event of a Medical Emergency ... 28 
7.2.3 Breaking the Blind for Individual Participants at Study Completion or Early 
Termination ......................................................................................................................... 28 
8 
PARTICIPANT COMPLIANCE ........................................................................................... 29 
8.1 Compliance ....................................................................................................................... 29 
8.2 Allowed Concomitant Psychoactive Medications .............................................................. 29 
8.3 Rescue Lorazepam ........................................................................................................... 29 
8.4 Prohibited Concomitant Medications ................................................................................. 30 
9 
PHARMACOKINETICS (PK) OF PRAZOSIN .................................................................... 30 
10 
STUDY ASSESSMENTS AND PROCEDURES ................................................................. 30 
10.1 ADCS-Clinical Global Impression of Change in Agitation (CGIC-A) ............................... 31 
10.2 Neuropsychiatric Inventory (NPI, home care setting) and Neuropsychiatric Inventory–
Nursing Home version (NPI-NH, LTC setting) ........................................................................ 31 
10.3 ADCS-Activities of Daily Living–Severe Dementia version (ADCS-ADL-Severe) ........... 31 
10.4 Cohen Mansfield Agitation Inventory (CMAI) .................................................................. 32 
10.5 Total mg Lorazepam Administered and Study Days Completed. ................................... 32 
10.6 Treatment Blinding Questionnaire ................................................................................... 32 
10.7 Physical and Neurological Examination .......................................................................... 32 
10.8 Electrocardiogram (ECG) ................................................................................................ 32 
10.9 Clinical Laboratory Evaluations ....................................................................................... 33 
10.10 Vital Signs ..................................................................................................................... 33 
10.10.1 Blood Pressure (BP) and Heart Rate (HR) Measurements .................................... 33 


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10.11 Adverse Symptoms Checklist ....................................................................................... 34 
10.12 Open-ended AE Reporting ............................................................................................ 34 
10.13 Locomotor Activity and Nighttime Sleep Continuity (Actigraphy Sub-Study) ................ 34 
11 
SAFETY .............................................................................................................................. 34 
11.1 Adverse Events (AEs), Serious Adverse Events (SAEs), and Reporting ........................ 34 
11.2 Adverse Events (AEs) ..................................................................................................... 34 
11.2.1 Adverse Events of Special Interest .......................................................................... 35 
11.3 Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions 
(SUSARs) ............................................................................................................................... 36 
11.3.1 Definition of Life Threatening ................................................................................... 37 
11.3.2 Definition of Hospitalization ...................................................................................... 37 
11.3.3 Definition of Disability ............................................................................................... 37 
11.3.4 Definition of Important Medical Events ..................................................................... 37 
11.3.5 Reporting Serious Adverse Events (SAEs) .............................................................. 38 
12 
SCHEDULE OF EVALUATIONS AND PROCEDURES .................................................... 38 
12.1 Pre-screening .................................................................................................................. 38 
12.2 Screening (within 28 days prior to randomization) .......................................................... 39 
12.2.1 Confirmation of Eligibility .......................................................................................... 39 
12.3 Baseline/Randomization (Titration - Day 1) .................................................................... 40 
12.4 Titration Visits - Days 8, 15, 22, and 29 (± 1 Day until Day 15, then ± 2 Days) .............. 40 
12.5 Maintenance Visits .......................................................................................................... 40 
12.5.1 Safety Assessments – Weeks 5, 6, and 10 (± 2 Days) ............................................ 40 
12.5.2 Outcome Assessment – Week 8 (± 2 Days) ............................................................ 41 
12.6 End of Study - Week 12 (± 2 Days) or Early Termination ............................................... 41 
12.7 Between Visits ................................................................................................................ 42 
13 
STATISTICAL METHODS .................................................................................................. 42 
13.1 Power and Sample Size Determination .......................................................................... 42 
13.2 Selection of Participants to be Used in Analysis ............................................................. 42 
13.3 Efficacy Analysis ............................................................................................................. 43 
13.3.1 Analysis of the Primary Outcome(s) ......................................................................... 43 
13.3.2 Analysis of Secondary Outcomes ............................................................................ 43 
13.3.3 Analysis of Exploratory Outcomes ........................................................................... 44 
13.3.4 Safety Analysis ......................................................................................................... 44 


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13.3.5 Safety Endpoints ...................................................................................................... 45 
13.3.6 Blood Pressure (BP) and Heart Rate (HR) .............................................................. 45 
13.4 Criteria for the Termination of the Trial ........................................................................... 45 
14 
DATA AND SAFETY MONITORING BOARD (DSMB) ...................................................... 45 
15 
RECORDING AND COLLECTION OF DATA .................................................................... 46 
15.1 Source Documents and Electronic Case Report Forms (eCRF) ..................................... 46 
15.2 Study Files and Participant Source Documents .............................................................. 46 
15.3 Release of Information .................................................................................................... 47 
16 
ADMINISTRATIVE PROCEDURES ................................................................................... 47 
16.1 Study Timeline ................................................................................................................ 47 
16.2 Ethics and Regulatory Considerations ............................................................................ 47 
16.2.1 Good Clinical Practice (GCP) ................................................................................... 47 
16.2.2 Institutional Review Board (IRB) .............................................................................. 48 
16.2.3 Informed Consent and HIPAA Compliance .............................................................. 48 
16.2.4 Inclusion of Children as Participants in Research Involving Human Subjects ......... 49 
16.3 Study Monitoring ............................................................................................................. 49 
16.4 Audit ................................................................................................................................ 49 
16.5 Records Retention .......................................................................................................... 49 
16.6 Publication Policy ............................................................................................................ 50 
16.7 Sharing of Final Research Data ...................................................................................... 50 
17 
PERSONNEL REQUIREMENTS – ROLES AND RESPONSIBILITIES ............................ 50 
18 
POTENTIAL RISKS AND BENEFITS ................................................................................ 51 
18.1 Potential Risks of Study Drug ......................................................................................... 51 
18.2 Potential Risks of Actigraphy Sub Study ......................................................................... 52 
18.3 Potential Benefits ............................................................................................................ 52 
18.4 Relationship of this Intervention to Current Treatment Practices in AD .......................... 53 
19 
REFERENCES .................................................................................................................... 54 
20 
APPENDICES ..................................................................................................................... 57 
APPENDIX 1 DOSE TITRATION DIAGRAM .......................................................................... 57 
APPENDIX 2 SCHEDULE OF EVENTS ................................................................................. 58 
APPENDIX 3 LIST OF TABLES .............................................................................................. 59 
APPENDIX 4 STUDY SCHEMATIC ........................................................................................ 60 
 


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LIST OF ABBREVIATIONS  
AD 
 
 
Alzheimer’s disease 
ADCS  
 
Alzheimer's Disease Cooperative Study 
ADCS-ADL-Severe 
ADCS Activities of Daily Living–Severe Dementia version 
ADCS-CGIC  
ADCS-Clinical Global Impression of Change 
ADCS-CGIC-A 
ADCS-Clinical Global Impression of Change in Agitation 
ADL 
 
 
Activities of Daily Living 
AE 
 
 
Adverse Event 
AR 
 
 
Adrenoreceptor 
BID 
 
 
Twice Per Day 
BL 
 
 
Baseline 
BP 
 
 
Blood Pressure 
BPRS  
 
Brief Psychiatric Rating Scale 
CBC 
 
 
Complete Blood Count 
CFR 
 
 
Code of Federal Regulations 
CGIC  
 
Clinical Global Impression of Change 
CGIC-A 
 
Clinical Global Impression of Change in Agitation 
CMAI  
 
Cohen Mansfield Agitation Inventory 
CNS 
 
 
Central Nervous System 
CRA 
 
 
Clinical Research Associate 
CSF 
 
 
Cerebrospinal Fluid 
DSM  
 
Diagnostic and Statistical Manual of Mental Disorders 
DSMB  
 
Data Safety Monitoring Board 
ECG 
 
 
Electrocardiogram 
eCRF  
 
Electronic Case Report Form 
FDA 
 
 
Food and Drug Administration 
GCP 
 
 
Good Clinical Practice 
HCl 
 
 
Hydrochlorate 
HIPAA  
 
Health Insurance Portability and Accountability Act 
HIV 
 
 
Human Immunodeficiency Virus  
HR 
 
 
Heart Rate 
ICF 
 
 
Informed Consent Form 
ICH 
 
 
International Conference on Harmonisation 
IEC 
 
 
Independent Ethics Committee 
IND 
 
 
Investigational New Drug 
IP 
 
 
Investigational Product 
IRB 
 
 
Institutional Review Board 
IRT 
 
 
Interactive Response Technology 


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ITT 
 
 
Intent-to-Treat 
LAR 
 
 
Legally Authorized Representative  
LC 
 
 
Locus Ceruleus 
LOCF  
 
Last Observation Carried Forward 
LTC 
 
 
Long-Term Care 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MMRM  
 
Mixed Effects Model for Repeated Measures 
MMSE  
 
Mini Mental State Exam 
NE 
 
 
Norepinephrine 
NIA 
 
 
National Institute on Aging 
NIH 
 
 
National Institutes of Health 
NINCDS-ADRDA 
National Institute of Neurological and Communicative Disorders and 
Stroke and Alzheimer's Disease and Related Disorders Association 
NPI 
 
 
Neuropsychiatric Inventory 
NPI-NH 
 
Neuropsychiatric Inventory-Nursing Home version 
OHRP  
 
Office for Human Research Protections  
PEACE-AD 
 
Prazosin for Disruptive Agitation in Alzheimer’s Disease 
PI 
 
 
Principal Investigator 
PHI 
 
 
Protected Health Information 
PK 
 
 
Pharmacokinetics 
PO 
 
 
By Mouth 
PT 
 
 
Preferred Term 
PTSD  
 
Posttraumatic Stress Disorder 
QAM  
 
Every Day at Mid-Morning 
QHS 
 
 
At Bedtime 
SAE 
 
 
Serious Adverse Event 
SD 
 
 
Standard Deviation 
SOC 
 
 
System Organ Class 
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
TDD 
 
 
Total Daily Dose 
TEAE  
 
Treatment-Emergent Adverse Event 
VA 
 
 
Veterans Affairs


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PROTOCOL AGREEMENT 
 
(SIGNATURES ON FILE AT ADCS) 
 
 
 
_______________________________________ 
 
___________________ 
Elaine Peskind, MD 
 
 
 
 
 
Date (DD/MMM/YYYY) 
Project Co-Director 
Seattle Institute for Biomedical & Clinical Research 
 
 
_______________________________________ 
 
___________________ 
Murray Raskind, MD  
 
 
 
 
Date (DD/MMM/YYYY) 
Project Co-Director 
Seattle Institute for Biomedical & Clinical Research 
 
 
_______________________________________ 
 
___________________ 
Howard Feldman, MDCM, FRCP(C)  
 
 
Date (DD/MMM/YYYY) 
Director,  
Alzheimer’s Disease Cooperative Study (ADCS) 
 
 
_______________________________________ 
 
___________________ 
Gabriel Leger, MD 
 
 
 
 
 
Date (DD/MMM/YYYY) 
Medical Monitor 
Alzheimer's Disease Cooperative Study (ADCS) 
 


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Version: 11.0 06DEC2021  
1 
 PROTOCOL SYNOPSIS 
Protocol Title 
Prazosin for Disruptive Agitation in Alzheimer’s Disease (AD) 
(PEACE-AD) 
Project Co-
Directors 
Elaine Peskind, MD, Murray Raskind, MD 
Coordinating 
Center 
Alzheimer’s Disease Cooperative Study (ADCS) 
Participating 
Sites 
Approximately 12-18 ADCS PIs will participate in this trial. PIs will enroll 
participants residing in either a long-term care (LTC) facility associated 
with the site or at home with full-time caregiving.  An LTC is defined as 
either an assisted living or skilled nursing facility. Full time caregiving is 
defined as having continuous daily caregiving.  
Study Design  
This is a Phase IIb multicenter, randomized, double-blind, placebo-
controlled study evaluating the efficacy and safety of prazosin in 35 
participants with Alzheimer’s disease (AD) complicated by disruptive 
agitation residing in an LTC  or in the home with full-time caregiving. 
Duration of Study 
Participation 
The total active study duration is approximately 3 years, including start-
up, recruitment of all participants and follow-up periods.   
The total duration of individual study participation is approximately 16 
weeks.   
Individual study participation consists of the following: 
• Screening period up to 28 days. 
• Duration of treatment of 12 weeks. 
Randomization 
Schedule 
Participants on this study will be randomized 2:1 (prazosin:placebo), for 
approximately 23 participants in the active group and 12 in the placebo 
control group. 
Summary of 
Investigational 
(Intervention) 
Product 
Oral prazosin HCl capsules will be administered twice daily, with 
individualized doses up to a maximum of 4 mg mid-morning (QAM) and 6 
mg at bedtime (QHS), or matching placebo capsules  
Inclusion Criteria 
 
 
1. Males and females with probable or possible AD by NINCDS-ADRDA 
criteria utilizing medical history; medical records review; and 
documented physical, neurological, and other examinations and 
laboratory tests. At Screening, physical, neurological and other 
examinations; and laboratory tests will be performed as possible and 
tolerated by the agitated participants. Brain imaging is not a 
requirement. 
2. Participants must reside in either a participating LTC or at home with 
full-time caregiving.  


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3. Participants must have disruptive agitation significant enough to 
disrupt caregiving and, in the opinion of the Site Principal Investigator, 
to justify further treatment. Disruptive agitation, defined as having any 
combination of the following target behaviors, a) irritability, b) 
physically and/or verbally aggressive behavior, c) physically resistive 
to necessary care, and/or d) pressured motor activity (e.g., pressured 
pacing), must have occurred nearly daily during the previous week 
and at least intermittently for 4 weeks prior to screening, documented 
on the Behavioral Inclusion Criteria Checklist at Screening. Target 
behaviors may be any combination of the listed domains as long as 
they meet the above-described criteria for frequency and severity. 
4. Psychotropic medication, if used, should be stable for at least 2 
weeks prior to randomization.  
5. If taking cholinesterase inhibitor and/or memantine, must be on stable 
dose(s) for 3 months prior to randomization.  
6. During the week before randomization, the above-described 
behaviors must be rated as of at least “moderate” severity. These 
behaviors must be problematic in that they cause participant and 
caregiver distress and/or interfere with essential care or disrupt their 
living environment.  
Exclusion Criteria 
1. History of schizophrenia, schizoaffective disorder, or bipolar disorder 
according to the criteria of the most current version of the Diagnostic 
and Statistical Manual of Mental Disorders (DSM). 
2. Other neurodegenerative diseases, including Parkinson’s disease and 
Huntington’s disease, or cerebral tumor. 
3. Dementia other than probable or possible AD per NINCDS-ADRDA 
criteria, such as human immunodeficiency virus (HIV) dementia, 
Creutzfeldt-Jakob disease, frontotemporal dementia, multiple cerebral 
infarctions, or normal pressure hydrocephalus. 
4. Current treatment for seizure disorder. (Note: anticonvulsants 
prescribed for disruptive agitation are acceptable). 
5. Abnormal laboratory values with clinical significance in the opinion of 
the site Principal Investigator.  
6. Current unstable medical illness including delirium, worsening 
congestive heart failure, unstable angina, recent myocardial infarction 
(within the past 3 months), acute infectious disease, severe renal or 
hepatic failure, severe respiratory disease, metastatic cancer, or other 
conditions that, in the Site Principal Investigator’s opinion, could 
interfere with the analyses of safety and efficacy in this study.  
7. Bedbound; participants may be ambulatory or use a wheelchair. 
8. Absence of any comprehensible language. 
9. Participation in another clinical trial for an investigational agent and 
took at least one dose of study drug (unless unblinded to placebo) 
within 12 weeks prior to screening. (The end of a previous 
investigational trial is defined as the date of the last dose of an 
investigational agent).  


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10. Preexisting recurrent hypotension (systolic blood pressure [BP] 
<110). 
11. Preexisting orthostatic hypotension (>20 mmHg drop in systolic BP 
following 2 minutes of standing posture [or sitting if unable to stand], 
accompanied by dizziness, lightheadedness, or syncope). 
12. A 2-week washout is required prior to BL for the following 
exclusionary medications: prazosin or other alpha-1 blocker, 
sildenafil, vardenafil, tadalafil, and avanafil. 
13. Women of childbearing potential (must be at least 2 years post-
menopausal or surgically sterile for inclusion). 
14. The participant may not be an immediate family member of personnel 
directly affiliated with this study, the study site or study funding 
agency. Immediate family member is defined as a spouse, parent, 
child, or sibling, any of whom may be related by blood, adoption, or 
marriage. 
15. Participants whom the Site Principal Investigator deems to be 
otherwise unsuitable for participation. 
Primary Outcome 
Measure 
The primary outcome measure for this study is the ADCS-Clinical Global 
Impression of Change in Agitation (ADCS-CGIC-A) targeting disruptive 
agitated behaviors. 
Key Secondary 
Outcome 
Measure  
The key secondary outcome measure is the: 
• Neuropsychiatric Inventory (home based) (NPI) / Neuropsychiatric 
Inventory-Nursing Home version (NPI-NH) 
Other Secondary 
Outcome 
Measures 
Other secondary outcome measures are: ADCS Activities of Daily Living–
Severe Dementia version (ADCS-ADL-Severe) 
• Number of study days completed 
• Total mg of rescue lorazepam administered 
Exploratory 
Outcome 
Measures 
The exploratory outcome measures are: 
• Analysis of the Cohen-Mansfield Agitation Inventory12, which will be 
administered at Baseline and Week 12 to assess specific symptoms 
of agitation. 
• Analysis of a subset of NPI/NPI-NH Agitation/Aggression, Anxiety, 
Disinhibition, Irritability/Lability, and Aberrant Motor Behavior domains 
that likely are related to increased central nervous system (CNS) 
noradrenergic activity is planned. 
• At a subset of participating ADCS sites, locomotor activity and 
nighttime sleep continuity as measured by wrist actigraphy (e.g., 
accelerometry) will be collected. This will be referred to hereafter as 
the “actigraphy sub-study”. 
Safety Endpoints 
Incidence and severity of treatment-emergent adverse events (TEAEs), 
serious adverse events (SAEs), and withdrawals due to adverse events 
(AEs); changes from baseline (BL) in the following safety assessments: 
supine and orthostatic BP and heart rate (HR) measurements. 


