Prazosin for Agitation in Alzheimer's Disease

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
defined as having at least one of any of the following target behaviors with ≥ moderately
severe rating at least 5 times per week for a minimum of 4 weeks: 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) in approximately 186 Alzheimer's
disease (AD) residents in long-term care (LTC) settings. 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).

Inclusion Criteria:

1. Males and females with probable or possible AD by NINCDS-ADRDA criteria utilizing
medical history; medical records review; physical, neurological, and psychiatric exam;
and screening laboratory tests, who are residing in a LTC facility. Brain imaging is
not a requirement.

2. At Baseline (BL), participants must have disruptive agitation (documented on the
Behavioral Inclusion Criteria Checklist and detailed on the ADCS-CGIC-A BL Worksheet)
defined as having at least one of the following target behaviors with > moderately
severe rating at least 5 times per week for a minimum duration of 4 weeks: 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). These behaviors must be problematic in that they cause participant and
caregiver distress and/or interfere with essential care or disrupt the LTC
environment. Target behaviors may be any combination of the listed domains, as long as
there are 5 or more instances per week of at least moderate severity.

3. Psychotropic medication, if used, should be stable for at least 2 weeks prior to
randomization.

4. If taking cholinesterase inhibitor and/or memantine, must be on stable dose(s) for 3
months prior to randomization.

5. Must be able to swallow capsules whole.

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.

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).

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, avanafil, and
trazodone.

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.