Prazosin for Agitation in Alzheimer's Disease

NCT03710642 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: ADC-042-PRAZ5U19AG010483
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 14

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

Conditions

Alzheimer's Disease; Disruptive Behavior

Keywords

Dementia; Agitation; PEACE-AD

Outcome Measures

Primary Outcomes (1)

• ADCS-Clinical Global Impression of Change in Agitation (ADCS-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 a direct examination of the participant and an interview of the participant's primary caregiver and other LTC facility staff. The baseline assessment is qualitative therefore there is no score at baseline; post-baseline scores represent a change score compared to baseline. 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. There is no baseline score; post-baseline scores range from 1 (improvement) to 7 (worsening). 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.

  From Baseline through Week 12.

Secondary Outcomes (6)

• Neuropsychiatric Inventory (NPI)/Neuropsychiatry Inventory-Nursing Home Version (NPI-NH)

  12 weeks

• Rescue Medication: Total mg Lorazepam Administered

  12 weeks

• Study Discontinuations

  12 weeks

• Responder Analysis on CGIC-A

  12 weeks

• ADCS-ADL-Severe

  12 weeks

Other Outcomes (3)

• Cohen Mansfield Agitation Inventory (CMAI).

  12 weeks

• Five-domain NPI/NPI-NH Subset Score

  12 weeks

• Sleep Continuity

  12 weeks

Study Arms (2)

Treatment (Prazosin)

ACTIVE COMPARATOR

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

Placebo oral capsule

PLACEBO COMPARATOR

Placebo medication will be administered in a titration schedule mimicking the active comparator treatment.

Drug: Placebo oral capsule

Interventions

Prazosin DRUG

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

Also known as: Prazosin HCl, Minipress

Treatment (Prazosin)

Placebo oral capsule DRUG

Placebo capsule matched to appearance of active drug.

Also known as: Placebo

Placebo oral capsule

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must meet all of the following criteria be included in the study:
• 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.
• Participants must either reside in an LTC that is associated with the study site or at home with full-time caregiving.
• 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:
• irritability,
• physically and/or verbally aggressive behavior,
• physical resistiveness to necessary care
• Psychotropic medication, if used, should be stable for at least 2 weeks prior to randomization.
• If taking cholinesterase inhibitor and/or memantine, must be on stable dose for 3 months prior t o randomization.
• During the week before randomization, the above-described behaviors of eligible participants must be rated as of at least moderate severity.

You may not qualify if:

• Participants meeting any of the following criteria must not be included in the study:
• 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).
• Other neurodegenerative diseases, including Parkinsons disease and Huntingtons disease, or cerebral tumor.
• 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.
• Current treatment for seizure disorder (Note: anticonvulsants prescribed for disruptive agitation in the absence of seizure disorder will be allowed).
• Abnormal laboratory values with clinical significance in the opinion of the site Principal Investigator.
• 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.
• Bedbound; participants may be ambulatory or use a wheelchair.
• Absence of any comprehensible language.
• 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).
• Preexisting recurrent hypotension (systolic BP \<110).
• If a reading of \<110 systolic is measured at screening,
• 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).
• 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)

Sponsors & Collaborators

• Alzheimer's Disease Cooperative Study (ADCS): lead
• National Institute on Aging (NIA): collaborator
• VA Puget Sound Health Care System: collaborator
• Alzheimer's Association: collaborator

Study Sites (14)

Banner Sun Health Research Institute

Sun City, Arizona, 85351, United States

Location

University of Southern California

Los Angeles, California, 90033, United States

Location

University of California, San Diego (UCSD)

San Diego, California, 92093, United States

Location

Alta California Medical Group

Simi Valley, California, 93065, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

University of Kentucky

Lexington, Kentucky, 40506, United States

Location

Northern Light/Acadia Hospital Eastern Maine Medical Center

Bangor, Maine, 04401, United States

Location

SUNY Upstate Medical University

Syracuse, New York, 13210, United States

Location

VAMC: James J Peters

The Bronx, New York, 10468, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Roper St. Francis Hospital

Charleston, South Carolina, 29401, United States

Location

University of Texas, Health Science Center San Antonio

San Antonio, Texas, 78229, United States

Location

University of Washington

Seattle, Washington, 98104-2499, United States

Location

University of Washington

Seattle, Washington, 98108, United States

Location

Related Publications (6)

• 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.

  PMID: 7654129 BACKGROUND

• 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.

  PMID: 3399726 BACKGROUND

• 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.

  PMID: 8988954 BACKGROUND

• 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.

  PMID: 10494443 BACKGROUND

• 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.

  PMID: 17069768 BACKGROUND

• 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.

  PMID: 23846759 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease; Problem Behavior; Dementia; Psychomotor Agitation

Interventions

Prazosin

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Behavioral Symptoms; Behavior; Child Behavior; Dyskinesias; Neurologic Manifestations; Psychomotor Disorders; Neurobehavioral Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Aberrant Motor Behavior in Dementia

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

Following COVID-19, it became clear that it would not be possible to recruit the target sample size of 186 participants exclusively at LTC facilities. In 2021 we adjusted the trial size and incorporated the goal of gathering pilot data to demonstrate the feasibility of enrolling home dwelling participants and using remote visits. These changes resulted in the study sample size being re-estimated. Final enrollment was 35 randomized participants, of which 32 were at home with full time caregiving.

Results Point of Contact

• Title: Clinical Operations
• Organization: Alzheimer's Disease Cooperative Study (ADCS)

alzinfo@ucsd.edu

858-246-1333

Study Officials

• Howard Feldman

  Alzheimer's Disease Cooperative Study (ADCS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 9, 2018
• First Posted: October 18, 2018
• Study Start: October 23, 2018
• Primary Completion: January 5, 2022
• Study Completion: January 5, 2022
• Last Updated: February 6, 2023
• Results First Posted: February 6, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

US (14)