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2 
 INTRODUCTION  
2.1 Overview 
Prazosin for Disruptive Agitation in Alzheimer’s Disease (PEACE-AD) is a Phase IIb multicenter, 
randomized, double-blind, placebo-controlled trial of 12-weeks treatment with the brain active 
alpha-1 adrenoreceptor (AR) antagonist prazosin for disruptive agitation in 35 Alzheimer’s 
disease (AD) residents in either a long-term care (LTC) setting or at home with full-time 
caregiving allowing remote (telephone or video) or home visits. Disruptive agitation is defined as 
having any combination of the following target behaviors: a) irritability, b) physically and/or 
verbally aggressive behavior, c) physically resistive to necessary care, and/or d) pressured 
motor activity (e.g., pressured pacing). LTC is defined as assisted living or skilled nursing 
facility. A previous single site pilot study addressing disruptive agitation in 22 predominantly 
LTC-residing AD participants demonstrated efficacy of prazosin on all three primary outcome 
measures.1 The current multicenter study is funded by the National Institute on Aging (NIA), and 
coordinated through the NIA-funded Alzheimer’s Disease Cooperative Study (ADCS) with 
supplemental funding from the Alzheimer’s Association. 
Rationale for inclusion of AD outpatients with disruptive agitation residing at home with full-time 
caregiving, including the impact of the COVID-19 pandemic. The current COVID-19 pandemic 
has had its greatest mortality and morbidity in residents of LTC facilities. In response, LTCs 
across the nation are in “lockdown” with severe restrictions on visitors, including PEACE-AD 
study personnel. Furthermore, many facilities have reduced availability for new admissions and 
many families providing home caregiving for AD patients with disruptive agitation are reluctant 
to seek LTC placement for fear of exposing their loved one to the deadly coronavirus. In fact, 
the loss of dementia day care, respite care, and similar caregiver-supportive programs, as well 
as isolation at home of both AD patients and caregivers, has led to caregivers struggling to 
manage even more severe disruptive agitated behaviors at home. These COVID-19 related 
problems provide strong rationale and even necessity for including home-dwelling AD patients 
in PEACE-AD. 
Rationale for flexibility in using remote technology for visits. Recommended COVID-19 safety 
measures for high risk elderly persons severely limit access of study personnel to LTC settings 
and argue for performing as many study procedures as possible remotely in both LTC and 
home caregiving settings to optimize safety for participants, caregivers, and study personnel. 
Where possible, the screening visit should be conducted in person. However, depending on 
local restrictions and safety recommendations, sites will have the flexibility to perform screening 
visits in the LTC, clinic, or through a home visit. Although it is preferable, if possible, to have the 
screening visit done in person, any of these three options can be done via remote technology, if 
necessary. All subsequent visits will be performed either in-person or via remote technology.  
2.1.1 Rationale for Studying Prazosin 
Prazosin is a generically available alpha-1 AR antagonist that crosses the blood brain barrier18 
and blocks central nervous system (CNS) alpha-1 AR activation when administered orally.19 In a 
placebo-controlled pilot trial in predominantly LTC-residing AD patients, prazosin was 
significantly and substantially superior to placebo for disruptive agitation (see Section 3 
Preliminary Studies). 


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2.1.2 Rationale for Study Design 
Data from AD clinical and postmortem brain tissue studies15-17 suggest that noradrenergic 
stimulation via the CNS alpha-1 AR contributes to the pathophysiology of agitation in AD. Thus, 
blockade of excessive CNS noradrenergic activation with the brain active alpha-1 AR 
antagonist, prazosin, is a rational approach to the treatment of disruptive agitation in AD. 
2.1.3 Rationale for the Dose 
Although the successful pilot study of prazosin for disruptive agitation in AD used a total daily 
dose (TDD) of 6 mg, there were participants who did not fully respond to the maximum dose 
and there were very few adverse events. It was determined that a higher maximum TDD of 10 
mg/day using a flexible dose titration based on response and tolerability to optimum 
maintenance dose will provide greater benefit without appreciably increasing risk. 
2.1.4 Rationale for Length of Trial 
A 12-week participant treatment (prazosin or placebo) duration was chosen to allow adequate 
time for the 29-day study drug titration (necessary for safety) while providing a sufficient 8-week 
observation period at optimum achieved maintenance dose. Because agitated dementia 
patients are themselves distressed as well as highly difficult for caregivers and disruptive in their 
living environment, a longer treatment trial would be impractical. 
2.1.5 Rationale for Actigraphy Sub-Study 
Agitation and aggression, particularly during the afternoon to nighttime hours, present a 
significant problem in patients with AD who reside in long-term care and home caregiving 
settings. Prazosin has shown promise in treating disruptive agitation in AD in both an open label 
feasibility study as well as a small placebo-controlled pilot study. However, primary outcomes in 
these small studies have relied on subjective caregiver-based questionnaires, which may be 
subjective and dependent upon personnel and resources. The effect of prazosin on objective 
outcome measures of nighttime agitation, including locomotor activity, would add valuable 
information to the clinical trial. 
A small European placebo-controlled study used wrist actigraphy as the primary outcome to 
assess the effect of melatonin or dronabinol on agitation in participants with AD35. In this 
inpatient study, 24 participants with probable AD and 20 control participants wore a wrist 
Actiwatch for 14-16 days, including a 2-day period of baseline assessment prior to 
pharmacological intervention. A treatment: baseline ratio of motor activity as detected by wrist 
actigraphy was calculated for each participant, and means across participants were compared 
between active study drug and placebo groups (lower ratio = less agitation). This ratio was 
significantly decreased during the 12-hour nighttime period in the active study drug compared to 
the placebo condition (P<0.05, Kruskal Wallis test). Exact effect sizes could not be inferred from 
this publication due to missing data. 
A second study used wrist activity to assess the effect of dronabinol on nighttime agitation in 
participants with AD and dementia36. Six participants, five with AD and one with vascular 
dementia, wore wrist actigraphy devices while receiving 2.5mg dronabinol for two weeks. 
Nocturnal activity was compared used repeated-measures, comparing baseline levels to those 
after two weeks of treatment. Treatment with dronabinol significantly decreased nocturnal 
activity compared to baseline (P<0.05, Wilcoxon signed rank test, corresponding to a Cohen’s d 
effect size of ~0.9). Furthermore, participants’ agitation symptoms as assessed using the NPI 


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before and after treatment showed significant improvement in NPI scores in the treatment group 
(P<0.05, Wilcoxon signed rank test, again corresponding to a Cohen’s d effect size of ~0.9). 
2.2 Background and Significance 
Disruptive agitation is a common distressing problem for AD patients, their caregivers, and 
families, whether they reside in LTC or at home..2-7 This group of behaviors in AD patients 
residing at home is the most common precipitant of LTC placement.8 Prior to the COVID-19 
pandemic, LTC placement helped reduce the burden on the frequently exhausted family 
caregiver. With COVID-19, the option of LTC placement is now less readily available. Even 
when AD patients with disruptive agitation are able to be admitted to LTC, the burden of 
managing disruptive agitation is only shifted to the LTC staff, but remains a very difficult and 
challenging care issue in LTC facilities. In this protocol, the term “disruptive agitation” includes a 
group of behaviors that are highly prevalent in the later stages of AD and that often cluster 
together: irritability and anger outbursts, physical resistiveness to necessary care, verbal and/or 
physical aggression, and pressured motor hyperactivity (e.g., pressured pacing). These 
behaviors become more frequent as dementia progresses and are eventually expressed for at 
least some period of time by the majority of AD patients.7,9 Disruptive agitation in later stage AD 
patients is arguably the most serious and difficult to treat behavioral problem in both the LTC or 
at home.10,11 Effective treatments for disruptive agitation in later stage AD patients remains an 
important unmet need. In this protocol, whether residing in LTC facilities or continuing to be 
cared for at home, the patient population with AD complicated by disruptive agitation does not 
differ.  
3 
PRELIMINARY STUDIES 
3.1 Neurobiologic Rationale for the Alpha-1 AR Antagonist, Prazosin, as a Potential Therapeutic 
for Disruptive Agitation in AD 
Norepinephrine (NE) released from pontine locus ceruleus (LC) neurons that project to 
postsynaptic AR in neocortical and limbic brain areas has long been recognized to increase 
arousal and activation.20,21 Excessive activation by NE of these postsynaptic AR (predominantly 
alpha-1 AR and beta AR) produces hyperarousal, agitation, irritability, and the “fight-or-flight” 
response. Although LC neuronal number is reduced in AD,22 brain NE release remains normal 
or even increased in AD as indicated by normal or increased cerebrospinal fluid (CSF) NE 
concentrations.23 This apparently paradoxical finding likely reflects compensatory upregulation 
of NE production in surviving LC neurons as demonstrated in postmortem human brain tissue 
studies by Drs. Peskind’s and Raskind’s group and other laboratories24, 25 and not decreased 
clearance of NE from brain in AD.26 The postmortem brain tissue studies also demonstrated 
increased expression of alpha-1 AR in brain areas mediating arousal and activation in AD 
patients, especially those with an antemortem history of disruptive agitation.16 Others similarly 
have demonstrated increased alpha-1 AR expression in AD patients with antemortem 
aggressive behavior.17 Finally, Drs. Peskind and Raskind demonstrated that equivalent CSF NE 
increases following yohimbine administration produced agitated behaviors only in persons with 
AD and not in cognitively normal older persons.15 
The studies described above support excessive activation of brain alpha-1 AR by NE 
contributing to the pathobiology of disruptive agitation in AD. If so, an alpha-1 AR antagonist 
that crosses from blood into brain is a rational choice as a pharmacologic treatment for this 
major clinical problem. Prazosin, the most lipophilic and thus most brain-penetrant, of clinically 


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available alpha-1 AR antagonists has been demonstrated selectively to antagonize neuronal 
responses mediated by alpha-1 AR in brain when administered peripherally.19 Given the clinical 
availability of prazosin as an inexpensive generic drug, its good safety record (including rarely 
producing sedation), and the demonstration of prazosin efficacy for severe hyperarousal 
symptoms in posttraumatic stress disorder (PTSD),27, 28 a placebo-controlled pilot study of 
prazosin for moderate to severe disruptive agitation in persons with advanced AD participants 
both residing in LTC facilities and at home was conducted.1 
3.2 Placebo-Controlled Pilot Study of Prazosin for Disruptive Agitation in AD 
This was a double-blind, placebo-controlled trial of prazosin for disruptive agitation in AD. 
Twenty-two male and female participants with probable or possible AD (mean [± standard 
deviation (SD)] age 80 ± 11.2 years, age range 59 to 95 years) and severe disruptive agitation 
of at least one-month duration were randomized to prazosin (n=11) or placebo (n=11) for 8 
weeks. The participants were nursing home residents (N=14) and participants residing at home 
(N=8). Prazosin was initiated at 1 mg at bedtime (QHS) and titrated using a flexible dose 
algorithm to optimal dose (maximum dose 2 mg every morning at mid-morning [QAM] plus 4 mg 
at bedtime [QHS]). Maintenance psychotropic and cognitive acting drugs were held constant 
during the trial. Outcome measures were the ADCS-Clinical Global Impression of Change 
(CGIC), Neuropsychiatric Inventory (NPI) total score, and Brief Psychiatric Rating Scale 
(BPRS). NPI and BPRS were obtained at baseline (BL) and then every two weeks; CGIC was 
obtained every 2 weeks post-BL.  
Participants assigned to prazosin (mean dose 5.7 ± 0.9 mg/day) had significantly greater 
improvements in behavioral outcome measures compared to those assigned to placebo (mean 
dose 5.6 ± 1.2 mg/day). For the CGIC, end-point scores were 2.6 ± 1.0 vs. 4.5 ± 1.6, p=0.011. 
For the Neuropsychiatric Inventory (NPI) total score, the change from BL was 19 ± 21 vs. -2 ± 
15, p=0.01. The five disruptive agitation-relevant NPI domains all favored prazosin (Table 1). 
Table 1. Change from BL in agitation-relevant NPI domains in prazosin and placebo 
groups 
 
NPI Items (LOCF: change from BL [mean ± SD]) 
Agitation/ 
Aggression 
Anxiety 
Disinhibition 
Irritability/ 
Lability 
Aberrant Motor 
Behavior 
Prazosin (n=11) -3.6 ± 4.5 
-2.6 ± 3.5 
-2.4 ± 3.1 
-1.7 ± 4.6 
-1.9 ± 4.6 
Placebo (n=11) 
-0.8 ± 3.1 
0.4 ± 3.6 
1.5 ± 2.9 
-1.0 ± 3.4 
1.5 ± 3.0 
3.3 Safety and Compliance 
Prazosin was generally well-tolerated and adverse effects were similar between prazosin and 
placebo groups (Table 2). Mean change from BL in Mini Mental State Exam (MMSE) scores in 
the testable participants was -1 ± 1.2 in the prazosin group and -2 ± 2.1 in the placebo group. 
There were no deleterious effects of prazosin on cognition or activities of daily living (ADL) in 
this pilot study. 
 
 


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Table 2. Adverse effects 
 
Prazosin 
Placebo 
a One participant in each group terminated from 
the study early due to peripheral edema. 
b One participant in each group terminated from 
the study early due to orthostatic hypotension; 
the other prazosin participant’s hypotension 
resolved when concomitant antihypertensive 
medications were adjusted. 
c One participant in the placebo group 
terminated from the study early due to rash. 
Sedation 
3 
3 
Confusion 
1 
4 
Lower extremity edemaa 
1 
2 
Hypotensionb 
2 
1 
Headache 
0 
2 
Cough 
2 
0 
Hallucinations 
1 
1 
Dizziness on standing 
2 
0 
Rashc 
0 
2 
In summary, there were statistically and clinically significant differences favoring prazosin over 
placebo in behavioral outcome measures of disruptive agitation and prazosin was well tolerated. 
Patterns of improvement were similar between LTC and home-dwelling participants. Several of 
the home-dwelling AD participants whose families were actively considering LTC placement 
because of disruptive agitation opted to continue care at home with maintenance prazosin. 
These preliminary data support the need for a larger placebo-controlled study to establish 
efficacy and safety of prazosin for disruptive agitation in individuals with AD, in both LTC and 
home caregiving settings.  
4 
SPECIFIC AIMS 
Specific Aim 1 (Primary Aim): To evaluate the efficacy and safety of the alpha-1 AR 
antagonist, prazosin, in the treatment of disruptive agitation as defined in this protocol in 
participants with probable or possible AD residing either in an LTC or at home with full-time 
caregiving. 
Hypothesis 1a: Participants randomized to prazosin will manifest greater benefit on the primary 
outcome measure – the ADCS-Clinical Global Impression of Change-Agitation (ADCS-CGIC-A) 
anchored to disruptive agitation. 
Hypothesis 1b: Participants randomized to prazosin will manifest greater benefit on the key 
secondary outcome measure – the Neuropsychiatry Inventory. 
Hypothesis 1c: Participants randomized to prazosin will receive a lower total dose of lorazepam 
“rescue medication” administered during the trial. 
Hypothesis 1d: Study discontinuation (“dropout”) due to persistent or worsening intolerable 
disruptive agitation will occur sooner in the placebo group than in the prazosin group. 
Hypothesis 1e: There will be larger proportion of responders to prazosin (defined as moderate 
or marked improvement) vs non-responders (defined as minimal improvement; no change; or 
minimal, moderate, or marked worsening) on the ADCS-CGIC-A. 
Hypothesis 1f: The incidence of adverse events (AEs) will not differ between participants 
randomized to prazosin and those randomized to placebo. 


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Specific Aim 2 (Secondary Aim): To evaluate the impact of prazosin treatment for disruptive 
agitation on participants’ function. 
Hypothesis 2: Participants randomized to prazosin will manifest greater benefit on the ADCS-
Activities of Daily Living-Severe Dementia version (ADCS-ADL-Severe). 
Specific Aim 3 (Secondary Aim): To evaluate the impact of prazosin treatment for disruptive 
agitation on the LTC environment or home caregiver distress in the home caregiving 
environment 
Hypothesis 3: Participants randomized to prazosin will have a greater reduction in the NPI-NH 
“occupational disruptiveness”/NPI “caregiver distress” items. 
Specific Aim 4 (Exploratory Aim): To evaluate the ability of the CMAI to detect prazosin 
effects on signs and symptoms of disruptive agitation in AD. The CMAI was developed to 
provide a detailed frequency assessment of 29 signs and symptoms of agitation in persons with 
dementia. It has been sensitive to treatment effects in other agitation randomized controlled 
trials. 
Hypothesis 4: Participants randomized to prazosin will manifest greater benefit on the CMAI. 
Similar analyses to that described for the primary analysis will be performed on the CMAI. An 
MMRM analysis will compare active vs placebo at 12 weeks. 
Specific Aim 5 (Exploratory Aim): To evaluate the ability of five noradrenergic activity-relevant 
NPI/NPI-NH behavioral domains (Agitation/Aggression, Anxiety, Disinhibition, Irritability/Lability, 
and Aberrant Motor Behavior) to detect prazosin effects on disruptive agitation in AD. 
Hypothesis 5: Improvement in the five domain NPI/NPI-NH subset score will have a greater 
effect size in response to prazosin treatment than the 12-domain NPI-NH total score. 
Specific Aim 6 (Exploratory Aim): To examine locomotor activity and nighttime sleep 
continuity as measured by wrist actigraphy (e.g., accelerometry) in a subset of study 
participants over the 24-hour period and the 12-hour nighttime period for each week during the 
12-week study duration.  
Hypothesis 6: Participants randomized to Prazosin will manifest greater improvement in sleep 
continuity during the 12-hour nighttime period and at each week during the 12-week study 
duration. 
5 
STUDY DESIGN 
5.1 Study Population  
The trial as initially designed included up to 186 participants with probable or possible AD and 
disruptive agitation. Before the COVID 19 pandemic in March 2020, it was intended that the trial 
be conducted in the LTC setting exclusively. However, following the COVID 19 pandemic the 
trial was redesigned to allow participants to be recruited from either the LTC setting or at home 
with full-time caregiving. (protocol amendment v8). Furthermore, with the impact of the 
pandemic the feasibility of enrolling this study sample was reviewed and a redesignation of the 
trial as a pilot study with a revised sample size of between 25-80 participants was made (see 
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5.2 Participating Sites 
ADCS site PIs will collaborate with one or several local LTC facilities where study participants 
reside and will also identify participants who reside at home with full-time caregiving. The ADCS 
will serve as the Coordinating Center for the study. Approximately 12-18 ADCS sites will 
participate in this trial, each of which may have an associated 1-4 long-term care (LTC) facilities 
and/or serve a population of AD patients with disruptive agitation still residing at home with full-
time caregiving. LTC is defined as assisted living or skilled nursing facility. Home-dwelling 
participants must have a primary caregiver who supports and lives with them at home, and who 
will act as the Study Partner. The Study Partner may or may not be the LAR. They may have 
additional assistance from paid or unpaid caregivers. The Study Partner must agree to and in 
the opinion of the site PI be able to provide information for study assessments, measure 
participant blood pressure and heart rate, oversee administration of study medication and 
rescue lorazepam under direction of the site PI, maintain regular contact with study team, 
participate in study visits, and report adverse events. 
5.3 Inclusion Criteria 
Participants must meet all of the following criteria be included in the study: 
1. Men and women with probable or possible AD by NINCDS-ADRDA criteria utilizing 
history; medical records review; physical and neurological exam; and laboratory tests (as 
applicable). Brain neuroimaging is not a requirement. 
2. Participants must either reside in an LTC that is associated with the study site or at 
home with full-time caregiving. 
3. Participants must have disruptive agitation significant enough to disrupt caregiving and, 
in the opinion of the Site Principal Investigator, to justify treatment. Disruptive agitation, 
defined as having any combination of the following target behaviors, must have occurred 
nearly daily during the previous week and at least intermittently for 4 weeks prior to 
screening:  
a) irritability, 
b) physically and/or verbally aggressive behavior, 
c) physical resistiveness to necessary care  
d) pressured motor activity (e.g., pressured pacing)  
These behaviors must be problematic in that they cause participant and caregiver 
distress and/or interfere with essential care or disrupt their living environment. Target 
behaviors may be any combination of the listed domains. Disruptive agitation must meet 
this threshold at Screening, documented on the Behavioral Inclusion Criteria Checklist.  
4. Psychotropic medication, if used, should be stable for at least 2 weeks prior to 
randomization.  
5. If taking cholinesterase inhibitor and/or memantine, must be on stable dose for 3 months 
prior to randomization. 
6. During the week before randomization, the above-described behaviors of eligible 
participants must be rated as of at least “moderate” severity.  
5.4 Exclusion Criteria  
Participants meeting any of the following criteria must not be included in the study: 


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1. History of schizophrenia, schizoaffective disorder, or bipolar disorder according to the 
criteria of the most current version of the Diagnostic and Statistical Manual of Mental 
Disorders (DSM). 
2. Other neurodegenerative diseases, including Parkinson’s disease and Huntington’s 
disease, or cerebral tumor.  
3. Dementia other than probable or possible AD per NINCDS-ADRDA criteria, such as 
human immunodeficiency virus (HIV) dementia, Creutzfeldt-Jakob disease, 
frontotemporal dementia, multiple cerebral infarctions, or normal pressure 
hydrocephalus. 
4. Current treatment for seizure disorder (Note: anticonvulsants prescribed for disruptive 
agitation in the absence of seizure disorder will be allowed). 
5. Abnormal laboratory values with clinical significance in the opinion of the site Principal 
Investigator. 
6. Current unstable medical illness including delirium, worsening congestive heart failure, 
unstable angina, recent myocardial infarction (within the past 3 months), acute infectious 
disease, severe renal or hepatic failure, severe respiratory disease, metastatic cancer, 
or other conditions that, in the Site Principal Investigator’s opinion, could interfere with 
the analyses of safety and efficacy in this study. 
7. Bedbound; participants may be ambulatory or use a wheelchair. 
8. Absence of any comprehensible language. 
9. Participation in another clinical trial for an investigational agent and took at least one 
dose of study drug (unless unblinded on placebo) within 12 weeks prior to screening. 
(The end of a previous investigational trial is defined as the date of the last dose of an 
investigational agent). 
10. Preexisting recurrent hypotension (systolic BP <110). 
o If a reading of <110 systolic is measured at screening,  
 
If the individual is taking antihypertensive medication: The Site PI should 
reassess the need for such medication and consider medication 
adjustments in consultation with the participant’s physician. One week 
following adjustment of antihypertensive(s), screening BP will be repeated 
for reassessment of eligibility. Further adjustment of antihypertensive 
medication regimen by the participant’s health care prescriber, may be 
indicated if systolic pressure remains <110. For inclusion, new systolic 
measurement following medication adjustment must be ≥110.  
 
