We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Prazosin for Agitation in Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03710642
Recruitment Status : Completed
First Posted : October 18, 2018
Last Update Posted : July 11, 2022
Sponsor:
Collaborators:
National Institute on Aging (NIA)
VA Puget Sound Health Care System
Alzheimer's Association
Information provided by (Responsible Party):
Alzheimer's Disease Cooperative Study (ADCS)

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


Condition or disease Intervention/treatment Phase
Alzheimer's Disease Disruptive Behavior Drug: Prazosin Drug: Placebo oral capsule Phase 2

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).

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 35 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Prazosin for Disruptive Agitation in Alzheimer's Disease (AD) (PEACE-AD)
Actual Study Start Date : October 23, 2018
Actual Primary Completion Date : January 7, 2022
Actual Study Completion Date : February 28, 2022


Arm Intervention/treatment
Active Comparator: Treatment (Prazosin)

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.

Drug: Prazosin
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
Other Names:
  • Prazosin HCl
  • Minipress

Placebo Comparator: Placebo oral capsule
Placebo medication will be administered in a titration schedule mimicking the active comparator treatment.
Drug: Placebo oral capsule
Placebo capsule matched to appearance of active drug.
Other Name: Placebo




Primary Outcome Measures :
  1. ADAS-Clinical Global Impression of Change in Agitation (CGIC) [ Time Frame: 12 weeks.Time will be treated as categorical. ]
    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 a direct examination of the participant and an interview of the participant's primary caregiver and other LTC facility staff. The participant is rated on a 7-point Likert scale. Scores can range from 1 (improvement) to 7 (worsening).


Secondary Outcome Measures :
  1. Neuropsychiatric Inventory Nursing Home version (NPI-NH) [ Time Frame: 12 weeks ]
    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. 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.

  2. Neuropsychiatric Inventory(home based) (NPI) [ Time Frame: 12 weeks ]
    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. 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.

  3. Rescue Mediation: total mg Lorazepam Administered [ Time Frame: 12 weeks ]
    Cumulative total dose of Lorazepam rescue medication administered during the trial.Information on the total mg rescue lorazepam administered 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.

  4. Study discontinuations due to persistent or worsening disruptive agitation. [ Time Frame: 12 weeks ]
    Cox proportional hazard modelling comparing the median time to drop out between groups.

  5. Responder analysis on CGIC-A [ Time Frame: 12 weeks ]
    Comparison of proportions of responders with moderate or marked improvement versus non responders on the ADCS-CGIC-A.

  6. ADCS-ADL-Severe [ Time Frame: 12 weeks ]
    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. 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).

  7. Caregiver distress on NPI/NPI-NH [ Time Frame: 12 weeks ]
    Comparison of effects on caregiver distress/occupational disruptiveness scores on the NPI/NPI-NH.


Other Outcome Measures:
  1. Cohen Mansfield Agitation Inventory (CMAI). [ Time Frame: 12 weeks ]
    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 rating. The CMAI will be completed at baseline and study termination.

  2. Five-domain NPI/NPI-NHsubset score [ Time Frame: 12 weeks ]
    The NPI/NPI-NH subset score includes agitation/aggression, anxiety, disinhibition, irritability/lability and abherent motor activity.

  3. Sleep Continuity [ Time Frame: 12 weeks ]
    Actigraphy measures of locomotor activity during the night will be compared between groups.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03710642


Locations
Layout table for location information
United States, Arizona
Banner Sun Health Research Institute
Sun City, Arizona, United States, 85351
United States, California
University of Southern California
Los Angeles, California, United States, 90033
University of California, San Diego (UCSD)
San Diego, California, United States, 92093
Alta California Medical Group
Simi Valley, California, United States, 93065
Stanford University
Stanford, California, United States, 94305
United States, Kentucky
University of Kentucky
Lexington, Kentucky, United States, 40506
United States, Maine
Northern Light/Acadia Hospital Eastern Maine Medical Center
Bangor, Maine, United States, 04401
United States, New York
VAMC: James J Peters
Bronx, New York, United States, 10468
SUNY Upstate Medical University
Syracuse, New York, United States, 13210
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, South Carolina
Roper St. Francis Hospital
Charleston, South Carolina, United States, 29401
United States, Texas
University of Texas, Health Science Center San Antonio
San Antonio, Texas, United States, 78229
United States, Washington
University of Washington
Seattle, Washington, United States, 98104-2499
University of Washington
Seattle, Washington, United States, 98108
Sponsors and Collaborators
Alzheimer's Disease Cooperative Study (ADCS)
National Institute on Aging (NIA)
VA Puget Sound Health Care System
Alzheimer's Association
  Study Documents (Full-Text)

Documents provided by Alzheimer's Disease Cooperative Study (ADCS):
Study Protocol  [PDF] December 6, 2021
Statistical Analysis Plan  [PDF] February 8, 2022
Informed Consent Form  [PDF] April 5, 2021

Publications:

Layout table for additonal information
Responsible Party: Alzheimer's Disease Cooperative Study (ADCS)
ClinicalTrials.gov Identifier: NCT03710642    
Other Study ID Numbers: ADC-042-PRAZ
5U19AG010483 ( U.S. NIH Grant/Contract )
First Posted: October 18, 2018    Key Record Dates
Last Update Posted: July 11, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Data sharing is integral to the ADCS's mission to develop and execute innovative clinical trials focused on interventions that may prevent, delay, or treat the expression of Alzheimer's disease and related dementias. The ADCS is committed to sharing resources and tools, including data, biospecimens, trial designs, outcome and analysis measures following NIH guidelines.

DATA SHARING: The ADCS Data and Sample Sharing Committee (DSSC) grants access to de-identified data to individuals who complete the request process and agree to the conditions in an ADCS/UCSD Data Use Agreement (DUA). After approval and receipt of the fully executed DUA, applicants are authorized to acquire data. Non-compliance with the DUA, including the requirement to provide requested updates will jeopardize further access to data.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: 01 March 2023
Access Criteria: Data requestors must complete an ADCS data and sample sharing request form. Upon approval, requestors must complete a data use agreement prior to accessing the data.
URL: https://www.adcs.org/data-sharing/

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alzheimer's Disease Cooperative Study (ADCS):
Dementia
Agitation
PEACE-AD
Additional relevant MeSH terms:
Layout table for MeSH terms
Alzheimer Disease
Psychomotor Agitation
Problem Behavior
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Dyskinesias
Neurologic Manifestations
Psychomotor Disorders
Neurobehavioral Manifestations
Behavioral Symptoms
Prazosin
Antihypertensive Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs