Alzheimer's Disease, Disruptive Behavior
Conditions
Keywords
Dementia, Agitation, PEACE-AD
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).
Interventions
DRUGPrazosin
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
DRUGPlacebo oral capsule
Placebo capsule matched to appearance of active drug.
Sponsors
National Institute on Aging (NIA)
VA Puget Sound Health Care System
Alzheimer's Association
Alzheimer's Disease Cooperative Study (ADCS)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ADCS-Clinical Global Impression of Change in Agitation (ADCS-CGIC-A) | From Baseline through Week 12. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Study Discontinuations | 12 weeks | Cox proportional hazard modelling comparing the median time to drop out between treatment groups. |
| Responder Analysis on CGIC-A | 12 weeks | 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. |
| ADCS-ADL-Severe | 12 weeks | 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. |
| Caregiver Distress on NPI/NPI-NH | 12 weeks | 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. |
| Neuropsychiatric Inventory (NPI)/Neuropsychiatry Inventory-Nursing Home Version (NPI-NH) | 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. 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. |
| Rescue Medication: Total mg Lorazepam Administered | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Sleep Continuity | 12 weeks | Actigraphy measures of locomotor activity during the night will be compared between groups. |
| Cohen Mansfield Agitation Inventory (CMAI). | 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 rates 29 agitated behaviors, each on a 7-point scale (1-7) of frequency ranging from never to several times per hour. Ratings pertain to the 2-week period preceding the rating. A higher score means a worse outcome. |
| Five-domain NPI/NPI-NH Subset Score | 12 weeks | The Neuropsychiatric Inventory (NPI)/Neuropsychiatry Inventory-Nursing Home version (NPI-NH) subset score includes agitation/aggression, anxiety, disinhibition, irritability/lability and aberrant motor activity. Minimum and maximum values are 0 and 60 respectively. A higher score is a worse outcome. |
Countries
United States
Participant flow
Recruitment details
Recruitment initiated September 2018: The research was initially approved for enrollment at Long Term Care facilities. Covid-19 impacted these facilities, and protocol amendments were approved to allow home-dwelling participants with full-time caregivers to enroll into the trial. Recruitment came from a blend of LTC facilities and institution/clinics.
Pre-assignment details
Of the 54 participants consented and screened, 35 were eligible to participate in the trial and 19 were screening failures. Of the 35 participants randomized, 34 participants went on to receive study drug. One patient discontinued after randomization but prior to first dose administration.
Participants by arm
| Arm | Count |
|---|---|
| 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.
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 | 26 |
| Placebo Oral Capsule Placebo medication will be administered in a titration schedule mimicking the active comparator treatment.
Placebo oral capsule: Placebo capsule matched to appearance of active drug. | 8 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 1 |
| Overall Study | NA-no code provided | 1 | 0 |
| Overall Study | non-site physician recommendation | 1 | 0 |
| Overall Study | other is selected as the reason for study termination | 1 | 3 |
| Overall Study | Participant unwilling or unable to participate | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Treatment (Prazosin) | Total | Placebo Oral Capsule |
|---|---|---|---|
| Age, Continuous | 80.02 years STANDARD_DEVIATION 11.27 | 79.67 years STANDARD_DEVIATION 10.5 | 78.53 years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 4 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 29 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 32 Participants | 8 Participants |
| Region of Enrollment United States | 26 participants | 34 participants | 8 participants |
| Sex: Female, Male Female | 19 Participants | 25 Participants | 6 Participants |
| Sex: Female, Male Male | 7 Participants | 9 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 8 |
| other Total, other adverse events | 13 / 26 | 4 / 8 |
| serious Total, serious adverse events | 5 / 26 | 0 / 8 |
Outcome results
Primary
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.
Time frame: From Baseline through Week 12.
Population: The population analyzed for this outcome includes: 20 study completers, and 3 early terminations that completed their termination visit at or after the week 10 timepoint. Therefore, the N analyzed is higher than the numbers of completers listed in the participant flow section.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Prazosin) | ADCS-Clinical Global Impression of Change in Agitation (ADCS-CGIC-A) | 3.434 score on a scale | Standard Error 0.2833 |
| Placebo Oral Capsule | ADCS-Clinical Global Impression of Change in Agitation (ADCS-CGIC-A) | 3.442 score on a scale | Standard Error 0.6141 |
p-value: 0.9904Regression, Linear
Secondary
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.
Time frame: 12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Prazosin) | ADCS-ADL-Severe | -1.47055 score on a scale | Standard Error 1.0062 |
| Placebo Oral Capsule | ADCS-ADL-Severe | -4.53993 score on a scale | Standard Error 2.1863 |
p-value: 0.2038Regression, Linear
Secondary
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.
Time frame: 12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Prazosin) | Caregiver Distress on NPI/NPI-NH | -2.4438 score on a scale | Standard Error 2.332 |
| Placebo Oral Capsule | Caregiver Distress on NPI/NPI-NH | 0.9446 score on a scale | Standard Error 5.043 |
p-value: 0.54133Regression, Linear
Secondary
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.
Time frame: 12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Prazosin) | Neuropsychiatric Inventory (NPI)/Neuropsychiatry Inventory-Nursing Home Version (NPI-NH) | -6.033 units on a scale | Standard Error 4.692 |
| Placebo Oral Capsule | Neuropsychiatric Inventory (NPI)/Neuropsychiatry Inventory-Nursing Home Version (NPI-NH) | 5.506 units on a scale | Standard Error 10.149 |
p-value: 0.30328Regression, Linear
Secondary
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Prazosin) | Rescue Medication: Total mg Lorazepam Administered | 0.25 mg | Standard Deviation 0.69 |
| Placebo Oral Capsule | Rescue Medication: Total mg Lorazepam Administered | 0.14 mg | Standard Deviation 0.24 |
p-value: 0.21981Regression, Linear
Secondary
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.
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Prazosin) | Responder Analysis on CGIC-A | 7 Participants |
| Placebo Oral Capsule | Responder Analysis on CGIC-A | 1 Participants |
p-value: 0.9267Regression, Logistic
Secondary
Study Discontinuations
Cox proportional hazard modelling comparing the median time to drop out between treatment groups.
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Treatment (Prazosin) | Study Discontinuations | 65.63 days | Standard Deviation 32.63 |
| Placebo Oral Capsule | Study Discontinuations | 54.62 days | Standard Deviation 33.29 |
p-value: 0.6366Regression, Cox
Other Pre-specified
Cohen Mansfield Agitation Inventory (CMAI).
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 rates 29 agitated behaviors, each on a 7-point scale (1-7) of frequency ranging from never to several times per hour. Ratings pertain to the 2-week period preceding the rating. A higher score means a worse outcome.
Time frame: 12 weeks
Other Pre-specified
Five-domain NPI/NPI-NH Subset Score
The Neuropsychiatric Inventory (NPI)/Neuropsychiatry Inventory-Nursing Home version (NPI-NH) subset score includes agitation/aggression, anxiety, disinhibition, irritability/lability and aberrant motor activity. Minimum and maximum values are 0 and 60 respectively. A higher score is a worse outcome.
Time frame: 12 weeks
Other Pre-specified
Sleep Continuity
Actigraphy measures of locomotor activity during the night will be compared between groups.
Time frame: 12 weeks