If the individual is not taking antihypertensive medication: repeat at least 3 
BP measures over the course of 7-14 days. For inclusion, all three follow-
up systolic measurements must be ≥110. 
 
Any systolic reading <100 is exclusionary.  
11. Preexisting orthostatic hypotension (>20 mmHg drop in systolic BP following 2 minutes 
of standing posture [or sitting if unable to stand] and accompanied by dizziness, 
lightheadedness, or syncope). 
12. A 2-week washout is required prior to BL for the following exclusionary medications: 
prazosin or other alpha-1 blocker, sildenafil, vardenafil, tadalafil, and avanafil. 
13. Women of childbearing potential are not included in this study.  Women of non-
childbearing potential are defined as any of the following:  
o have been postmenopausal (no menstrual cycle for past 24 months)  
o do not have a uterus,  


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o have bilateral tubal ligation,  
o have undergone bilateral salpingectomy, and/or bilateral oophorectomy 
14. The participant may not be an immediate family member of personnel directly affiliated 
with this study, the study site or funding agency. Immediate family is defined as a 
spouse, parent, child, or sibling, any of whom may be related by blood, adoption, or 
marriage. 
15. Participants whom the Site Principal Investigator deems to be otherwise unsuitable for 
participation. 
5.5 End of Study/Participant Withdrawal/Early Study Termination 
A study participant will be considered to have completed this study at the end of 12 weeks of 
treatment (i.e., Week 12 or end of study). In the event of withdrawal or early study termination, 
participants will complete the Week 12 or end of study assessments as defined in Appendix 2. 
Withdrawal/early termination assessments will be completed as soon as possible; if safety is a 
concern, withdrawal/early termination assessments can be omitted. Caregivers will be instructed 
to report any newly occurring or changes in previously reported AEs and SAEs that occur 
between the early termination visit and 30 days after the last dose to the ADCS Site Study 
Coordinator or designee. Withdrawn participants will not be replaced in the study population.  
5.5.1 Reasons for Early Termination 
Participants may be terminated from study participation for reasons such as: 
1. Death 
2. AEs. The participant has experienced an intolerable AE that, in the opinion of the Site 
Principal Investigator, requires early study discontinuation or participant cannot tolerate 
a minimum of 1 mg BID of study drug. 
3. Protocol violation. The participant fails to meet protocol entry criteria or did not adhere to 
protocol requirements. 
4. Non-compliance. The participant is non-compliant with intake of study drugs.  i.e., does 
not take any study drug for more than 7 consecutive days. 
5. Consent is withdrawn. The participant wishes to withdraw from the study, or the LAR 
wishes the participant to be withdrawn. 
6. Withdrawal by Site Principal Investigator. Consult the Medical Monitor for withdrawal for 
other reasons. 
7. Coordinating Center request.  The ADCS Coordinating Center determines it is in the 
participant’s best interest to discontinue participation from the study. 
8. Study termination. The PEACE-AD study is terminated by the ADCS, alone or at the 
recommendation of the Project Co-Directors, Data Safety Monitoring Board (DSMB), NIA 
or NIA Program Official. 
6 
STUDY DRUG AND COMPARATOR 
6.1 Name and Description of Investigational Product (IP) and Comparator 
Commercially available prazosin HCl 1 mg and 2 mg capsules and inactive matching placebo 
capsules will be used in this study. 


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6.1.1 Formulation Packaging and Labeling  
Prazosin or placebo (“study drug”) is provided as 1 mg and 2 mg capsules. Dispensing will allow 
for 7 days of dosing at QAM and QHS from BL up to Week 6 and then 14 days of dosing at 
QAM and QHS from Week 6 until Week 12 completion (or early termination). The supplies will 
be labeled in accordance with all applicable guidelines and/or regulations and will be blinded as 
to participant treatment assignment.  
6.1.2 Mode of Administration   
Study drug will be orally administered (PO) and is ideally intended to be swallowed whole. Study 
drug administration may be assisted by applesauce or similar food if that allows the drug to be 
swallowed whole. However, if a participant cannot swallow the capsules whole, an alternative is 
to open the capsules and administer with food. In the LTC setting, this will be done by an 
unblinded study team member. In the home setting, the blind is maintained even if the capsule 
is opened, because the caregiver will not be exposed to both the active and placebo forms of 
study drug. 
In the LTC setting, each site will create and document procedures to protect the study blind with 
the designation of an unblinded individual who will administer study drug that has been opened 
and mixed with food (e.g., applesauce or pudding) to participants. This method of study drug 
administration will only be followed when participants are unable to swallow the capsules whole. 
Unblinded individuals involved in opening the capsules and mixing with food will not provide 
information for any blinded ratings. 
6.1.3 Shipping, Storage and Handling of IP  
Study drug will be shipped directly from the study drug warehouse to the ADCS site 
investigational or research pharmacist once the site has been granted ADCS approval to enroll. 
Upon receipt of the study drug shipment at the ADCS site, the pharmacist or delegated site staff 
will verify the condition of the study drug supplies, register the study drug via the Oracle 
Interactive Response Technology (IRT) system, and document receipt per instructions in the 
Procedures Manual.  
Once a new study participant has been randomized, the ADCS site pharmacist will prepare the 
individual participant prescription based on designated treatment arm assignment at the lowest 
dose level per protocol, 1mg QHS (see Section 6.2.1). Study drug supply will be dispensed per 
the number of dosing days as described in Section 6.1.5. Study drug will be packaged and 
labeled in accordance with local pharmacy standard procedure.  
The prepared initial study drug prescription will be dispensed to the ADCS Site Study 
Coordinator or delegated site staff for either transport or secure mailing to the LTC facility or 
home caregiver. For participants residing in an LTC, responsible research team member at the 
LTC will be designated to receive participant study drug from ADCS Site Study Coordinator or 
delegated site staff upon arrival at the LTC facility. LTC facility staff will document their receipt of 
the study drug for each participant as it is received.  LTC facility staff or home caregiver will be 
responsible for individual participant dose administration. 
At each weekly or bi-weekly study drug dispensing interval, the site pharmacist will prepare 
subsequent prescriptions for each participant based on the current dose titration level 
determined by the prescribing clinician and in accordance with the dose titration schedule 


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described in Section 6.2.1. Subsequent prescriptions for each participant will be prepared, 
transported or mailed and documented in the same manner as the initial study drug prescription. 
At the time of each study visit, the ADCS Site Study Coordinator or delegated site staff will 
return unused study drug from the previous dispensing interval to the ADCS site pharmacy. For 
participants residing in an LTC, the ADCS Site Study Coordinator or delegated site staff will 
receive any unused study drug from the LTC or home caregiver from the previous dispensing 
interval for return to the ADCS site pharmacy.  
All study drug-related transactions at the ADCS site and LTC facility or home caregiver will be 
documented by delegated study team staff on Drug Accountability Logs provided by the ADCS.  
Further instructions related to the chain of custody for study drug are detailed in the study 
Procedures Manual. 
Study drug must be stored in a limited access area at LTC facilities or safely in the home 
caregiving setting at room temperature (15-30 °C; 59-86 °F). Only authorized site study 
personnel or the home caregiver may access study drug. 
Based on local differences in the logistical relationships between ADCS sites and LTC facilities 
or home caregivers, alternative scenarios for the study drug chain of custody may be 
considered on a case-by-case basis with Project Directors and ADCS Coordinating Center. 
6.1.4 Replacement Procedures for IP  
Instructions for resupply shipments or replacement of study drug are referenced in the 
Procedures Manual.  
6.1.5 Study Drug Dispensing  
One week of study drug will be dispensed at the at the in-person or remote BL Visit (Day 1). The 
study staff, either at the site clinic or LTC, either in person or via remote visit, will follow the 
dosing titration procedures as outlined in Section 6.2 of this protocol. To allow a window for 
study visits, 7 days of study drug plus a 1-day extra supply will be provided at the BL, Day 8, 
and Day 15 titration visits. From Day 22 through Week 5, 7 days of study drug plus a 2-day 
extra supply will be provided at each visit. From Week 6 until Week 12 (or early termination), 14 
days of study drug plus a 2-day extra supply will be provided at each visit either in person or by 
mail. For participants residing in an LTC, LTC staff will maintain the study drug supply and 
administer study drug to the participant. For home-dwelling participants, their caregiver will 
administer study drug to the participant. Each participant’s drug supply will be dispensed 
according to the randomization ID assigned by the ADCS Electronic Data Capture (EDC) 
system. 
6.1.6 Accountability and Return of IP  
It is the responsibility of the ADCS Site Principal Investigator to oversee accurate monitoring of 
the receipt, storage, dispensing, and accounting of all study drug according to accepted medical 
and pharmaceutical practice. Copies of all invoices of study drug shipments must be retained. 
Accurate, original records of study drug inventory and dispensing must be maintained using 
drug accountability logs provided by ADCS. 
All study drug receipt, dispensing, return and destruction documentation related to Site Drug 
Accountability must be kept in investigational or research pharmacy records at the ADCS site.  
For participants residing in an LTC, the LTC facility will maintain medication dispensing records. 
For home-dwelling participants, the Study Partner will document medication doses dispensed in 


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a medication log. All study drug receipt and return documentation related to LTC Facility Drug 
Accountability will be retained by the ADCS Site Study Coordinator or delegated site staff. All 
disposition records must be made available for inspection by ADCS or its representatives upon 
request. Drug Accountability Logs will be provided by ADCS for the accounting of study drug for 
each study participant and for maintaining the overall balance. A reason(s) must be given for 
any capsules that are not accounted for. Any unused study drug assigned to participants for the 
previous 7-day dosing period from BL to Week 6 or 14-day dosing period from Weeks 6-12 (or 
early termination) will be collected, and a new supply of study drug will be dispensed. The 
ADCS Site Study Coordinator or delegated site staff will inspect all returned study drug and will 
record the number of used and unused capsules on the electronic case report form (eCRF) and 
the Drug Accountability Logs. Each ADCS site must keep all used and unused study drug in 
their original containers for inspection by the Study Coordinator and until the ADCS monitor 
performs drug accountability during a site visit. If any unused capsules remain at the end of the 
study, they will be accounted for at the site close-out visit in the presence of the ADCS monitor. 
Once authorized by the ADCS monitor, during an interim monitoring visit or close-out visit, 
unused study drug may be destroyed at the ADCS site according to the site drug destruction 
policy. 
6.2 Dosing Administration and Schedule 
6.2.1 Study Drug Dose Escalation  
The dose titration schedule is divided into a fixed dose titration phase from Day 1-14 and a 
flexible dose titration phase from Day 15-29, followed by a maintenance dose period for the 
remainder of the 12-week study. An algorithm-based dose titration procedure to optimum dose 
prazosin or placebo (maximum dose 4 mg QAM and 6 mg QHS for 10 mg TDD) will be 
employed. The Project Directors may be contacted (see contact information on Page 2 of this 
protocol) at any point throughout the trial for any questions or cases in need of additional 
support on dosing decisions. 
Table 3. Dose titration schedule 
Day(s) 
AM Dose (QAM) 
Bedtime Dose (QHS) 
1-3 
none 
1 mg 
4-7 
1 mg 
1 mg 
8-10 
1 mg 
2 mg 
11-14 
2 mg 
2 mg 
15-21 
3 mg 
3 mg 
22-28 
4 mg 
4 mg 
29 
4 mg 
6 mg 
Dose increases will be allowed only during the fixed and flexible dosing period (Days 1-29). No 
further dose escalation will be allowed throughout the maintenance period (Day 30 through 
study completion or early termination). Dose escalation must occur in a step-wise manner, 
increasing a single-dose level at a time. 
The first dose of study drug (1 mg QHS) must be administered to the study participant only after 
all assessments are performed for the BL Visit. Study drug will be administered QHS on study 


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Days 1-3. On study Day 4 and for the remainder of the 12-week study (study completion) or until 
early termination, study drug will be administered twice daily (at approximately mid-morning and 
QHS).  The time and date of each study drug administration will be recorded in the LTC 
medication records by LTC staff for LTC-dwelling participants and on the medication log by the 
Study Partner for home-dwelling participants. Study drug can be taken without regard to food 
consumption. 
6.2.1.1 Fixed Dose Titration 
A starting dose of prazosin 1 mg QHS will be administered for three days (Days 1-3). During 
fixed dose titration, the dose will be gradually increased to 1 mg QAM and 1 mg QHS (Days 4-
7), then to 1 mg QAM and 2 mg QHS (Days 8-10), and then to 2 mg QAM and 2 mg QHS (Days 
11-14) in the absence of unacceptable AEs. When the end of the fixed dose titration phase is 
completed, the participant may begin the flexible dose phase. Note: LTC staff for LTC-dwelling 
participants and Study Partners for home-dwelling participants will be instructed in safety 
precautions for administration of initial dose and up-titrated doses of study drug.  
6.2.1.2 Flexible Dose Titration 
During the flexible dose titration phase (Days 15-29), two conditions must be met for the study 
drug dose to be increased: 
1. The participant does NOT have “marked improvement” in agitation/aggression behaviors 
as determined by the Clinician-Rated Change in Behavioral Symptoms Assessment. 
Marked improvement is defined as complete or almost complete resolution of symptoms 
of disruptive agitation. 
2. The participant does NOT have unacceptable AEs on the Adverse Symptom Checklist 
and does not have hypotension or orthostatic hypotension as defined above.  
If both conditions are met, dose increases will occur on Day 15 to 3 mg QAM and 3 mg QHS, on 
Day 22 to 4 mg QAM and 4 mg QHS, and finally on Day 29 to a maximum of 4 mg QAM and 6 
mg QHS for a TDD of 10 mg.  
Participants who are rated as having “marked improvement” prior to achieving the maximum 
allowed dose per the titration schedule and who then have reemergence of agitation symptoms 
will be allowed to increase the dose during the titration period following the specific dose 
increments in Table 3 until Day 29. No further dose increases will be allowed after Day 29. 
Lorazepam exception: If the participant received a dose of lorazepam within 48 hours of the 
dose titration visit, the study drug dose will be increased unless the participant is experiencing 
an unacceptable AE on the Adverse Symptom checklist or has hypotension or orthostatic 
hypotension. The dose will increase regardless of rating as “marked improvement” or any other 
rating. 
6.2.2 Dose Reductions and Re-Challenges 
If the participant experiences an unacceptable or intolerable AE during the dose titration period, 
the dose will be reduced to the last tolerated dose (dose reduction per Table 4) until the side 
effects remit, or are acceptable/tolerable. For safety purposes, the dose may be decreased at 
any time throughout the study. 
Specifically, in the event of orthostatic hypotension, a dose increase cannot occur if the 
orthostatic blood pressure measurement reveals a 20 mm Hg or greater drop in systolic blood 


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pressure after two minutes of upright posture (or after two minutes of sitting if unable to stand). 
The Clinician Prescriber and ADCS Site PI (if different from Clinician Prescriber) must be 
informed by LTC staff or Study Partner of any drop in systolic blood pressure by 20 mm Hg or 
more. The dose will either be maintained at the current level or decreased to the last tolerated 
dose based on clinical judgment of the Clinician Prescriber. The Clinician Prescriber will assess 
associated factors (such as intercurrent illness, hot weather, dehydration) in response to the 
orthostatic hypotension and utilize clinical judgment in determining best course of action, such 
as temporarily not administering a dose of study drug, reducing the dose, or possible dose re-
challenge following symptom resolution.  
If the AE resolves at the lower dose, the Site Principal Investigator utilizing clinical judgment 
may choose to re-challenge with the higher dose. A re-challenge is permitted only during the 
dose titration period (Days 1-29), according to the dose titration steps described in Table 3 
above. A maximum of two dose re-challenges is allowed. Requests for additional dose re-
challenge (more than two times during dose titration period) may be submitted to the ADCS 
Coordinator Center, and will be reviewed on a case-by-case in consultation with the Project 
Directors.  
Dose reductions and re-challenges must occur in a step-wise manner, with doses as outlined in 
Tables 3 and 4. 
Table 4: Dose reductions 
Current Dose 
Dose Reduction 
Midmorning 
QHS 
Midmorning 
QHS 
 
1 mg 
Study 
Discontinuation 
Study 
Discontinuation 
1 mg 
1 mg 
 
1 mg 
1 mg 
2 mg 
1 mg 
1 mg 
2 mg 
2 mg 
1 mg 
2 mg 
3 mg 
3 mg 
2 mg 
2 mg 
4 mg 
4 mg 
3 mg 
3 mg 
4 mg 
6 mg 
4 mg 
4 mg 
If the participant is not able to tolerate a minimum of 1 mg twice per day (BID) of study drug, he 
or she will undergo early termination procedures.  
6.2.3 Overdose  
For the purposes of this study, an overdose of study drug is defined as ingestion by a study 
participant of more than the daily dose prescribed per 24-hour period. Any overdose event must 
be reported on the Protocol Deviation eCRF. Any AEs related to the overdose must be reported 
on the AE and/or SAE eCRF. An overdose that is associated with an AE will be analyzed as an 
AE. Refer to the eCRF Completion Guidelines for details.  


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6.2.4 Study Drug Orders 
Study drug orders will be written per the Titration Schedule. To allow a window for study visits, 7 
days of study drug plus a 1-day extra supply will be provided at the BL, Day 8, and Day 15 
titration visits. From Day 22 through Week 5, 7 days of study drug plus a 2-day extra supply will 
be provided at each titration visit. From Week 6 until Week 12 (or early termination), 14 days of 
study drug plus a 2-day extra supply will be provided at each titration visit. Study drug orders will 
include mid-week dose changes per the titration schedule above. See Procedures Manual for 
details regarding study drug orders. 
 
