Prazosin for Agitation in Alzheimer's Disease

Study Overview
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Brief Summary
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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
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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).

Official Title
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Prazosin for Disruptive Agitation in Alzheimer's Disease (AD) (PEACE-AD)

Conditions
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Alzheimer's Disease, Disruptive Behavior

Intervention / Treatment
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* Drug: Prazosin
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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. 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. Exclusion Criteria: 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, 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. 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). 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. 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 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. P articipants whom the Site Principal Investigator deems to be otherwise unsuitable for participation.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment (Prazosin)<br>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 mg QAM and 2 mg QHS for days 8 to 10 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<br>* 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<br>* Other names: Minipress;|
| Placebo Comparator: Placebo oral capsule<br>Placebo medication will be administered in a titration schedule mimicking the active comparator treatment. | Drug: Placebo oral capsule<br>* Placebo capsule matched to appearance of active drug.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuropsychiatric Inventory (NPI)/Neuropsychiatry Inventory-Nursing Home Version (NPI-NH) | 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. Minimum score is 0 and highest score is 144. A higher score means a worse outcome. This outcome is the change from baseline to week 12. | 12 weeks | 
| Rescue Medication: Total mg Lorazepam Administered | 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. | 12 weeks | 
| Study Discontinuations | Cox proportional hazard modelling comparing the median time to drop out between treatment groups. | 12 weeks | 
| Responder Analysis on CGIC-A | Comparison of proportions of responders versus non responders on the ADCS-CGIC-A. Responders are defined as those with moderate or marked improvement in agitation symptoms compared to baseline assessment. | 12 weeks | 
| ADCS-ADL-Severe | The ADCS-ADL-Severe questionnaire is a secondary outcome measure aimed at detecting functional decline in people with severe AD. 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). This outcome is the change from baseline to week 12. | 12 weeks | 
| Caregiver Distress on NPI/NPI-NH | Comparison of effects on caregiver distress/occupational disruptiveness scores on the NPI/NPI-NH. Minimum score is 0 and maximum score is 60. A higher score is a worse outcome. This outcome is the change from baseline to week 12. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dementia, Agitation, PEACE-AD