Clinical trial NCT03710642: Prazosin for Agitation in Alzheimer's Disease
Official title: Prazosin for Disruptive Agitation in Alzheimer's Disease (AD) (PEACE-AD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Disruptive Behavior
Keywords: Dementia
Agitation
PEACE-AD
Lead sponsor: Alzheimer's Disease Cooperative Study (ADCS)
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: VA Puget Sound Health Care System
name: Alzheimer's Association
First posted: 2018-10-18
Enrollment: 35
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: 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:

   1. irritability,
   2. physically and/or verbally aggressive behavior,
   3. physical resistiveness to necessary care
   4. 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 t o randomization.
6. During the week before randomization, the above-described behaviors of eligible participants must be rated as of at least moderate severity.

Exclusion Criteria:

Participants meeting any of the following criteria must not be included in the study:

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 Parkinsons disease and Huntingtons 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 Investigators 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).

    * 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 participants 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 participants 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:

    * have been postmenopausal (no menstrual cycle for past 24 months)
    * do not have a uterus,
    * have bilateral tubal ligation,
    * 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. P articipants whom the Site Principal Investigator deems to be otherwise unsuitable for participation.

Primary outcomes:
measure: ADCS-Clinical Global Impression of Change in Agitation (ADCS-CGIC-A)
timeFrame: From Baseline through Week 12.
Secondary outcomes:
measure: Neuropsychiatric Inventory (NPI)/Neuropsychiatry Inventory-Nursing Home Version (NPI-NH)
timeFrame: 12 weeks
measure: Rescue Medication: Total mg Lorazepam Administered
timeFrame: 12 weeks
measure: Study Discontinuations
timeFrame: 12 weeks
measure: Responder Analysis on CGIC-A
timeFrame: 12 weeks
measure: ADCS-ADL-Severe
timeFrame: 12 weeks
measure: Caregiver Distress on NPI/NPI-NH
timeFrame: 12 weeks
Other outcomes:
measure: Cohen Mansfield Agitation Inventory (CMAI).
timeFrame: 12 weeks
measure: Five-domain NPI/NPI-NH Subset Score
timeFrame: 12 weeks
measure: Sleep Continuity
timeFrame: 12 weeks
Locations:
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: San Diego
country: United States
facility: University of California, San Diego (UCSD)
state: California
city: Simi Valley
country: United States
facility: Alta California Medical Group
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Bangor
country: United States
facility: Northern Light/Acadia Hospital Eastern Maine Medical Center
state: Maine
city: Bronx
country: United States
facility: VAMC: James J Peters
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Charleston
country: United States
facility: Roper St. Francis Hospital
state: South Carolina
city: San Antonio
country: United States
facility: University of Texas, Health Science Center San Antonio
state: Texas
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: Alzheimer's Disease Cooperative Study (ADCS)
name: Howard Feldman
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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 Sep;52(9):774-82. doi: 10.1001/archpsyc.1995.03950210068012.
citation: Torroba Alvarez L, Hermida Donate JM, Ezpeleta Baquedano C, Munoz Zato E. [Methemoglobinemia secondary to the treatment of opportunistic infections in patients with AIDS]. Rev Clin Esp. 1988 Mar;182(5):289-90. No abstract available. Spanish.
citation: 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 Jan;154(1):25-30. doi: 10.1176/ajp.154.1.25.
citation: 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 Sep 15;46(6):756-65. doi: 10.1016/s0006-3223(99)00008-6.
citation: 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 Apr 15;61(8):928-34. doi: 10.1016/j.biopsych.2006.06.032. Epub 2006 Oct 25.
citation: 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 Sep;170(9):1003-10. doi: 10.1176/appi.ajp.2013.12081133.