 


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7 
METHODS OF ASSIGNING PARTICIPANTS TO TREATMENT 
GROUPS 
7.1 Randomization 
Eligible participants per site will be randomized using a 2:1 schedule to prazosin or placebo and 
stratified by site and gender.  
7.2 Blinding/Masking 
7.2.1 Blinding at the Study Site  
This study is a double-blind, randomized, placebo-controlled trial. Study treatment group 
information (prazosin or placebo) will remain blinded to the participant, family members, family 
or paid or unpaid home caregivers, and all members of the study team (e.g., Site Principal 
Investigators, Study Coordinators, Research Nurses, and LTC facility staff) until participant 
study completion (completion at week 12 or early termination). ADCS periodic safety reviews 
will be performed in a blinded manner unless the data warrant unblinding due to safety 
concerns. The treatment code may be broken (unblinded) between randomization and study 
termination if that knowledge, i.e., knowing exactly which study drug the participant is taking, is 
essential to the medical management of the participant. Procedures for emergency unblinding 
are described below. These procedures ensure that neither ADCS monitoring staff nor the Site 
Principal Investigator(s), other site and/or LTC facility staff or home caregivers have premature 
access to the study participants’ treatment assignments.  
7.2.2 Premature Unblinding of Study Participants in the Event of a Medical Emergency  
Only in the case of an emergency, when knowledge of whether the participant has received the 
investigational product is essential for the clinical management or welfare of the participant, may 
the investigator request to unblind a participant’s treatment assignment. If the investigator needs 
the blind to be unmasked for a participant for any reason, the investigator must contact the 
ADCS Medical Monitor (and/or Project Directors) to obtain an approval. The blind will need to be 
broken centrally at the ADCS Coordinating Center. If the blind is broken, whether it be by 
accident or for the welfare of the participant, the investigator MUST contact the ADCS Medical 
Monitor. The Site Principal Investigator or designee must report every instance of unblinding to 
ADCS within 24 hours. When premature breaking of the blind occurs, whether accidental or for 
participant safety, the Blind Break Notification Form must be completed and submitted to ADCS 
by fax. Refer to the Procedures Manual for more detailed procedures related to breaking the 
blind and reporting requirements. The Site Principal Investigator or designee is responsible for 
ensuring that the instructions on how to perform a blind break are stored safely, that their 
location is known, and that access is readily available to the relevant staff in case of an 
emergency. Breaking the blind for medical necessity is extremely rare.  
Any other reason to reveal a participant’s treatment identity prior to the participant’s study 
completion or early termination must be approved by ADCS. If unblinding is necessary, an early 
termination visit should be completed prior to blind breaking whenever possible.  All instances of 
premature unblinding by the study site must be documented on the eCRF.  
7.2.3 Breaking the Blind for Individual Participants at Study Completion or Early Termination  
At the participant’s study completion, the study drug assignment for each participant will be 
unblinded by the Site Principal Investigator or designee. Breaking of the blind for an individual 


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study participant will occur after completion of the end of study visit (Week 12) or after 
completion of early termination visit procedures. A participant may early terminate from the 
study according to the reasons listed in Section 5.5 of this protocol only.  
The necessity for breaking the blind is based on patient care and safety requirements related to 
discontinuation of active study drug, prazosin, and to provide for optimal follow-up management 
by the participant’s health care provider/LTC facility. The pilot study found that important clinical 
factors in the treatment of these difficult to manage patients argues for breaking the blind to 
provide optimal post-study management. Treatment with prazosin in individual participants 
following completion of study requirements is at the discretion of the participant’s treating 
clinician. There are no provisions for open-label extension use of prazosin within this protocol.  
It should be emphasized that the Clinician Rater, who will perform all outcome assessment 
measures, will be kept blind to all participants’ study drug assignments, rescue lorazepam, 
adverse effects, and vital signs throughout the study. 
8 
PARTICIPANT COMPLIANCE 
8.1 Compliance 
Study drug compliance will be reviewed by the Study Coordinator weekly by two means: review 
of the medication dispensing records and by capsule counts. Any drug lost will also be recorded 
by the site. Percent compliance will be calculated. Less than 80% compliance at each study visit 
will be documented as a protocol deviation. 
If a participant has taken no study drug for 3 or more consecutive days, the Clinician Prescriber 
or designee must contact the Project Directors or designee for re-titration instructions. If the 
participant has taken no study drug for more than 7 consecutive days, the participant will be 
early terminated from the study. 
8.2 Allowed Concomitant Psychoactive Medications 
Participants may continue on stable dose of psychotropic medications at the dose the 
participant is receiving at enrollment. The dose must be stable for 2 weeks prior to 
randomization. For cholinesterase inhibitors (donepezil [Aricept], rivastigmine [Exelon], or 
galantamine [Razadyne], memantine [Namenda], and/or donepezil/memantine [Namzaric]) a 
stable dose for 3 months prior to randomization is required.  
8.3 Rescue Lorazepam 
Lorazepam is the only medication allowed as a “rescue” medication during the 12-week study 
treatment period. In the LTC setting, lorazepam to be provided by the participant’s primary care 
provider, who will be responsible for any necessary discussion of lorazepam use and possible 
benefits versus risks with the participant and legally authorized representative (LAR). In the 
outpatient home setting, lorazepam will be prescribed by the site PI and dispensed by the 
caregiver. This exact approach has been successfully and safely used as a “rescue strategy” in 
the CitAD outpatient study of the antidepressant citalopram for agitation in Alzheimer’s 
disease13. No other rescue medications to treat agitation will be allowed during the 12-week 
treatment period. 
Rescue lorazepam 0.5 mg PO (may be taken twice for a total dose of 1.0 mg/day) is allowed as 
a rescue medication for moderate to severe disruptive agitation for a maximum of 21 days 
during the 12-week treatment period. In the LTC setting, rescue lorazepam use will be 


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documented per medication dispensing records as per usual care. Doses of lorazepam will be 
recorded on the Lorazepam Source Document Worksheet for both LTC and home-dwelling 
participants.  
8.4 Prohibited Concomitant Medications  
Use of any prohibited concomitant medication will result in early termination.  
Prohibited concomitant medications include: 
• 
Prazosin or other alpha-1 blocker  
• 
Sildenafil, vardenafil, tadalafil or avanafil is prohibited starting 2 weeks prior to BL. Any 
of these drugs combined with prazosin may increase risk of hypotension and/or priapism  
• 
Current or past enrollment in an investigational drug trial with at least one dose of study 
drug taken within 12 weeks of screening  
Note that the initiation, dose increase, or dose decrease of any psychoactive medication 
other than allowed rescue lorazepam (for a maximum of 21 days) after BL is prohibited 
and will result in early termination from the study. 
9 
PHARMACOKINETICS (PK) OF PRAZOSIN 
Absorption:   Prazosin is well absorbed from the gastrointestinal tract with an average of 60% 
(43 -82%). Prazosin is not affected by food. After oral administration, the time to peak plasma 
concentration is 1-3 hours. Prazosin plasma concentrations usually do not correlate with 
therapeutic effect. 
Distribution:  Protein binding is very high at 92% to 97%. Volume of distribution is approximately 
0.5 – 0.9 L/kg. 
Metabolism: Prazosin in metabolized extensively in the liver. The major pathways are 
demethylation and conjugation, and it is excreted unchanged or as metabolites. The major 
metabolite O-demethylated metabolite accounts for 75% to 80% of elimination; minor 
metabolites account for about 2% to 10% of elimination. The active metabolite is the major 
metabolite; all metabolites are less active than prazosin in lowering blood pressure. CYP450 is 
unknown. The plasma half-life has been reported to be 2-4 hours after oral ingestion.  
Excretion: Prazosin is mostly excreted in bile and feces (< 90%) with 6% to 10% in urine. 5% to 
11% is excreted as unchanged drug and the remainder as metabolites. Elimination is slower in 
congestive heart failure patients.  
10 STUDY ASSESSMENTS AND PROCEDURES 
A skilled and experienced Clinician Rater who is blinded to treatment assignment, adverse 
events, vital signs, and doses of rescue lorazepam administered will conduct interview-based 
and cognitive assessments using the ADCS-CGIC-A, NPI/NPI-NH, and ADCS-ADL. Results of 
all study assessments described below will be captured on the eCRF through the ADCS EDC 
system. Note: Because of COVID-19 access restrictions and/or safety precautions, interviews 
for ratings may be performed by remote visit. 


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10.1 ADCS-Clinical Global Impression of Change in Agitation (CGIC-A)  
The ADCS-CGIC-A is the primary outcome measure. It will be anchored to disruptive agitation, 
the target behaviors in this study. It measures whether the effects of active treatment are 
substantial enough to be detected by a skilled and experienced clinician on the basis of both 
observation of the participant and an interview of the participant’s primary caregiver, and for 
participants residing in an LTC, other facility staff. The participant is rated on a 7-point Likert 
scale, ranging from 1 (marked improvement) to 4 (no change) to 7 (marked worsening). The 
ADCS-CGIC has demonstrated clinical utility in assessing change in AD clinical trials, and is 
considered a test for clinically meaningful change.31 It is a highly reliable measure that provides 
a clinically meaningful overall assessment of improvement (or worsening) of the target 
behavioral problems.  
At the BL visit, the Clinician Rater will fill out the ADCS-CGIC-A Baseline Worksheet which will 
provide detailed information on the target symptoms of irritability, physical and/or verbal 
aggressive behavior, physical resistiveness to necessary care, and pressured motor activity. 
Information from the primary caregiver, and for LTC residents, the LTC primary informant and 
other staff, as well as observation of the participant, will be used to provide detailed information 
on frequency and severity of symptoms and impact on caregiver(s). Subsequent outcome 
assessment visit ratings on the ADCS-CGIC-A will use this information to make comparisons to 
symptoms at BL. 
10.2 Neuropsychiatric Inventory (NPI, home care setting) and Neuropsychiatric Inventory–
Nursing Home version (NPI-NH, LTC setting) 
The NPI/NPI-NH is the key secondary outcome measure. The NPI was designed to characterize 
the neuropsychiatric symptoms and psychopathology of patients with AD and other dementias 
residing in the community about which information was obtained from family caregivers. The 
content of the questions and their scoring in the NPI-NH are identical to those of the NPI except 
for some slight rephrasing to be consistent with the LTC environment where information is 
gathered from professional caregivers.32  Assessment of the impact of behavioral disturbances 
on family and professional caregivers, is assessed by a “caregiver distress” scale in the NPI and 
an “occupational disruptiveness” scale in the NPI-NH; scoring of this component remains 
identical. 
10.3 ADCS-Activities of Daily Living–Severe Dementia version (ADCS-ADL-Severe) 
The ADCS-ADL-Severe questionnaire is a secondary outcome measure aimed at detecting 
functional decline in people with severe AD. It was developed as a result of a research project 
funded by the NIA and conducted by the ADCS to develop cognitive and functional instruments 
for the assessment of participants with AD with relevance to clinical trials.33 This scale is best 
suited for evaluating people with MMSE scores below 15/30, or equivalent.  Questions are 
administered to a qualified caregiver informant about a set of 19 basic and instrumental ADL. 
Instrumental ADL are selected to be relevant to this level of severity of dementia, e.g., obtaining 
a beverage, turning lights on and off, turning a faucet on and off. Performance of each of these 
activities during the past 4 weeks, as well as the level of performance, are rated. A total score is 
derived by summing scores across items, and ranges from 0 (maximal impairment) to 54 
(maximally independent function). 


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10.4 Cohen Mansfield Agitation Inventory (CMAI) 
The CMAI is an exploratory outcome measure for estimating frequency of agitated behaviors. 
The CMAI assesses the frequency of agitated behaviors in elderly persons and was developed 
for use in the LTC facility. The CMAI will be administered by the Clinician Rater who interviews 
LTC staff for LTC residents and the Study Partner for home-dwelling participants. The CMAI 
rates 29 agitated behaviors, each on a 7-point scale of frequency ranging from “never” to 
“several times per hour.” Ratings pertain to the 2-week period preceding the rating37. The CMAI 
will be completed at baseline and study termination. 
10.5 Total mg Lorazepam Administered and Study Days Completed. 
 
Information on the total mg rescue lorazepam administered and number of study days 
completed will be collected as additional secondary outcome measures. If prazosin is more 
effective than placebo, it is predicted that participants randomized to prazosin will be prescribed 
lower cumulative mg of rescue lorazepam for management of persistent or worsening disruptive 
agitation. Similarly, given that dropout from the study is an option if disruptive agitation remains 
unmanageable or worsens at the highest tolerated dose of study drug, it is reasonable that if 
prazosin is more effective than placebo, that participant dropout for persistent/increased 
disruptive agitation will occur sooner in the placebo group than in the prazosin group.  
10.6 Treatment Blinding Questionnaire  
The Treatment Blinding Questionnaire was created by the ADCS to assess the perception of 
blind being maintained until the end of the study. The questionnaire is to be completed by the 
Site Principal Investigator, Clinician Prescriber, Clinician Rater, and Caregiver at the end of 
study. 
10.7 Physical and Neurological Examination  
A medically qualified professional (may be MD, DO, ARNP, or PA-C) will perform a brief 
physical examination that addresses the major body systems (i.e., head/ears/eyes/nose/throat, 
cardiovascular, pulmonary, abdomen, musculoskeletal, and extremities). Neurological 
examination will include an assessment of cranial nerves, strength, coordination, reflexes, 
sensation, tremor, and gait. Because many agitated AD participants may not be cooperative 
with the physical exam, a recent documented physical exam (within the previous 12 months), 
together with observation of the participant at the screening visit, can be used to determine 
eligibility by the Site Principal Investigator. 
Height and weight will be recorded at screening. If participant is unable to stand for height 
and/or weight measurement, it will be obtained from medical records. Weight measurement will 
be repeated at 12 weeks.  
10.8 Electrocardiogram (ECG)  
A 12-lead ECG performed within one year prior to screening may be used for eligibility 
determination if available. The ECG must be reviewed, signed, and dated by the Site Principal 
Investigator (or a qualified designee). Those with clinically significant ECG findings will be 
referred for follow-up as deemed appropriate by the Site Principal Investigator and may, if 
clinically indicated, be excluded from the study. If a prior reading is not available, an 
appropriately qualified individual will conduct a standard 12-lead resting ECG. If the participant 
refuses an ECG at screening, the Site Principal Investigator will use their clinical judgement to 


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consider medical history, examination, and overall health to determine eligibility without an 
ECG. 
10.9 Clinical Laboratory Evaluations  
Laboratory values obtained within the year prior to screening may be used for eligibility 
determination if available. Laboratory reports will be reviewed, signed and dated by the Site 
Principal Investigator (or a qualified designee). If a value is outside of the laboratory’s reference 
range, the reviewer will indicate whether or not it is clinically significant. Those results that are 
deemed clinically significant shall be provided to the participant’s primary care provider for 
follow-up as needed. If laboratories have not been collected within the past year, collection of 
specimens for the following laboratory tests will be attempted: complete blood count, routine 
blood chemistries (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, 
glucose). Routine urinalysis will be performed at screening if indicated by clinical symptoms 
(e.g., urinary frequency). Laboratory samples will be analyzed by the local laboratory using local 
standard laboratory supplies. Laboratory evaluations may be repeated if necessary. Because 
many agitated AD participants are not cooperative, CBC, documented blood chemistries within 
the past year can be used to determine eligibility. If the participant refuses a blood draw or urine 
collection at screening, and blood chemistry results within the past year are not available, the 
Site Principal Investigator will use clinical judgement to consider medical history, examination, 
and overall health to determine eligibility without labs. 
10.10 Vital Signs 
10.10.1 Blood Pressure (BP) and Heart Rate (HR) Measurements  
Supine and orthostatic BP and HR measurements will be performed. Systolic and diastolic BP 
and HR will be obtained following at least 10 minutes of supine posture and then repeated 
immediately following 2 minutes of standing (or sitting if unable to stand). Supine and orthostatic 
BP and HR measurements will be performed at least daily during the titration period (up to Day 
35). For the 24-hour period following the first dose and each dose increase, supine and 
orthostatic BP and HR measurements will be taken both morning and evening. Beginning on 
Day 36 (Week 6), supine and orthostatic BP and HR measurements will be performed every 3 
days. 
For BP and HR parameters, unacceptable side effects will include supine hypotension (supine 
systolic BP <100), clinically meaningful orthostatic hypotension (> 20 mmHg drop in systolic BP 
accompanied by dizziness, lightheadedness or syncope), or clinically meaningful HR increase 
(20 beats per minute or more). 
For home-dwelling participants, the Study Partner will be provided an automated blood 
pressure/heart rate machine and trained in its use at the Screening visit. Training will include 
demonstration the cuff by the trainer, followed by observation of the study partner demonstrating 
the correct procedure including supine and standing measurements. The Study Partner will be 
trained on correct positioning of the cuff, how to read the display, and what to record in the 
diary. The Study Partner will be instructed to call study personnel if blood pressure 
measurements fall below levels in the paragraph above or if the participant experiences 
lightheadedness or dizziness. Study Partners will be instructed in cautions for orthostatic 
hypotension and will be given information on symptoms and precautions to prevent orthostatic 
hypotension. 


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10.11 Adverse Symptoms Checklist  
The Adverse Symptoms Checklist (targeting anticipated adverse effects of prazosin) will be 
completed at BL, each step of the prazosin dose titration phase, and at all subsequent visits. 
Occurrence of lightheadedness, dizziness on standing (if able to stand), palpitations, 
drowsiness, headache, nausea, lack of energy, weakness, depressed mood, and other adverse 
effects will be rated by the Clinician Prescriber. To be considered an AE, the symptom must be 
new or clinically meaningfully worse compared to BL assessment.  
10.12 Open-ended AE Reporting  
New and clinically meaningfully worse symptoms on the Adverse Symptom Checklist as well as 
all other AEs will be reported via open-ended AE reporting on the eCRF. 
10.13 Locomotor Activity and Nighttime Sleep Continuity (Actigraphy Sub-Study) 
Locomotor activity will be measured over the 24-hour period and the 12-hour nighttime period 
for each week during the 12-week study of prazosin dosing to efficacy. Sleep continuity will be 
extrapolated from total activity counts during the 12-hour nighttime period and compared at 
each week during the 12-week study duration.  
Activity levels will be monitored continuously during the entirety of the 12-week study using wrist 
actigraphy (Actiwatch, Philips Respironics). Wrist actigraphy includes an accelerometer, which 
produces voltage that reflects the amount of motion of the device. Within the sensor, the degree 
and force of all movements are calculated into activity counts, which are then recorded to the 
device. Activity counts will be exported manually after the study period via USB transfer of data 
from the device to a secure database residing on a password-protected computer. No PHI will 
be stored in this database. Activity counts will be calculated for every two minutes for the entire 
length of the trial. Continuous monitoring will be critical as the study design employs a flexible 
dose titration schedule as well as the use of rescue medications for agitation (e.g., lorazepam).  
11 SAFETY 
11.1 Adverse Events (AEs), Serious Adverse Events (SAEs), and Reporting 
Timely collection and assessment of AEs and SAE reports are critical for protecting the safety of 
clinical investigation participants. SAE reporting is a regulatory responsibility of ADCS under the 
Code of Federal Regulations (Title 21, Subpart B, Section 312.32) and the European Union 
Clinical Trials Directive 2001/20/EC. 9.1.  
11.2 Adverse Events (AEs) 
CRF Title 21 Food and Drugs, Chapter 1 FDA, Subchapter D Drugs for Human Use, Part 312 
Investigational New Drug Application, Section 32 IND safety reporting: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=312.32 
An AE is defined as any untoward (not favorable, unpleasant, bad) medical occurrence 
associated with the use of a drug, whether or not considered drug related. An AE can be 
any unfavorable and/or unintended sign, symptom, syndrome, or disease temporally associated 
with the use of an IP, whether or not considered related to the IP. Examples include:  
• 
All treatment-emergent signs and symptoms (change from the participant’s baseline 
status), e.g., an increase in severity or frequency of pre-existing disorder; 


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• 
Exacerbations of the underlying disease; 
• 
Extensions or exacerbations or symptomatology, subjective events reported by the study 
participant, new clinically significant abnormalities in clinical laboratory, physiological 
testing, or physical examination.  
• 
Any reactions from the IP, abuse of the IP, withdrawal phenomena, sensitivity, or toxicity 
to the IP; 
• 
Apparent unrelated illnesses; 
• 
Injury and/or accidents; 
• 
Minor skin irritation caused by actigraphy device (actigraphy sub-study only) 
Treatment-emergent AEs (TEAEs) are those AEs that occur after the first dose of study drug 
until 30 days after the last dose.  
Caregivers will be instructed to report any newly occurring or changes in previously reported 
AEs and SAEs that occur between the Final Study Visit (Week 12) and 30 days after the last 
dose to the ADCS Site Study Coordinator or designee. 
AEs will be collected from the time of informed consent until 30 days after the final dose of study 
drug. Additional information regarding AE definitions and documentation is located in the 
Procedures Manual. 
11.2.1 Adverse Events of Special Interest 
Orthostatic Hypotension: Per the Physicians’ Desk Reference (PDR), the risk for first dose 
hypotension is increased with initial doses over 2 mg. In the PEACE-AD study, the risk of first 
dose hypotension is minimized by using the starting dose of 1 mg at bedtime administered after 
the participant is in bed for the night. Caregivers must be available to assist participants to the 
bathroom in the night following first dose.  
 
ADCS Site PI and staff, as well as caregivers, will be trained in the appropriate process for 
performing supine and standing (or sitting if participant unable to stand) and orthostatic blood 
pressure measurements per protocol. Completion of training will be documented via 
certifications procedures as described in the Procedures Manual. 
For outpatient participants still residing at home, the caregiver will be provided an Omron (or 
similar) automated BP and HR measurement machine. The caregiver will be trained in the use 
of the device at the Screening Visit for those participants meeting study entrance criteria. The 
caregiver will be instructed to notify ADCS Site team member if the BP falls below level 
described below or participant experiences dizziness, lightheadedness or syncope.  
It is recognized that a sample of study participants with moderate to severe dementia and 
disruptive agitation may not be able to fully comply with 10 minutes of supine position followed 
by exactly two minutes of upright posture. Best efforts will be made, consistent with participant 
assent, to perform these measurements as outlined. Training procedures will include a 
discussion of how to handle such cases. Documentation on compliance will be retained in 
participant medical records. 
 
Supine and orthostatic BP and HR measurements will be performed at least daily during the 
titration period (up to Day 35). For the 24-hour period following the first dose and each dose 
increase, supine and orthostatic BP and HR measurements will be taken both morning and 
night. Beginning on Day 36 (Week 6), supine and orthostatic BP and HR measurements will be 


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performed every 3 days. Any abnormalities noted in these measurements will be reported to the 
Clinician Prescriber and ADCS Site PI (if different from the Clinician Prescriber) by the 
caregivers or ADCS site staff. 
Falls: All participants in PEACE-AD will be at some risk for falls. This risk for falls will be 
evaluated in all participants prior to randomization. The LTC facilities will assess fall risk, per 
Medicaid/Medicare and OBRA regulations. Home-dwelling participants will be similarly 
assessed for fall risk using a fall risk factors checklist. Risk factors for falls include fall history, 
unsteady gait, age, assistance for balance, transfer, walking, wandering, denial of physical 
limitation, orthostatic hypotension, urinary frequency or incontinence, infection, medications, 
sensory impairments, footwear, confusion/dementia, delirium or sedation, sleep disorders and 
impulsive behavior or poor judgment. Participant care plans will be developed for LTC resident 
and home-dwelling participants to prevent falls with interventions that may include (but are not 
limited to) assistive devices such as walker, cane, or wheelchair; assistance with ambulation; 
non-skid footwear; strength-building exercises; eyeglasses; pain management; adequate fluids; 
and toileting schedule and recommendations for any necessary alterations in the home 
environment (e.g., removal of throw rugs, clearing traffic pattern). 
During the screening period, each potential participant will have their fall risk formally reviewed 
and updated by a member of the LTC facility staff or the ADCS Site Principal Investigator for 
home-dwelling participants. This will include an assessment of balance and gait as part of the 
screening neurological examination. Where this study assessment identifies a fall risk of 
particular concern, this risk will be discussed with the legally authorized representative at the 
time of informed consent with a decision taken around suitability to continue screening for the 
trial. As part of a management plan for those with a fall risk of particular concern, there will be 
increased attention and awareness of significant postural blood pressure changes and 
monitoring of falls. Study Partners of home-dwelling participants will be provided information 
about prevention of falls. 
Falls will be recorded as an AE in the ADCS EDC and flagged for medical safety review to allow 
for real-time monitoring of any significant negative outcomes and reporting to the DSMB per 
standard procedure of reporting adverse events. 
Priapism: The risk of priapism in this participant population of elderly LTC residents is 
extremely low. Caregivers will be educated in the risk of priapism and instructed to observe 
participants for persistent erection and potential signs of distress related to persistent erection in 
the course of providing routine daily care. In the event of priapism, the ADCS Site PI will be 
contacted by the caregiver for further instruction and additional appropriate medical 
management. 
11.3 Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions 
(SUSARs)  
Each AE shall be classified by the Site Investigator as “serious” or “not serious.” The 
seriousness of an event is defined according to the applicable regulations and generally refers 
to the outcome of an event.  An SAE is one that meets one or more of the following: 
• 
Is fatal,  
• 
Is life threatening,  
• 
Requires inpatient hospitalization,  
• 
Prolongs existing hospitalization,  


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• 
Is persistently or substantially disabling (significant disruption of normal life functions),  
• 
Is a congenital anomaly or birth defect (in an offspring),  
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAEs if they have the potential to jeopardize 
participant safety or to require medical or surgical intervention to prevent one of the 
outcomes listed in this definition, e.g., allergic bronchospasm requiring intensive 
treatment in an emergency room, convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
All study participants experiencing an SAE will be seen by the Site Principal Investigator (or 
designee) as soon as feasible upon learning of the SAE.  
SAEs will be collected from the time of informed consent until 30 days after the final dose of 
study drug. Additional information regarding SAE definitions and documentation is located in the 
Procedures Manual. 
11.3.1 Definition of Life Threatening 
A life-threatening SAE is defined as an SAE that places the study participant at immediate risk 
of death from the event as it occurred. This does not include AEs, which, had they occurred in 
more severe forms, may have caused death.  
11.3.2 Definition of Hospitalization 
Hospitalization is defined by ADCS as a full admission to the hospital for diagnosis and 
treatment. This includes any prolongation of an existing inpatient hospitalization. Examples of 
visits to a medical facility that do not meet the study criteria for hospitalization include: 
• 
Emergency room visits (that do not result in a full hospital admission)  
• 
Outpatient surgery  
• 
Preplanned or elective procedures 
These events would not be reported as SAEs unless: 
• 
The event triggering the hospital visit is an SAE as defined by other SAE criteria such as 
life threatening, results in persistent or substantial disability/incapacity, or per medical 
judgment of the Site Principal Investigator.  
• 
Any other event fulfilling the definition of serious that develops as a result of the in-
hospital procedure or extends the hospital stay is an SAE.  
11.3.3 Definition of Disability 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions.  
11.3.4 Definition of Important Medical Events 
AEs that do not result in death, are not life threatening, or do not require hospitalization may be 
considered an SAE when the event jeopardizes the study participant or require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. An SAE may also 
include any event that the Site Principal Investigator or ADCS Medical Monitor judges to be 
serious or that suggests a significant hazard, contraindication, side effect, or precaution.  


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11.3.5 Reporting Serious Adverse Events (SAEs)  
For sites in the United States, the reporting of SAEs by ADCS to regulatory authorities is 
required. For sites in Canada, reporting of SUSARs will follow national requirements. In the 
event of any SAE, the caregiver will be instructed to contact the Site Principal Investigator (or 
designee) using the contact information provided in the Informed Consent Form.  
An SAE or overdose of study drug which occurs during the course of the investigation (i.e., any 
time after informed consent, regardless of study drug exposure) or within 30 days of receiving 
the last dose of study drug must be entered into the ADCS EDC by the Site Principal 
Investigator within 24 hours of learning of the event (refer to the Procedures Manual for further 
instruction). This entry will trigger an alert to the appropriate ADCS personnel and Project Co-
Directors. A notification will be sent to all participating sites and the DSMB once the report is 
available.  
At a minimum, events identified as serious, unexpected, possibly related to study drug must be 
immediately reported to the responsible Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC). Local IRB policy for reporting of SAEs must be followed as well.  
Expected adverse events are those listed on the Adverse Effects Checklist. Unexpected events 
are those not listed in the protocol, package insert or informed consent document. 
Open/unresolved SAEs will be followed for 30 days following the last dose of study drug or until 
the SAE is resolved – whichever occurs first.   
12 SCHEDULE OF EVALUATIONS AND PROCEDURES 
The protocol schedule of events is located in Appendix 2. 
The screening period may last up to 28-days followed by a maximum 12 weeks of treatment. 
12.1 Pre-screening 
During the prescreen phase, sites will identify potential participants through a variety of sources 
(i.e., reviewing potential participants residing at the LTC facility, in their outpatient practices, and 
referrals from other providers) and assess if they may potentially qualify for the study following 
the site’s standard practice for recruitment.  
Potential participants will be identified through multiple sources. Home-dwelling participants may 
be identified from the site’s known list of patients, from referrals from outside physicians, and 
through community outreach. Participants residing in an LTC may be identified by the LTC 
facility staff based on knowledge of the study eligibility criteria. Once a potential candidate is 
identified, LTC facility staff will contact the ADCS Site PI and Study Coordinator (or delegated 
site staff) for further review of participant details and assessment of eligibility.  
Following this initial identification, if deemed appropriate to proceed with informed consent and 
screening procedures, the ADCS site study staff will contact participant family members and/or 
LAR either directly (home-dwelling participants) or through the LTC staff (LTC residents) to 
schedule a meeting with ADCS site study team and all relevant parties to review the informed 
consent and study details. A copy of the informed consent will be provided to participant family 
members and/or LAR during the meeting. The ADCS Site Study Coordinator or delegated site 
staff will complete the informed consent process and proceed with formal screening procedures 
as described in section 12.2 if consent is signed.   


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12.2 Screening (within 28 days prior to randomization) 
For both LTC and home-dwelling potential participants, the participant’s LAR must sign an 
informed consent form (ICF) and Health Insurance Portability and Accountability Act (HIPAA) 
authorization prior to performance of any study procedures. For home-dwelling participants, the 
Study Partner will participate in the Informed consent process and will sign a separate “Study 
Partner Responsibilities Consent” to attest they will follow the required protocol procedures, 
under the PI’s oversight. The Study Partner is identified as a person living with the potential 
participant who will not be the subject of research, but rather the informant on behalf of the 
participant. The Study Partner’s role for the home-dwelling participants is pivotal in ensuring 
compliance to the protocol-required procedures. The Study Partner may also be the LAR for the 
participant and in this case will be expected to sign the ICF and HIPAA on behalf of the 
participant and also sign the Study Partner Responsibilities Consent.  
The screening assessment will determine eligibility to proceed to randomization, and may be 
conducted within 28 days of BL (Day 1). Screening procedures will include the following:  
• 
ICF/HIPAA: participant’s LAR for LTC participants and for home-dwelling participants,  
• 
For home-dwelling participants, the Study Partner must sign the Study Partner 
Responsibilities Consent. 
• 
Review of inclusion/exclusion criteria (including the Behavioral Inclusion Criteria 
Checklist) 
• 
Demographics review 
• 
Medical and psychiatric history 
• 
Record concomitant medications 
• 
Physical examination 
• 
Neurological examination 
• 
Obtain weight (if able to stand) 
• 
Supine and orthostatic (standing or sitting if unable to stand) systolic and diastolic BP 
and HR  
• 
Blood and urine collection for clinical labs, if not performed within a year of screening 
(refer to protocol section 10.9) 
o Complete blood count (CBC) 
o Blood chemistry: sodium, potassium, chloride, carbon dioxide, blood urea 
nitrogen, creatinine, and glucose,  
o Routine urinalysis (if indicated by clinical symptoms) 
• 
12-lead resting ECG, if not performed within a year of screening (refer to protocol 
section 10.8) 
12.2.1 Confirmation of Eligibility 
The participant may proceed to the BL visit if: 
• 
all inclusion/exclusion criteria are met 
• 
results from all required screening procedures have been reviewed 
• 
eligibility has been approved by: 
o Site Principal Investigator  
o Project Directors 
o ADCS Medical Safety 


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12.3 Baseline/Randomization (Titration - Day 1) 
The following will be performed at the BL visit: 
• 
Supine and orthostatic (standing or sitting if unable to stand) systolic and diastolic BP 
and HR  
• 
Review and record concomitant medications 
• 
Baseline Symptoms Checklist and open-ended AEs 
• 
Outcome assessments:  
o ADCS-CGIC-A Baseline Worksheet 
o NPI/NPI-NH 
o ADCS-ADL-Severe  
o CMAI 
• 
Initiate wrist actigraphy with Respironics Actiwatch device (actigraphy sub-study only). 
• 
Randomization: Each eligible participant will be assigned a randomization ID and will 
receive blinded study drug as assigned (placebo or prazosin). Randomization may occur 
up to 3 days prior to first dose of study drug. 
• 
Dispense 1-week study drug supply per randomization schedule. The starting dose will 
be 1 mg QHS (TDD=1 mg). Study drug will be dispensed at one week intervals from BL 
until Week 6 and then at 2 week intervals from Week 6 until Week 12 completion (or 
early termination). Additional information regarding drug orders is located in the 
Procedures Manual. 
12.4 Titration Visits - Days 8, 15, 22, and 29 (± 1 Day until Day 15, then ± 2 Days) 
The following will be performed at the Titration visits: 
• 
Supine and orthostatic (standing or sitting if unable to stand) systolic and diastolic BP 
and HR  
• 
Review and record concomitant medications 
• 
Adverse Symptoms Checklist and open-ended AEs 
• 
Clinician Prescriber rated change in behavioral symptoms 
• 
Dosing decision per Table 3, Dose Titration Schedule 
• 
Dispense and/or collect study drug 
• 
Study drug accountability 
• 
Check Respironics Actiwatch device is being worn continuously by participant 
(actigraphy sub-study only) 
For additional titration information, see Section 6.2, Dosing Administration and Schedule  
12.5 Maintenance Visits 
12.5.1 Safety Assessments – Weeks 5, 6, and 10 (± 2 Days) 
Safety assessments will be done at Weeks 5, 6 and 10.   
• 
Supine and orthostatic (standing or sitting if unable to stand) systolic and diastolic BP 
and HR  
• 
Review and record concomitant medications 
• 
Adverse Symptoms Checklist and open-ended AEs 
• 
Dispense and/or collect study drug 
• 
Study drug accountability  


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• 
Check Respironics Actiwatch device is being worn continuously by participant 
(actigraphy sub-study only) 
No dose increases are allowed following Day 29.  Dose may be decreased at any time due to 
intolerable adverse events. 
12.5.2 Outcome Assessment – Week 8 (± 2 Days) 
This visit collects outcome data; the following assessments will be performed: 
• 
Supine and orthostatic (standing or sitting if unable to stand) systolic and diastolic BP 
and HR  
• 
Review and record concomitant medications 
• 
Adverse Symptoms Checklist and open-ended AEs 
• 
Dispense and/or collect study drug 
• 
Study drug accountability 
• 
Outcome assessments: 
o ADCS-GCIC-A 
o NPI/NPI-NH 
o ADCS-ADL-Severe 
• 
Check Respironics Actiwatch device is being worn continuously by participant 
(actigraphy sub-study only) 
• 
No dose increases are allowed following Day 29.  Dose may be decreased at any time 
due to intolerable adverse events. 
12.6 End of Study - Week 12 (± 2 Days) or Early Termination 
The following procedures will be performed at this visit: 
• 
Supine and orthostatic (standing or sitting if unable to stand) systolic and diastolic BP 
and HR  
• 
Weight (if participant able to stand) 
• 
Review and record concomitant medications 
• 
Adverse Symptoms Checklist and closure of open-ended AEs as appropriate 
• 
Collect unused study drug 
• 
Study drug accountability 
• 
Outcome assessments: 
o ADCS-GCIC-A 
o NPI/NPI-NH 
o ADCS-ADL-Severe 
o CMAI 
• 
Removal of Respironics Actiwatch device for return to analyzing site (actigraphy sub-
study only)  
• 
Administer Treatment Blinding Questionnaires (Site PI, Clinician Prescriber, Clinician 
Rater and Caregiver) 
• 
Break the blind after all study procedures completed 
• 
Develop, discuss, and document follow-up care plan 


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12.7 Between Visits 
LTC or home caregivers will be responsible for performing supine and orthostatic (standing or 
sitting if unable to stand) systolic and diastolic BP and HR at least daily during the titration 
period (up to Day 35). For the 24-hour period following the first dose and each dose increase, 
supine and orthostatic BP and HR measurements will be taken both morning and evening. 
Beginning on Day 36 (Week 6), supine and orthostatic BP and HR measurements will be 
performed every 3 days. These recordings will be maintained in a log that is completed either at 
the participant’s home residence or at the LTC facility. In addition, BP and HR measurements 
will be performed by caregiver, or if an in-person visit can take place, by the ADCS Site Study 
Coordinator, or Clinician Prescriber on study visit days for recording in the eCRF. If it is 
necessary to conduct the visit remotely, the LTC or home caregiver-provided BP and HR 
measurements will be entered into the eCRF. 
For those sites participating in the wrist actigraphy sub-study, caregivers will be responsible for 
ensuring that the Actiwatch device is worn by the participant continuously during the entirety of 
the 12-week study. ADCS Site personnel will assist with receipt of the watch by mail, putting the 
watch on the non-dominant wrist of the participant, and removing/mailing the watch back to the 
analyzing site every four weeks for the duration of the 12 week trial.  
13 STATISTICAL METHODS  
This study is a multicenter, randomized, double-blind, placebo-controlled trial comparing 
efficacy and safety of prazosin versus placebo in AD patients with disruptive agitation. 
13.1 Power and Sample Size Determination 
Power calculations for PEACE-AD were based on two-sample t-tests. Sample sizes were 
estimated targeting a power=80%, assuming a 2-sided alpha=5%, a standardized effect size of 
.44 SDs,and a dropout rate of 10%. This is a reasonable estimate of attrition given the study 
population and the relatively short follow-up period. Based on these considerations, 186 total 
participants are required; 124 in the active group, and 62 in the control group 
Following COVID-19 it became clear that it would not be possible to successfully recruit this 
sample size to this protocol. In turn, a decision was made to change the focus to being a pilot 
trial of between 25-80 participants, a target number that was considered feasible in the 
aftermath of the pandemic. The range of sample sizes were then considered  as a function of 
the standardized effect size delta; for delta = .71 the required sample size is 80 (53 in the 
prazosin group, and 27 in the control group), for delta = .79 the required sample size is 65 (43 in 
the prazosin group, and 22 in the control group), for delta = .91 the required sample size is 50 
(33 in the prazosin group, and 17 in the control group), for delta = 1.0 the required sample size 
is 40 (27 in the prazosin group, and 13 in the control group), for delta = 1.2 the required sample 
size is 30 (20 in the prazosin group, and 10 in the control group). The statistical analyses at 
study conclusion will be based on longitudinal data analysis that is expected to increase 
statistical power. 
13.2 Selection of Participants to be Used in Analysis 
The intent-to-treat (ITT) data set will include all eligible individuals who are randomized. The 
modified ITT data set will include all eligible individuals who are randomized and completed the 
fixed dose titration period at Day 14. The per-protocol data set will include all eligible 
participants who: 1) complete the 12-week assessments for the primary analysis, and 2) 


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demonstrate 80% drug compliance as documented in medication administration records. The 
safety analysis population is defined as those subjects that are randomized and took at least 
one dose of study drug.   
13.3 Efficacy Analysis 
13.3.1 Analysis of the Primary Outcome(s)  
Hypothesis 1a: Participants randomized to prazosin will manifest greater benefit on the primary 
outcome measure – the ADCS-Clinical Global Impression of Change in Agitation (ADCS-CGIC-
A) anchored to disruptive agitation. 
The mITT data set will be used for primary analysis in this study. To address the aims for the 
primary efficacy analysis (Hypothesis 1a), longitudinal ADCS-CGIC-A scores from first post-BL 
visit through 12 weeks will be analyzed using a mixed effects model for repeated measures 
(MMRM) to assess differences in ADCS-CGIC-A. The ADCS-CGIC-A is a 7-point scale that is 
structured as the clinician’s assessment of change from BL compared to the ADCS-CGIC-A 
Baseline Worksheet. A score of 1-2 indicates clinically meaningful improvement; a score of 3-5 
indicates no clinically meaningful change; a score of 6-7 indicates clinically meaningful 
worsening. The MMRM will include terms for time, intervention, intervention-by-time interaction 
plus covariates site and gender. Time will be treated as categorical.  
Categorical safety data will be analyzed, compared between treatment arms, using the exact 
contingency table method, Fisher’s Exact Test. 
Differences in the primary outcome of change in ADCS-CGIC-A between intervention groups 
will be tested at the two-sided 5% significance level. No adjustment to the type 1 error level will 
be made for secondary analyses. 
A secondary sensitivity analysis of the primary outcome measure will also be performed to 
address the aims for Hypothesis 1a. The details of this analysis are further described in the 
Statistical Analysis Plan (SAP). 
13.3.2 Analysis of Secondary Outcomes 
Hypothesis 1b: Participants randomized to prazosin will manifest greater benefit on the key 
secondary outcome measure – the Neuropsychiatric Inventory (NPI)/Neuropsychiatry Inventory-
Nursing Home version (NPI-NH). Similar analyses to that described for the primary analysis will 
be performed on the NPI/NPI-NH. An MMRM analysis will compare active vs placebo at 12 
weeks. 
Hypothesis 1c: Participants randomized to prazosin will receive a lower total dose of lorazepam 
“rescue medication” administered during the trial. Similar analyses to that described for the 
primary analysis will be performed on the total dose of rescue lorazepam. An MMRM analysis 
will compare active vs placebo at 12 weeks. 
Hypothesis 1d: Study discontinuation (“dropout”) due to persistent or worsening intolerable 
disruptive agitation will occur sooner in the placebo group than in the prazosin group. A Cox 
proportional hazards model will be used to compare the median time to dropout between groups 
adjusting for potential confounding factors. 
Hypothesis 1e: There will be larger proportion of responders to prazosin (defined as moderate 
or marked improvement) vs nonresponders (defined as minimal improvement; no change; or 
minimal, moderate, or marked worsening) on the ADCS-CGIC-A. A logistic regression model 


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will be used to compare percent of responders (ADCS-CGIC-A scores of 1 and 2) vs. minimal or 
no change (ADCS-CGIC-A scores of 3, 4, and 5) vs. worsening (ADCS-CGIC-A scores of 6 and 
7).  
Hypothesis 2: Participants randomized to prazosin will manifest greater benefit on the ADCS-
Activities of Daily Living-Severe Dementia version (ADCS-ADL-Severe). Similar analyses to that 
described for the primary analysis will be performed on the ADCS-ADL-Severe. An MMRM 
analysis will compare active vs placebo at 12 weeks. 
Hypothesis 3: Participants randomized to prazosin will have a greater reduction in the NPI/NPI-
NH “caregiver distress”/ “occupational disruptiveness” score. Similar analyses to that described 
for the primary analysis will be performed on the NPI/NPI-NH “caregiver distress”/ “occupational 
disruptiveness” score. An MMRM analysis will compare active vs placebo at 12 weeks. 
13.3.3 Analysis of Exploratory Outcomes 
Hypothesis 4: Participants randomized to prazosin will manifest greater benefit on the CMAI. 
Similar analyses to that described for the primary analysis will be performed on the CMAI. An 
MMRM analysis will compare active vs placebo at 12 weeks. 
Hypothesis 5: Improvement in the five domain NPI/NPI-NH subset score will have a greater 
effect size in response to prazosin treatment than the 12-domain NPI/NPI-NH total score. An 
MMRM analysis will compare active vs placebo at 12 weeks. 
Hypothesis 6: Participants randomized to prazosin will manifest greater improvement in sleep 
continuity during the 12-hour nighttime period and at each week during the 12-week study 
duration. Improvement in the primary actigraphy outcome measures will be defined as a 
decrease in locomotor activity as assessed by total activity counts over the 24-hour period, 
specifically a decrease in the 12-hour period from 6 PM to 6 AM for each week of the 12 weeks 
of the study. Univariate means analysis will be performed to compare activity counts between 
participants on prazosin and participants on placebo for each time period. Secondary actigraphy 
outcome measures will include logistic regression of motor activity counts to changes in 
NPI/NPI-NH subscores for agitation for each participant.  
13.3.4 Safety Analysis 
Hypothesis 1f: The incidence of adverse events (AEs) will not differ between participants 
randomized to prazosin and those randomized to placebo. Fishers exact test will be used to 
compare rates of dropout due to AEs between treatment groups.  
Safety will be assessed by summarizing and analyzing AEs during the intervention period. AEs 
will be coded according to established Medical Dictionary for Regulatory Activities (MedDRA) 
terms and summarized by MedDRA System Organ Class (SOC) and Preferred Term (PT). 
Treatment-emergent adverse events (TEAEs) will be defined as events that first occurred or 
worsened on or after randomization. 
An overview of AEs, including the number and percentage of participants who died, suffered 
SAEs, discontinued due to AEs, and who suffered TEAEs, will be provided. A comparison 
between intervention arms will be performed. 
The number and percentage of the following types of AEs will be reported: 
• 
TEAEs  


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o All TEAEs 
o TEAEs that led to study participant termination  
o TEAEs related to study drug 
o TEAEs by maximum severity 
• 
SAEs 
o All SAEs 
o SAEs related to study drug 
• 
AEs  
o A listing of AEs will be reported 
Summaries of AEs by within system organ class will be provided for the following: 
• 
Preexisting conditions 
• 
TEAEs 
• 
SAEs 
• 
Participant terminations due to AEs will also be listed 
13.3.5 Safety Endpoints 
Safety results will be summarized by treatment group using descriptive statistics. No formal 
statistical testing will be performed for any of the safety endpoints; hence no p-values will be 
reported.  All safety analyses will be performed using the Safety Set.  
13.3.6 Blood Pressure (BP) and Heart Rate (HR) 
Changes from BL in supine and orthostatic (standing or sitting if unable to stand) systolic and 
diastolic BP and HR will be summarized using descriptive statistics. Similar analyses to that 
described for the primary analysis will be performed on supine and orthostatic systolic and 
diastolic BP and HR. An MMRM analysis will compare active vs placebo at 12 weeks.  
13.4 Criteria for the Termination of the Trial 
The trial may be terminated early by the Data Safety Monitoring Board (DSMB) based on safety 
and feasibility, or by the Project Co-Directors, DSMB, NIA and NIA Program Official 
recommendations. The trial may be terminated early at an individual participating site based on 
site IRB recommendations as well.  
14 DATA AND SAFETY MONITORING BOARD (DSMB) 
The ADCS DSMB will review the safety of all participants enrolled in the trial on an ongoing 
basis. The initial task of the DSMB will be to review the protocol to identify any necessary 
modifications. If modifications are necessary, revisions will be reviewed by the DSMB prior to its 
recommendation on initiation of the project. The DSMB, based on its review of the protocol, will 
work with ADCS Medical and Safety Core personnel to identify the study-specific data 
parameters and format of the information to be regularly reported. The DSMB will meet regularly 
at approximately 3-month intervals. The DSMB will initially be provided with data blinded to 
treatment status, but they may request unblinded data if there is a safety concern. The DSMB 
and NIA representative will meet in person or by conference call on a quarterly basis. 
Additionally, the DSMB will be informed of the occurrence of any SAEs within 7 days of being 
reported to the ADCS. The DSMB may at any time request additional information from the 
ADCS.  


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Based on the review of safety data, the DSMB will make recommendations regarding the 
conduct of the study. These may include amending safety monitoring procedures, modifying the 
protocol or consent, terminating the study or continuing the study as designed. Using the ADCS 
safety review process and the DSMB, there is substantial oversight and case review to alert the 
Site Principal Investigators, in a timely manner, to any safety issues that may arise. For further 
details, please refer to the DSMB charter. 
15 RECORDING AND COLLECTION OF DATA  
15.1 Source Documents and Electronic Case Report Forms (eCRF) 
The Site Principal Investigator or designee will record all data collected (either written or 
electronic record). Written data will be entered on source documents. Electronic data will be 
entered on the eCRF through the ADCS EDC system. The site staff will be suitably trained on 
the use of the eCRF and appropriate site personnel will be authorized to provide electronic 
signatures. The Site Principal Investigator is responsible to verify the integrity of the data and 
acknowledge as such by signature. 
All site entries will be made in a secured web site and the Site Principal Investigator or designee 
will review the record for completeness. If corrections are necessary to the eCRFs, the Site 
Principal Investigator or designee will update the eCRF and provide documentation of the 
reason for change.  
Completed eCRFs will be submitted according to the eCRF Completion Guidelines, and 
reviewed by the ADCS to determine their acceptability. If necessary, data correction data 
queries will be generated by ADCS for resolution by the study site.  
15.2 Study Files and Participant Source Documents 
Participant confidentiality is strictly held in trust by the participating Site Principal Investigator, 
research staff, and the ADCS and/or participating institution and their agents. The study 
protocol, documentation, data and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any 
unauthorized third party, without prior written approval of the ADCS or funding agency. 
Authorized representatives of the ADCS or funding agency may inspect all documents and 
records required to be maintained by the Site Investigator, including but not limited to, medical 
records (LTC facility, office, clinic or hospital) and pharmacy records for the participants in this 
study. The study site will permit access to such records. All records will be kept behind two 
locks (e.g., in a locked cabinet located in a locked office). Identifiable and coded data will be 
stored separately. Any transport of files that must occur between the study site and the 
participants’ place of residence (in the home or an LTC facility) will occur in compliance with 
HIPAA of 1996. All computer entry and networking programs will be done using participant 
identification numbers only.  
Information about study participants will be kept confidential and managed according to the 
requirements of the HIPAA of 1996. Those regulations require a signed participant HIPAA 
Authorization informing the participant of the following:  
• What protected health information (PHI) will be collected from participants in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 


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• The rights of a research participant or LAR to revoke their authorization for use of their 
PHI.  
In the event that a participant/LAR revokes authorization to collect or use PHI, the Site Principal 
Investigator, by regulation, retains the ability to use all information collected prior to the 
revocation of participant/LAR authorization. Each Site Principal Investigator, under the guidance 
of his/her IRB, is responsible for ensuring that all applicable HIPAA regulations and State laws 
are met. 
15.3 Release of Information 
The following study information will be released as documented in the informed consent form 
and/or HIPAA authorization: 
• 
Clinically meaningful abnormal laboratory values to the participant/LAR and participant’s 
health care provider. 
• 
Study condition (prazosin or placebo) and dose to participant/LAR and participant’s 
health care provider at study termination (completion or early termination). 
• 
Information necessary for safety and regulatory monitoring by IRB, the FDA, the NIA, the 
Office for Human Research Protections (OHRP), and others as required. 
No other information will be released without written permission of the participant/LAR. 
16 ADMINISTRATIVE PROCEDURES 
16.1 Study Timeline  
The approximate timeline for this study is projected as follows: (1) approximately 5 months for 
study startup activities that will include communication with the Food and Drug Administration 
(FDA) regarding Investigational New Drug (IND) application requirements, site IRB and 
regulatory approvals, and the Investigator training meeting; (2) recruitment will last for 
approximately 9 months; and (3) 4 months of follow up. The study will therefore be active for 
approximately 1.5 years. 
It is anticipated that this study will require approximately 14 months for all participants to 
complete all visits from Screening through Week 12. 
16.2 Ethics and Regulatory Considerations 
16.2.1 Good Clinical Practice (GCP) 
This study will be conducted in compliance with the protocol and accordance with GCP 
guidelines, as defined by the International Conference on Harmonisation (ICH) Guideline, Topic 
E6, the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) – Protection of 
Human Subjects and Part 56 – Institutional Review Boards (IRBs), HIPAA, Federal and State 
regulations and all other applicable local regulatory requirements and laws. 
Study personnel involved in conducting this study will be qualified by education, training and 
experience to perform their respective task(s) in accordance with GCP. LTC facility personnel 
responsible for performing study activities on this trial will be required to undergo training on 
human research protections and Good Clinical Practice in line with NIH guidance, as well as 
training on the protocol.  All training activity for LTC facility personnel will be documented, and 
training certifications maintained on file at the ADCS participating site and ADCS Coordinating 
Center. 


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For participants who reside at home, the study oversight remains the responsibility of the 
Investigator and his/her delegates and relies on training and providing resources to the Study 
Partners via close contact and documented communication. The responsibilities and 
expectations for the Study Partners are described in the document “Study Partner 
Responsibilities Consent” that requires the Study Partner’s signature before any study activity 
begins.  
16.2.2 Institutional Review Board (IRB)  
IRBs and Research Ethics Boards must be constituted and their authority delegated through the 
institution’s normal process of governance according to applicable State and Federal 
requirements for each participating location. Each participating institution must provide for the 
review and approval of this protocol and the associated informed consent documents and 
recruitment material by an appropriate IRB registered with the OHRP. The single IRB will follow 
Federal Policy or the “Common Rule” as described in HHS regulations, 45 CFR 46. Any 
amendments to the protocol or consent materials must also be approved before they are placed 
into use. In the United States, only institutions holding a current US Federal-wide Assurance 
issued by OHRP may participate. Refer to: http://www.hhs.gov/ohrp/assurances/. 
The Site Principal Investigator must obtain approval from the IRB for all subsequent ADCS 
protocol amendments and, when warranted, changes to the informed consent document. 
Protocol and ICF amendments can be made only with the prior approval of the ADCS. The Site 
Principal Investigator may not implement any protocol deviation without prior notification to the 
ADCS and prior review and documented approval of the IRB of record, except where necessary 
to eliminate an immediate hazard to study participants, or when change(s) involve only logistical 
or administrative aspects of the trial (ICH 4.5.4). The Site Principal Investigator shall notify the 
IRB of deviations from the protocol or SAEs occurring at the site, in accordance with procedures 
as defined by the IRB of record.  
16.2.3 Informed Consent and HIPAA Compliance 
Informed consent will be obtained in accordance with US 21 CFR 50.25, the Tri-Council Policy 
Statement: Ethical Conduct of Research Involving Humans and Health Canada requirements.  
Applicable HIPAA privacy notifications will be implemented and HIPAA authorizations signed 
before protocol procedures are carried out. Information should be given in both oral and written 
form as deemed appropriate by the Site’s IRB. 
Prior to the beginning of the trial, the Site Principal Investigator must have the IRB’s written 
approval of the ICF and any other written information to be provided to participants and be 
approved by ADCS Regulatory Affairs. Consent forms must be in a language fully 
comprehensible to the prospective participants and/or their LAR. Participants, their relatives, 
guardians, or LAR will be given ample opportunity to inquire about the details of the study. Prior 
to a participant’s participation in the trial, the written ICF must be signed and personally dated 
by the participant’s LAR, the participant (if possible), and by the person who conducted the 
informed consent discussion.  In cases where the LAR is unable to attend the consenting 
session on-site (e.g., lives in another state), remote consenting will be allowed by telephone or 
use of video conferencing (e.g., Skype or FaceTime). If telephone or video conferencing is 
used, the session may not be recorded for any reason. The blank ICF will be sent to the LAR via 
mail ahead of a pre-arranged consent meeting during which the consent process with the legally 
authorized representative will occur. Where appropriate, the participant may also be included in 


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this consent meeting and asked to provide assent at this time.  After the consenting discussion, 
if he/she agrees, the LAR will send the completed signed consent form via facsimile, email or 
via telephone (using text or applications such as “Genius Scan”). In all cases, the LAR will be 
asked to return the original copy via mail as a follow up for the final informed consent record. 
Participants/LAR should be provided copies of the signed ICF and HIPAA authorization. For 
face to face or remote informed consent discussions, copies of the ICF and HIPAA authorization 
shall be placed in the participant’s medical record, either at the study site or at the LTC. 
16.2.4 Inclusion of Children as Participants in Research Involving Human Subjects 
Not applicable. No children will be enrolled in this study. 
16.3 Study Monitoring 
The ADCS monitor is responsible for inspecting the eCRFs and source documentation at 
regular intervals throughout the study to verify adherence to the protocol, completeness and 
accuracy of the data, and adherence to local regulations on the conduct of clinical research. The 
monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, drug accountability, compliance with regulatory 
requirements and continued adequacy of the investigational site and its facilities. The Site 
Principal Investigator will cooperate in the monitoring process by ensuring the availability of the 
eCRFs, source documents and other necessary documents at the time of the monitoring visits. 
The Site Investigator will promptly address any matters brought to his/her attention by the 
monitor. The Site Principal Investigator may also be asked to meet in-person with the site 
monitor during certain visits. 
The CRAs assigned to the study are responsible for verifying the following with respect to IP: 
• 
Storage time and condition is acceptable, and that supplies are sufficient throughout the 
trial 
• 
IP is supplied only to participants who are eligible to receive it and at the protocol 
specified dose(s) 
• 
LTC facilities, site staff, and home caregivers are provided with necessary instruction on 
properly receiving, using, handling, storing, and returning the IP 
• 
Receipt, use, and return of the IP is controlled and documented adequately 
• 
Destruction of unused IP at the ADCS sites complies with applicable regulatory 
requirement(s) and is performed in accordance with site drug destruction policy. 
16.4 Audit 
In accordance with ICH GCP, representatives of the ADCS and/or regulatory agency may select 
this study for audit. The Site Principal Investigator and study staff are responsible for 
maintaining the site investigator file containing all study-related regulatory documentation as 
outlined by ADCS Regulatory Affairs that will be suitable for inspection at any time by ADCS, its 
designees, and/or regulatory agencies. Inspection of site facilities (e.g., pharmacy, laboratories) 
to evaluate the trial conduct and compliance with the protocol may also occur.  
16.5 Records Retention 
No study document shall be destroyed without prior written agreement between the ADCS and 
the Site Principal Investigator. Should the Site Principal Investigator wish to assign study 
records to another party or move them to another location, he/she may do so only with the prior 
written consent of the ADCS.  


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Essential documents and study records must be retained for a minimum of seven years 
following primary publication of study results, or per the requirements of the local regulatory 
guidelines, whichever is longer. The ADCS Coordinating Center will notify sites when retention 
of such documents is no longer required. 
16.6 Publication Policy 
The results of this study will be published. To coordinate dissemination of data from this study, a 
publication committee will be formed. The committee will consist of the PEACE-AD Co-
Directors, ADCS Publication Committee, interested Site Principal Investigators and appropriate 
ADCS personnel.  The committee will solicit input and assistance from other Investigators as 
appropriate and adhere to all ADCS publication policies. 
16.7 Sharing of Final Research Data  
Data from this research will be shared with other researchers pursuant to the 02/26/2003 
National Institutes of Health (NIH) Final Statement on Sharing Research Data. The ADCS grant 
contains a data sharing policy consistent with the goals of the NIH but which also respects the 
rights of commercial partners. The NIH policy can be found at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html. 
NIH believes that data sharing is important for further translation of research results into 
knowledge, products, and procedures to improve human health. The NIH endorses the sharing 
of final research data to serve these and other important scientific goals. To protect participants’ 
rights and confidentiality, identifiers will be removed from the data before they are shared. 
17 PERSONNEL REQUIREMENTS – ROLES AND RESPONSIBILITIES 
The Site Principal Investigator is responsible for the overall conduct of the study at the site.  The 
Site Principal Investigator will supervise study personnel, including sub-investigators, Study 
Coordinator, and Clinician Rater. The Site Principal Investigator will ensure that Clinician 
Rater(s) maintain a high level of skill and accuracy in conducting assessments. Additionally, the 
Site Principal Investigator or designee will perform or supervise clinical evaluation of all 
participants, assure that inclusion and exclusion criteria are met prior to study drug 
randomization, and ensure protocol adherence.  
The Clinician Prescriber may be the Site Principal Investigator or a clinician designee and may 
be an MD, DO, ARNP, or PA-C. The Clinician Prescriber will perform physical and neurological 
exams, make dose titration decisions, and document and manage adverse events. 
The Clinician Rater will perform the ADCS-CGIC-A, NPI/NPI-NH, ADCS-ADL-Severe, and 
CMAI. The Clinician Rater may be an MD, PhD clinical psychologist, ARNP, PA-C, MSW, or RN 
with the appropriate clinical experience and training to perform the outcome assessments. In the 
absence of clinical credentials, the Project Directors may accept a combination of education and 
experience on a case-by-case basis. The Clinician Rater will at all times remain blinded to 
treatment assignment, vital signs, adverse events, and concomitant medications. The Clinician 
Rater CANNOT also fulfill duties of the Clinician Prescriber or Study Coordinator.  
The Study Coordinator will perform study visits, including scheduling visits, conducting the 
informed consent process, as well as ensuring availability of the Clinician Prescriber and 
Clinician Rater to perform their duties.  


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Participants who reside at home will ideally come to the study site for visits. When possible, the 
Screening visit should be performed in-person either at the study site or by home visit. If in-
person screening is contraindicated due to safety concerns or local COVID-19 restrictions, 
screening may be conducted as a remote visit. If conducting screening as a remote visit, a 
combination of telephone and video conference can be used; at a minimum, the observational 
elements of the Physical and Neurological Exam including visual assessment of participant gait 
should be done via video conference.  
Subsequent to the screening visit, if travel from home to the study site is precluded by 
participant agitation or COVID-19 restrictions and/or safety precautions, home visits will be 
performed when feasible. Alternatively, safety and outcome data may be obtained from the 
caregiver by remote visit. For home-based participants, the caregiver training on proper 
completion of BP and HR measurements must be done either in person or via video conference 
(not by telephone alone) in order to ensure correct placement of the blood pressure cuff and 
ability to record systolic and diastolic BP and HR recordings accurately both lying and standing. 
For participants who reside in an LTC, the Study Coordinator will serve as primary liaison to the 
LTC facility to ensure availability of the participant’s LTC facility primary caregiver and other 
staff for interview by the Clinician Rater at BL and outcome visits. Similarly, COVID-19 
restrictions and/or safety precautions may require that these visits take place by remote visit. 
The Study Coordinator will gather information as necessary from source documents and 
caregivers on BP and HR measurements (and may perform these measurements at study visits 
if LTC access is possible), doses of rescue lorazepam and other concomitant medications, and 
adverse events. The Study Coordinator will enter data into the eCRFs. 
LTC and home-based caregivers will be available to the Clinician Rater for providing information 
to enable interview-based outcome assessments. Caregivers will also perform BP and HR 
measurements, record medication dosing per usual clinical requirements, and inform study 
personnel of adverse events. LTC Caregivers may also identify potentially eligible participants to 
Site Investigator and delegated ADCS site staff for further review and consideration. For those 
sites participating in the actigraphy sub-study, caregivers will ensure that the Actiwatch device is 
worn by the participant continuously during the entirety of the 12-week study.  
Additional key personnel may be required, which is outlined in the Procedures Manual or 
depending on COVID-related restrictions and/or safety precautions 
18 POTENTIAL RISKS AND BENEFITS 
18.1 Potential Risks of Study Drug 
Prazosin was first introduced in 1973 as Minipress (Pfizer) for clinical management of 
hypertension, and later became widely prescribed off label for urinary outflow obstruction 
secondary to benign prostatic hyperplasia. It has been prescribed safely to large numbers of 
middle-aged and older persons over the past four decades.  
The following information regarding the side effect profile and safety record of prazosin is a 
synopsis from the Minipress “package insert”29:  The most important adverse effect to be 
considered when prescribing prazosin is a “first dose effect” manifested by syncope with sudden 
loss of consciousness believed to be due to postural hypotension in approximately 1% of 
patients given an initial dose of 2 mg or greater. This rare adverse effect is self-limiting and in 
most cases does not recur after the initial period of therapy or during subsequent dose titration. 


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For safety, patients should always be started on 1 mg of prazosin. Additionally, for this study, 
the initial dose is administered at night in order to mitigate effects of any hypotensive response.  
In clinical trials of prazosin, most frequent adverse reactions were: dizziness (10%), headaches 
(8%), drowsiness (8%), lack of energy (7%), weakness (7%), palpitations (5%), and nausea 
(5%). Less frequent adverse reactions (1-4%) were: vomiting, diarrhea, constipation, edema, 
orthostatic hypotension, dyspnea, syncope, vertigo, depression, nervousness, rash, urinary 
frequency, and nasal congestion. Fewer than 1% of patients have reported the following (causal 
relations sometimes not established): abdominal discomfort or pain, tachycardia, paresthesias, 
hallucinations, pruritus, incontinence, impotence, and priapism. 
Data from the placebo-controlled feasibility study of prazosin for disruptive agitation in AD 
support this safety record. Change in BP and HR from BL to last observation did not differ 
between prazosin and placebo groups. Of the 22 participants in the pilot placebo-controlled 
study, two participants (one assigned to prazosin and one to placebo) underwent early 
termination for orthostatic hypotension and two participants (one assigned to prazosin and one 
to placebo) underwent early termination for worsening peripheral edema, which readily reversed 
upon discontinuation of prazosin. In addition, many thousands of veterans with PTSD (including 
many elderly World War II and Korean War veterans) have now been treated with prazosin 
across the national Veterans Affairs (VA) system.30 Prazosin for treatment of PTSD is generally 
well tolerated. Most common adverse effects have been transient orthostatic dizziness, nasal 
congestion, or headache.  
Safety procedures in this study for the use of prazosin include exclusion of persons with 
unstable angina, recent myocardial infarction, preexisting recurrent hypotension (systolic <110) 
or orthostatic hypotension (> 20 mmHg drop in systolic BP accompanied by dizziness, 
lightheadedness or syncope); chronic severe renal failure; hepatic failure; or any unstable or 
severe medical disease. Screening procedures include 12-lead ECG, screening laboratory 
assessments, and physical/neurological examination; ECG and/or laboratory values obtained 
within the year prior to screening may be used for eligibility determination if available (refer to 
Protocol sections 10.8 and 10.9 for additional detail). Safety assessments during study 
participation include measurements of supine and orthostatic BP and HR performed at least 
daily during the titration period and one week after the last titration step in the flexible titration 
phase (up to Day 35). For the 24-hour period following the first dose and each dose increase, 
supine and orthostatic BP and HR measurements will be taken both morning and night. 
Thereafter, supine and orthostatic BP and HR measurements will be taken every 3 days. In 
addition, study participants will undergo assessment for adverse effects at each study visit.  
During the course of the study, members of the Project Co-Directors team will be on-call to 
advise the Site Principal Investigator(s) or caregivers regarding eligibility, dosing decisions, and 
management of AEs.  Any unexpected AE or SAE will be reported as described above. 
18.2 Potential Risks of Actigraphy Sub Study 
Participants may have mild skin irritation caused by the wrist band of the device, if this occurs, 
the device should be removed.  
18.3 Potential Benefits 
Participants in this trial who receive active prazosin may experience less disruptive agitation 
and/ or aggression which are common distressing problems in persons with AD.  


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18.4 Relationship of this Intervention to Current Treatment Practices in AD 
Disruptive agitation is a common distressing problem in persons with AD residing in LTC 
facilities.2-7 Current psychopharmacologic approaches to agitation in LTC residents in the 
advanced stages of AD are suboptimal. The widely prescribed antipsychotics often lack efficacy 
and the incidence of adverse effects is high.10, 12 Although the antidepressant citalopram has 
been demonstrated modestly effective for mild/moderate agitation in earlier stage AD patients 
still at home, citalopram was actually inferior to placebo for agitation in more advanced AD 
patients in the LTC setting.14 The development of well-tolerated pharmacologic treatments for 
moderate to severe agitation in later stage AD patients, including both those residing at home 
and in an LTC, remains an important unmet need. 


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19 REFERENCES  
1. Wang LY, Shofer JB, Rohde K, Hart KL, Hoff DJ, McFall YH, Raskind MA, Peskind ER. 
Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with 
agitation and aggression. Am J Geriatr Psychiatry. 2009, 17(9):744-51. PMCPMC2842091.     
2. Coen RF, Swanwick GR, O'Boyle CA, Coakley D. Behaviour disturbance and other predictors 
of carer burden in Alzheimer's disease. Int J Geriatr Psychiatry. 1997, 12(3):331-6. 
PMID9152717.     
3. Clyburn LD, Stones MJ, Hadjistavropoulos T, Tuokko H. Predicting caregiver burden and 
depression in Alzheimer's disease. J Gerontol B Psychol Sci Soc Sci. 2000, 55(1):S2-13. 
PMID10728125.     
4. Lopez OL, Wisniewski SR, Becker JT, Boller F, DeKosky ST. Psychiatric medication and 
abnormal behavior as predictors of progression in probable Alzheimer disease. Arch Neurol. 
1999, 56(10):1266-72. PMID10520944.     
5. Borson S, Liptzin B, Nininger J, Rabins P. Psychiatry and the nursing home. Am J Psychiatry. 
1987, 144(11):1412-8. PMID3314537.     
6. Rabins PV, Mace NL, Lucas MJ. The impact of dementia on the family. JAMA. 1982, 
248(3):333-5. PMID7087127.     
7. Swearer JM, Drachman DA, O'Donnell BF, Mitchell AL. Troublesome and disruptive 
behaviors in dementia. Relationships to diagnosis and disease severity. J Am Geriatr Soc. 
1988, 36(9):784-90. PMID3411060.     
8. Steele C, Rovner B, Chase GA, Folstein M. Psychiatric symptoms and nursing home 
placement of patients with Alzheimer's disease. Am J Psychiatry. 1990, 147(8):1049-51. 
PMID2375439.     
9. Rovner BW, Kafonek S, Filipp L, Lucas MJ, Folstein MF. Prevalence of mental illness in a 
community nursing home. Am J Psychiatry. 1986, 143(11):1446-9. PMID3777239.     
10. Ballard CG, Margallo-Lana M, Fossey J, Reichelt K, Myint P, Potkins D, O'Brien J. A 1-year 
follow-up study of behavioral and psychological symptoms in dementia among people in care 
environments. J Clin Psychiatry. 2001, 62(8):631-6. PMID11561936.     
11. Zuidema S, Koopmans R, Verhey F. Prevalence and predictors of neuropsychiatric 
symptoms in cognitively impaired nursing home patients. J Geriatr Psychiatry Neurol. 2007, 
20(1):41-9. PMID17341770.     
12. Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, Lebowitz BD, 
Lyketsos CG, Ryan JM, Stroup TS, Sultzer DL, Weintraub D, Lieberman JA, Group C-AS. 
Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med. 
2006, 355(15):1525-38. PMID17035647.     
13. Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, Frangakis C, Ismail Z, Marano C, 
Meinert CL, Mintzer JE, Munro CA, Pelton G, Rabins PV, Rosenberg PB, Schneider LS, Shade 
DM, Weintraub D, Yesavage J, Lyketsos CG, Cit ADRG. Effect of citalopram on agitation in 
Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014, 311(7):682-91. 
PMCPMC4086818.     
14. Schneider LS, Frangakis C, Drye LT, Devanand DP, Marano CM, Mintzer J, Mulsant BH, 
Munro CA, Newell JA, Pawluczyk S, Pelton G, Pollock BG, Porsteinsson AP, Rabins PV, Rein 
L, Rosenberg PB, Shade D, Weintraub D, Yesavage J, Lyketsos CG, Cit ADRG. Heterogeneity 


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Page 55 of 60 
 
 
Version: 11.0 06DEC2021  
of Treatment Response to Citalopram for Patients With Alzheimer's Disease With Aggression or 
Agitation: The CitAD Randomized Clinical Trial. Am J Psychiatry. 2016, 173(5):465-72. 
PMID26771737.     
15. Peskind ER, Wingerson D, Murray S, Pascualy M, Dobie DJ, Le Corre P, Le Verge R, Veith 
RC, Raskind MA. Effects of Alzheimer's disease and normal aging on cerebrospinal fluid 
norepinephrine responses to yohimbine and clonidine. Arch Gen Psychiatry. 1995, 52(9):774-
82. PMID7654129.     
16. Szot P, White SS, Greenup JL, Leverenz JB, Peskind ER, Raskind MA. Changes in 
adrenoreceptors in the prefrontal cortex of subjects with dementia: evidence of compensatory 
changes. Neuroscience. 2007, 146(1):471-80. PMCPMC3399726.     
17. Sharp SI, Ballard CG, Chen CP, Francis PT. Aggressive behavior and neuroleptic 
medication are associated with increased number of alpha1-adrenoceptors in patients with 
Alzheimer disease. Am J Geriatr Psychiatry. 2007, 15(5):435-7. PMID17463193.     
18. Hardman J, Limbird L, Milinioff P, Ruddon R, editors. Goodman & Gilman’s The 
Pharmacological Basis of Therapeutics, 9th edition. New York, NY: McGraw-Hill, 1996. 229 p.     
19. Menkes DB, Baraban JM, Aghajanian GK. Prazosin selectively antagonizes neuronal 
responses mediated by alpha1-adrenoceptors in brain. Naunyn Schmiedebergs Arch 
Pharmacol. 1981, 317(3):273-5. PMID6119624.     
20. Berridge C. The locus coeruleus-noradrenergic system and stress: Implications for post-
traumatic stress disorder. In: Shiromani P, Keane T, LeDoux J, editors, Post-Traumatic Stress 
Disorder: Basic Science and Clinical Practice. New York, NY: Humana, 2009.     
21. Valentino RJ, Curtis AL, Page ME, Pavcovich LA, Florin-Lechner SM. Activation of the locus 
ceruleus brain noradrenergic system during stress: circuitry, consequences, and regulation. Adv 
Pharmacol. 1998, 42:781-4. PMID9328014.     
22. Bondareff W, Mountjoy CQ, Roth M. Loss of neurons of origin of the adrenergic projection to 
cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology. 1982, 32(2):164-8. 
PMID7198741.     
23. Elrod R, Peskind ER, DiGiacomo L, Brodkin KI, Veith RC, Raskind MA. Effects of 
Alzheimer's disease severity on cerebrospinal fluid norepinephrine concentration. Am J 
Psychiatry. 1997, 154(1):25-30. PMID8988954.     
24. Szot P, White SS, Greenup JL, Leverenz JB, Peskind ER, Raskind MA. Compensatory 
changes in the noradrenergic nervous system in the locus ceruleus and hippocampus of 
postmortem subjects with Alzheimer's disease and dementia with Lewy bodies. J Neurosci. 
2006, 26(2):467-78. PMID16407544.     
25. Hoogendijk WJ, Feenstra MG, Botterblom MH, Gilhuis J, Sommer IE, Kamphorst W, 
Eikelenboom P, Swaab DF. Increased activity of surviving locus ceruleus neurons in 
Alzheimer's disease. Ann Neurol. 1999, 45(1):82-91. PMID9894881.     
26. Raskind MA, Peskind ER, Holmes C, Goldstein DS. Patterns of cerebrospinal fluid catechols 
support increased central noradrenergic responsiveness in aging and Alzheimer's disease. Biol 
Psychiatry. 1999, 46(6):756-65. PMID10494443.     
27. Raskind MA, Peskind ER, Hoff DJ, Hart KL, Holmes HA, Warren D, Shofer J, O'Connell J, 
Taylor F, Gross C, Rohde K, McFall ME. A parallel group placebo controlled study of prazosin 
for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress 
disorder. Biol Psychiatry. 2007, 61(8):928-34. PMID17069768.     


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Page 56 of 60 
 
 
Version: 11.0 06DEC2021  
28. Raskind MA, Peterson K, Williams T, Hoff DJ, Hart K, Holmes H, Homas D, Hill J, Daniels 
C, Calohan J, Millard SP, Rohde K, O'Connell J, Pritzl D, Feiszli K, Petrie EC, Gross C, Mayer 
CL, Freed MC, Engel C, Peskind ER. A trial of prazosin for combat trauma PTSD with 
nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry. 2013, 
170(9):1003-10. PMID23846759.     
29. Physician's Desk Reference. 55th ed. ed: Medical Economics Company, 2001. p. 2501-2 p.     
30. Bernardy NC, Lund BC, Alexander B, Friedman MJ. Prescribing trends in veterans with 
posttraumatic stress disorder. J Clin Psychiatry. 2012, 73(3):297-303. PMID22490256.     
31. Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, Schmitt FA, Grundman 
M, Thomas RG, Ferris SH. Validity and reliability of the Alzheimer's Disease Cooperative Study-
Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer 
Dis Assoc Disord. 1997, 11 Suppl 2:S22-32. PMID9236949.     
32. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. 
Neurology. 1994, 44(12):2308-14. PMID7991117.     
33. Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, Ferris S. An inventory 
to assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's 
Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997, 11 Suppl 2:S33-9. 
PMID9236950.     
34. Schmitt FA, Saxton J, Ferris SH, Mackell J, Sun Y. Evaluation of an 8-item Severe 
Impairment Battery (SIB-8) vs. the full SIB in moderate to severe Alzheimer's disease patients 
participating in a donepezil study. Int J Clin Pract. 2013, 67(10):1050-6. PMCPMC3930878.     
35. Mahlberg R, Walther S. Actigraphy in agitated patients with dementia. Monitoring treatment 
outcomes. Z Gerontol Geriatr. 2007, 40(3):178-84. PMID17565435. 
36. Walther S, Mahlberg R,Eichmann U, Kunz D. Delta-9-tetrahydrocannabinol for nighttime 
agitation in severe dementia. Psychopharmacology (Berl). 2006,185(4):524-8. PMID16521031. 
37. Cohen-Mansfield J. Instruction Manual for the Cohen-Mansfield Agitation Inventory (CMAI). 
The Research Institute of the Hebrew Home of Greater Washington, 1991 
 


Protocol Number: ADC-042-PRAZ 
 
Page 57 of 60 
 
 
Version: 11.0 06DEC2021  
20 APPENDICES  
APPENDIX 1 DOSE TITRATION DIAGRAM 
 
 
 


Protocol Number: ADC-042-PRAZ 
 
Page 58 of 60 
 
 
Version: 11.0 06DEC2021  
APPENDIX 2 SCHEDULE OF EVENTS 
Visit 
Screening 
Baseline 
Titration 
Titration 
Titration 
Titration 
Titration 
Titration 
Safety 
Safety 
Outcome 
Safety 
Final / 
Early 
Term. 
Study day/week number 
D-28 to D0 
D 1 
 D4 
(±1d) 
D8 
(±1d)  
 D11 
(±1d) 
D15 
(±1d)  
D22 
(±2d) 
D29 
(±2d) 
Wk5 
(±2d) 
Wk 6 
(±2d) 
Wk 8 
(±2d) 
Wk 10 
(±2d) 
Wk 12 
(±2d) 
Obtain consent and HIPAA authorization (LAR and, if 
possible, participant)1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion/exclusion criteria (incl. Behavioral 
Inclusion Criteria Checklist) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical/Neurological exam  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Fall Risk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Labs (CBC, blood chemistry, routine urinalysis)2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead resting ECG3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (including supine & orthostatic BP, HR)4 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Review LTC/Study Partner-recorded supine & orthostatic BP, 
HR (for day 4 & day 11 titration only) 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Clinician-Rated Change in Behavioral Symptoms (for dose 
titration purposes)5 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
ADCS-CGIC-A Baseline Worksheet5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ADCS-GCIC-A5 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
NPI / NPI-NH5 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
ADCS-ADL-Severe5 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
CMAI5 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Record Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Symptoms Checklist 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/Collect Study Drug /Drug Accountability 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Place Actiwatch on Participant (Actigraphy Sub-Study Only) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Check Actiwatch Device (Actigraphy Sub-Study Only) 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Remove Actiwatch Device and Return to Analysis Center 
(Actigraphy Sub-Study Only) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Break Study Drug Blind 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1 Consent may occur on a different day, before screening measures 
2 Existing laboratory values may be used if obtained within one year of Screening. If 
the participant refuses blood draw or urinalysis at screening, the clinical judgement of 
the Site PI will determine inclusion. 
3 Existing ECG results may be used if obtained within one year of Screening. If the 
participant refuses an ECG at screening, the clinical judgement of the Site PI will 
determine inclusion. 
4 Supine and orthostatic BP and HR measurements will be performed at least daily 
during the titration period (up to Day 35). For the 24-hour period following the first 
dose and each dose increase, supine and orthostatic BP and HR measurements will 
be taken both morning and night. Beginning on Day 36 (Week 6), supine and 
orthostatic BP and HR measurements will be performed every 3 days. 
5 Assessment involves study partner as an informant, or requires information 
recorded by study partner  in the weekly diary


Protocol Number: ADC-042-PRAZ 
 
Page 59 of 60 
 
 
Version: 11.0 06DEC2021  
APPENDIX 3 LIST OF TABLES 
Table 1. Change from BL in agitation-relevant NPI domains in prazosin and placebo groups 
Table 2. Adverse effects 
Table 3. Dose titration schedule 
Table 4. Dose decrease 
 
 


Protocol Number: ADC-042-PRAZ 
 
Page 60 of 60 
 
 
Version: 11.0 06DEC2021  
APPENDIX 4 STUDY SCHEMATIC 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
HOWARD FELDMAN, MDCM, FRCP(C)  
PROFESSOR, DEPARTMENT OF NEUROSCIENCES 
DIRECTOR, ALZHEIMER’S DISEASE COOPERATIVE STUDY (ADCS) 
DEAN, ALZHEIMER’S DISEASE AND NEURODEGENERATIVE RESEARCH 
9500 Gilman Drive     La Jolla, California 92037-0949     TEL: (858) 246-1347   FAX: (858) 246-1414 
 
 
 
Prazosin for Disruptive Agitation in Alzheimer’s Disease (AD) (PEACE-AD) 
Short Title: Prazosin for Agitation in AD 
Protocol Number: ADC-042-PRAZ 
 
Statistical Analysis Plan (SAP) 
 
NCT03710642 
 
V 2 08FEB2022 
 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
 
 
ALZHEIMER’S DISEASE COOPERATIVE STUDY (ADCS) 
9500 Gilman Drive     La Jolla, California 92037-0949     TEL: (858) 246-1347     FAX: (858) 246-1414 
 
 
 
 
 
 
 
 


SIGNATURE PAGE
Protocol Title:
Prazosin for Disruptive Agitation in Alzheimer?s
Disease (AD) (PEACE-AD)
Sponsor:
ADCS/NIH
Protocol Number:
ADC-042-PRAZ
Document Version/Date:
V2 - 08 February 2022
Ronald G. Thomas, Ph.D., Professor
A u t h o r :
I n v e s t i g a t o r A p p r o v a l
By signing this d o c u m e n t , | a c k n o w l e d g e t h a t
| have read t h e d o c u m e n t and a p p r o v e o f t h e
p l a n n e d statistical analyses described herein.
| agree t h a t t h e p l a n n e d statistical analyses are
a p p r o p r i a t e f o r this study, are in accordance w i t h t h e study objectives, and are consistentw i t h
t h e statistical m e t h o d o l o g y described in t h e protocol.
| have discussed any questions
| have regarding the contents of this document with the
biostatistical author.
| also understand that any subsequent changes to the planned statistical analyses, as
described herein, will be updated within any publications related to the study.
Project D i r e c t o r Signatories:
Elaine Peskind, MD, co-PD
Signature:
Date:
Murray Raskind, MD, co-PD
Signature:
Date:
ADCS Principal Investigator Signatory:
Howard Feldman, MD, Director,
Signature:
Alzheimer?s Disease Cooperative
Study
Date:
ADC-042-PRAZ S.A.P.


SIGNATURE PAGE
Protocol Title:
Prazosin for Disruptive Agitation in Alzheimer’s
Disease (AD) (PEACE-AD)
Sponsor:
ADCS/NIH
Protocol Number:
ADC-042-PRAZ
Document Version/Date:
V2
- 08 February 2022
Author:
Ronald G. Thomas, Ph.D., Professor
Herbert Wertheim School of Public Health
and Human Longevity Science
University of California, San Diego
Signature:__________________________________
Date:______________________________________
Investigator Approval
By signing this document, I acknowledge that I have read the document and approve of the
planned statistical analyses described herein.
I agree that the planned statistical analyses are
appropriate for this study, are in accordance with the study objectives, and are consistent with
the statistical methodology described in the protocol.
I have discussed any questions
I have regarding the contents of this document with the
biostatistical author.
I also understand that any subsequent changes to the planned statistical analyses, as
described herein, will be updated within any publications related to the study.
Signature:
Date:____________________
Signature:
‘u-’ W/4
‘
“
/
Date:
1!
Signature:
Date:
LJf1( 2-O72-
Project Director Signatories:
Elaine Peskind, MD, co-PD
Murray Raskind, MD, co-PD
ADCS Principal Investigator Signatory:
Howard Feldman, MD, Director,
Alzheimer’s Disease Cooperative
Study
1
ADC-042-PRAZ S.A.P.




1 
ADC-042-PRAZ S.A.P. 
SIGNATURE PAGE 
Protocol Title: 
Prazosin for Disruptive Agitation in Alzheimer’s 
Disease (AD) (PEACE-AD) 
Sponsor: 
ADCS/NIH 
Protocol Number: 
ADC-042-PRAZ 
Document Version/Date: 
V2  - 08 February 2022 
Author:                    
Ronald G. Thomas, Ph.D., Professor 
Herbert Wertheim School of Public Health  
and Human Longevity Science 
University of California, San Diego 
Signature:____________________________________ 
Date:________________________________________ 
 
Investigator Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol.  
 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author.  
 
I also understand that any subsequent changes to the planned statistical analyses, as 
described herein, will be updated within any publications related to the study.  
 
Project Director Signatories: 
 
Elaine Peskind, MD, co-PD   
Signature:____________________________________ 
Date:________________________________________ 
Murray Raskind, MD, co-PD 
Signature:____________________________________ 
Date:________________________________________ 
 
ADCS Principal Investigator Signatory: 
Howard Feldman, MD, Director, 
Alzheimer’s Disease Cooperative 
Study 
Signature:____________________________________ 
Date:________________________________________ 
 
 


2 
ADC-042-PRAZ S.A.P. 
 
ALZHEIMER’S DISEASE COOPERATIVE STUDY (ADCS) 
 
 
 
Prazosin for Disruptive Agitation in Alzheimer’s Disease 
 
 
 
 
Statistical Analysis Plan 
 
 
Date: 08 February 2022 
Version: 2 
ADCS Biostatistics Core 
 
 


3 
ADC-042-PRAZ S.A.P. 
 
 
Table of Contents 
 
 
1. 
Introduction ............................................................................................................ 4 
1.1 Randomization / Study Design ................................................................................. 4 
2. 
Power and Sample Size Determination ................................................................... 4 
3. 
Selection of Participants to be Used in Analysis ...................................................... 4 
3.1 
Safety Analysis Population ................................................................................. 5 
4. 
Efficacy Analysis ...................................................................................................... 5 
4.1 
Analysis of the Primary Outcome ....................................................................... 5 
4.2 
Analysis of Secondary Outcomes ....................................................................... 5 
4.3 
Analysis of Exploratory Outcomes ..................................................................... 6 
5. 
Safety Analysis ........................................................................................................ 7 
6. 
Software ................................................................................................................. 8 
7. 
References .............................................................................................................. 8 
 
 


4 
ADC-042-PRAZ S.A.P. 
1. 
Introduction 
 
This study is a multisite, randomized, double-blind, placebo-controlled trial comparing efficacy and 
safety of prazosin versus placebo in AD patients with disruptive agitation either in long-term care or 
home-dwelling with a caregiver. 
 
1.1 
Randomization / Study Design 
 
In this randomized, double-blind study design, eligible participants per site will be randomized using a 
2:1 schedule to either the prazosin or placebo groups, and stratified by gender.  
 
2. 
Power and Sample Size Determination 
 
Power calculations for PEACE-AD were based on two-sample t-tests. Sample sizes were initially 
estimated targeting a power=80%, assuming a 2-sided alpha=5%, a standardized effect size of .44 SDs, 
and a dropout rate of 10%. This is a reasonable estimate of attrition given the study population and the 
relatively short follow-up period. Based on these considerations, 186 total participants are required: 
124 in the prazosin group, and 62 in the control group. 
 
Following COVID-19 in March 2020, it became clear that it would not be possible to successfully recruit 
this sample size to this protocol. In turn, a decision was made to change the focus to being a pilot trial 
of between 25-80 participants, a target number that was considered feasible in the aftermath of the 
pandemic. The range of sample sizes were then considered as a function of the standardized effect size 
delta; for delta = .71 the required sample size is 80 (53 in the prazosin group, and 27 in the control 
group), for delta = .79 the required sample size is 65 (43 in the prazosin group, and 22 in the control 
group), for delta = .91 the required sample size is 50 (33 in the prazosin group, and 17 in the control 
group), for delta = 1.0 the required sample size is 40 (27 in the prazosin group, and 13 in the control 
group), for delta = 1.2 the required sample size is 30 (20 in the prazosin group, and 10 in the control 
group).  
 
The statistical analyses at study conclusion will be based on longitudinal regression data analysis that is 
expected to increase statistical power over the initial estimates with two-sample t-tests. 
 
3. 
Selection of Participants to Be Used in Analysis 
 
The intent-to-treat (ITT) data set will include all eligible individuals who are randomized. The modified 
ITT data set will include all eligible individuals who are randomized and reached the minimum allowed 
dose of 1mg BID).  This definition has been adjusted from the protocol to allow the largest 
representation of treated participants who achieved a potentially therapeutic dose. 
 
The per-protocol data set will include all eligible participants who: 1) complete the 12-week 
assessments for the primary analysis, and demonstrate 80% drug compliance as documented in 
medication administration records.  
 


5 
ADC-042-PRAZ S.A.P. 
The modified ITT data set (mITT) will serve as the primary efficacy analysis. The ITT and per protocol 
analyses will also be performed as part of the secondary analytic plan. 
 
3.1  
Safety Analysis Population 
 
The safety analysis population is defined as those subjects that are randomized and took at least one 
dose of study drug.  Categorical safety data will be analyzed, compared between treatment arms, using 
the exact contingency table method, Fisher’s Exact Test.  
 
4. 
Efficacy Analysis 
 
4.1  
Analysis of the Primary Outcome 
 
Hypothesis 1a: Participants randomized to prazosin will manifest greater benefit on the primary 
outcome measure – the ADCS-Clinical Global Impression of Change in Agitation (ADCS-CGIC-A) 
anchored to disruptive agitation. The ADCS-CGIC-A is a 7-point scale that is structured as the clinician’s 
assessment of change from baseline compared to the ADCS-CGIC-A Baseline Worksheet. A score of 1-2 
indicates clinically meaningful improvement; a score of 3-5 indicates no clinically meaningful change; a 
score of 6-7 indicates clinically meaningful worsening. 
 
The mITT data set will be used for primary analysis in this study. To address the aims for the primary 
efficacy analysis (Hypothesis 1a), longitudinal ADCS-CGIC-A scores from first post-baseline visit through 
12 weeks will be analyzed using a mixed effects model for repeated measures (MMRM) to assess 
differences in ADCS-CGIC-A. The MMRM will include terms for time, intervention, intervention-by-time 
interaction plus covariates gender and severity of agitation at baseline defined as CMAI score. Time will 
be treated as categorical.  
 
Differences in the primary outcome, ADCS-CGIC-A, between intervention groups will be tested at the 
two-sided 5% significance level. No adjustment to the type 1 error level will be made for secondary 
analyses. 
 
4.2  
Analysis of Secondary Outcomes 
 
Hypothesis 1b: Participants randomized to prazosin will manifest greater benefit on the key secondary 
outcome measure – the Neuropsychiatric Inventory (NPI)/Neuropsychiatry Inventory-Nursing Home 
version (NPI-NH). Similar analyses to that described for the primary analysis will be performed on the 
total scores of the NPI/NPI-NH. An MMRM analysis as described above for the primary outcome 
measure will compare prazosin vs placebo at 12 weeks.  
 
Hypothesis 1c: Participants randomized to prazosin will receive a lower cumulative total dose of 
lorazepam “rescue medication” administered during the trial. Similar analyses to that described for the 
primary analysis will be performed on the total dose of rescue lorazepam. Multiple linear regression 


6 
ADC-042-PRAZ S.A.P. 
analysis will compare prazosin vs placebo through at 12 weeks. Gender and severity of agitation at 
baseline as measured by the CMAI will be included as covariates. 
 
Hypothesis 1d: Study discontinuation (“dropout”) due to persistent or worsening intolerable disruptive 
agitation will occur sooner in the placebo group than in the prazosin group. A Cox proportional hazards 
model will be used to compare the median time to dropout between groups adjusting for covariates 
(i.e., gender and baseline CMAI score). Those individuals who dropout for drug intolerance will be 
censored within this analysis according to their time from randomization to their last observation on 
protocol.  
 
Hypothesis 1e: There will be larger proportion of responders to prazosin (defined as moderate or 
marked improvement) vs non-responders (defined as minimal improvement; no change; or minimal, 
moderate, or marked worsening) on the ADCS-CGIC-A. A logistic regression model including covariates 
of gender and baseline severity on CMAI will be used to compare percent of responders (ADCS-CGIC-A 
scores of 1 and 2) vs minimal or no change (ADCS-CGIC-A scores of 3, 4, and 5) vs worsening (ADCS-
CGIC-A scores of 6 and 7).  
 
Hypothesis 2: Participants randomized to prazosin will manifest greater benefit on the modified ADCS-
Activities of Daily Living-Severe Dementia version (ADCS-ADL-Severe). Similar analyses to that 
described for the primary analysis will be performed on the ADCS-ADL-Severe. An MMRM analysis 
using the model specified for the primary outcome measure above will compare prazosin vs placebo at 
12 weeks. 
 
Hypothesis 3: Participants randomized to prazosin will have a greater reduction in the NPI/NPI-NH 
“caregiver distress”/ “occupational disruptiveness” score. Similar analyses to that described for the 
primary analysis will be performed on the NPI/NPI-NH “caregiver distress”/ “occupational 
disruptiveness” score. An MMRM analysis using the model specified for the primary outcome measure 
above will compare prazosin vs placebo at 12 weeks. 
 
 
4.3 
Analysis of Exploratory Outcomes 
 
Hypothesis 4: Participants randomized to prazosin will manifest greater benefit on the CMAI. Similar 
analyses to that described for the primary analysis will be performed on the CMAI. An MMRM analysis 
including gender as a covariate will compare prazosin vs placebo at 12 weeks. 
 
Hypothesis 5: Improvement in the five domain NPI/NPI-NH subset score (Agitation/Aggression, 
Anxiety, Disinhibition, Irritability/Lability, and Aberrant Motor Behavior) will have a greater effect size 
in response to prazosin treatment than the 12-domain NPI/NPI-NH total score. An MMRM analysis 
using the model specified for the primary outcome measure above will compare prazosin vs placebo at 
12 weeks.  
 
Hypothesis 6: Participants randomized to prazosin will manifest greater improvement in sleep 
continuity during the 12-hour nighttime period and at each week during the 12-week study duration. 
Improvement in the primary actigraphy outcome measures will be defined as a decrease in locomotor 


7 
ADC-042-PRAZ S.A.P. 
activity as assessed by total activity counts over the 24-hour period, specifically a decrease in the 12-
hour period from 6 PM to 6 AM for each week of the 12 weeks of the study.  
 
Due to small numbers, individual activity count time series and collection procedures will be reviewed 
by the Peace-AD actigraphy team (Drs. Jeff Kaye and Miranda Lim, OHSU) for practicability and 
hypothesis generation. No efficacy analyses will be performed.  
 
5. 
Safety Analysis 
 
Hypothesis 1f: The incidence of adverse events (AEs) will not differ between participants randomized 
to prazosin and those randomized to placebo. Fisher’s exact test will be used to compare rates of 
dropout due to AEs between treatment groups.  
 
Safety will be assessed by summarizing and analyzing AEs during the intervention period. AEs will be 
coded according to established Medical Dictionary for Regulatory Activities (MedDRA) terms and 
summarized by MedDRA System Organ Class (SOC) and Preferred Term (PT). 
 
Treatment-emergent adverse events (TEAEs) will be defined as events that first occurred or worsened on 
or after randomization. 
 
An overview of AEs, including the number and percentage of participants who died, suffered Serious 
Adverse Events (SAEs), discontinued due to AEs, and who suffered TEAEs, will be provided. A comparison 
between intervention arms will be performed. 
 
The number and percentage of the following types of AEs will be reported: 
• TEAEs  
• All TEAEs 
• TEAEs that led to study participant termination  
• TEAEs related to study drug 
• TEAEs by maximum severity 
• SAEs 
• All SAEs 
• SAEs related to study drug 
• AEs  
• A listing of AEs will be reported 
 
Summaries of AEs by within system organ class will be provided for the following: 
• Preexisting conditions 
• TEAEs 
• SAEs 
• Participant terminations due to AEs will also be listed 
 


8 
ADC-042-PRAZ S.A.P. 
Blood Pressure (BP) and Heart Rate (HR) 
Changes from baseline in supine (or sitting) and orthostatic (standing or sitting if unable to stand) 
systolic and diastolic BP and HR will be summarized using descriptive statistics. Similar analyses to that 
described for the primary analysis will be performed on supine and orthostatic systolic and diastolic BP 
and HR. An MMRM analysis will compare prazosin vs placebo at 12 weeks.  
 
6. 
Software 
 
Statistical software R (version 4.1.2) will be used http:www.r-project.org. 
 
7. 
References 
 
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric 
Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994 
Dec;44(12):2308-14. doi: 10.1212/wnl.44.12.2308. PMID: 7991117. 
 
Galasko D, Schmitt F, Thomas R, Jin S, Bennett D; Alzheimer's Disease Cooperative Study. Detailed 
assessment of activities of daily living in moderate to severe Alzheimer's disease. J Int Neuropsychol 
Soc. 2005 Jul;11(4):446-53. doi: 10.1017/s1355617705050502. PMID: 16209425. 
 
Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, Schmitt FA, Grundman M, Thomas RG, 
Ferris SH. Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global 
Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 
Suppl 2:S22-32. doi: 10.1097/00002093-199700112-00004. PMID: 9236949. 
 
Wang LY, Shofer JB, Rohde K, Hart KL, Hoff DJ, McFall YH, Raskind MA, Peskind ER. Prazosin for the 
treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. 
Am J Geriatr Psychiatry. 2009 Sep;17(9):744-51. doi: 10.1097/JGP.0b013e3181ab8c61. PMID: 
19700947; PMCID: PMC2842091. 
 
Weiner MF, Tractenberg RE, Jin S, Gamst A, Thomas RG, Koss E, Thal LJ. Assessing Alzheimer's disease 
patients with the Cohen-Mansfield Agitation Inventory: scoring and clinical implications. J Psychiatr 
Res. 2002 Jan-Feb;36(1):19-25. doi: 10.1016/s0022-3956(01)00047-4. PMID: 11755457.