Agitation and Aggression in Alzheimer's Disease
Conditions
Brief summary
To evaluate the efficacy of pimavanserin compared with placebo in treatment of agitation and aggression after 12 weeks of treatment
Interventions
Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth
Pimavanserin 20 mg, tablet, taken as two 10 mg tablets, once daily by mouth
OTHERPlacebo
Placebo, taken as two tablets, once daily by mouth
Sponsors
ACADIA Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, 50 years of age or older 2. Can understand the nature of the trial and protocol requirements and provide signed informed consent * from patient, if deemed competent to provide consent * from an appropriate person (e.g. patient's Legally Authorized Representative (LAR) with the patient's assent) if patient is deemed not competent to provide informed consent. 3. Has a diagnosis of probable AD according to the National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines 4. Meets criteria for agitation according to the International Psychogeriatric Association (IPA) guidelines 5. Lives at home or in an assisted living or care facility (but has the capacity to visit the clinic as an outpatient). Subjects must have been at their current location for at least 3 weeks prior to Screening and plan to remain at the same location for the duration of the trial. 6. Has a designated study partner/caregiver who is in contact with the patient at least 3 times a week on 3 separate days 7. Female patients must be of non-childbearing potential or must agree to use an acceptable method of contraception or abstinence , for at least 1 month prior to randomization, during the study, and 1 month following completion of the study 8. The patient and caregiver are willing and able to participate in all schedule evaluations and complete all required tests
Exclusion criteria
1. The agitation/aggression is attributable to concomitant medications, environmental conditions, substance abuse, or active medical or psychiatric condition 2. Patient is receiving skilled nursing care for any medical condition other than dementia 3. Treatment with an antipsychotic medication within 2 weeks of Baseline visit or 5 half lives, whichever is longer 4. Patient or study partner/caregiver has a medical condition (e.g., hearing, vision impairments) that would impair the ability to perform the study assessments. 5. Has had a myocardial infarction within the last six months 6. Has a history or symptoms of long QT syndrome 7. Has a history of a significant psychotic disorder before or during the diagnosis of probable Alzheimer's disease (including, but not limited to schizophrenia or bipolar disorder) 8. Patient is bedridden or has any significant medical condition that is unstable and would place the patient at undue risk from study drug or study procedures 9. Has a sensitivity to pimavanserin or its excipients 10\. Has previously participated in a clinical study with pimavanserin 11\. Has a Global Clinician Assessment of Suicidality (GCAS) score of 3 or 4 based on Investigator's assessment of behavior within the last 3 months at Screening or since last visit at Baseline
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohen-Mansfield Agitation Inventory (CMAI) | Baseline to 12 weeks | The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale to assess agitation. Each item is rated on a 7-point scale of frequency, from least (1) to most frequent (7). Items are summed to calculate the CMAI total score. The CMAI total score has a range of 29-203 points; higher scores indicate more severe agitation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Zarit Burden Interview | Baseline to 12 weeks | The Zarit Burden Interview (ZBI) assess the stresses experienced by caregivers of patients with dementia. It assesses 22 questions about the impact of the patient's disabilities on the caregiver's life, each rated from least (0) to most (4) frequent. Items are summed to calculate the ZBI total score. The ZBI total score ranges from 0 to 88; higher scores denoting more stresses experienced by caregivers. |
Countries
Chile, France, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study was planned to be conducted in approximately 432 subjects. For business reasons, and not related to safety, recruitment of subjects was stopped after 111 subjects were randomized. The last subject was randomized on 2 Nov 2017.
Pre-assignment details
The screening visit was followed by a 2- to 4-week screening period, including wash-out of antipsychotic agents which were prohibited during the Treatment period (exception: protocol specified agents). Subjects had to be on stable doses of permitted medications for \>=4 weeks before Baseline (\>=12 weeks for cholinesterase inhibitors and memantine).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo, taken as two tablets, once daily by mouth
Placebo: Placebo, taken as two tablets, once daily by mouth | 40 |
| Pimavanserin 20 mg Drug- pimavanserin tartrate, 20 mg, taken as two 10 mg tablets, once daily by mouth
Pimavanserin 20 mg: Pimavanserin 20 mg, tablet, taken as two 10 mg tablets, once daily by mouth | 35 |
| Pimavanserin 34 mg Drug- pimavanserin tartrate, 34 mg, taken as two 17 mg tablets, once daily by mouth
Pimavanserin 34 mg: Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth | 36 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 | 3 |
| Overall Study | Caregiver withdrew consent | 2 | 3 | 2 |
| Overall Study | Lack of Efficacy | 2 | 0 | 0 |
| Overall Study | Non-compliance with study drug | 2 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Progressive disease | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 2 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | Pimavanserin 20 mg | Pimavanserin 34 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 78.9 years STANDARD_DEVIATION 7.58 | 76.5 years STANDARD_DEVIATION 8.74 | 75.0 years STANDARD_DEVIATION 7.9 | 76.8 years STANDARD_DEVIATION 8.15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 16 Participants | 17 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 15 Participants | 18 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) White | 36 Participants | 31 Participants | 32 Participants | 99 Participants |
| Sex: Female, Male Female | 25 Participants | 15 Participants | 18 Participants | 58 Participants |
| Sex: Female, Male Male | 15 Participants | 20 Participants | 18 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 35 | 0 / 36 |
| other Total, other adverse events | 11 / 40 | 15 / 35 | 15 / 36 |
| serious Total, serious adverse events | 3 / 40 | 4 / 35 | 3 / 36 |
Outcome results
Primary
Cohen-Mansfield Agitation Inventory (CMAI)
The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale to assess agitation. Each item is rated on a 7-point scale of frequency, from least (1) to most frequent (7). Items are summed to calculate the CMAI total score. The CMAI total score has a range of 29-203 points; higher scores indicate more severe agitation
Time frame: Baseline to 12 weeks
Population: Full Analysis set, i.e. patients who had been randomized and treated and had both a baseline value and at least 1 post-baseline value for the CMAI total score.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Cohen-Mansfield Agitation Inventory (CMAI) | Week 12 | 54.3 score on a scale | Standard Error 4.3 |
| Placebo | Cohen-Mansfield Agitation Inventory (CMAI) | Baseline | 70.3 score on a scale | Standard Error 4.5 |
| Placebo | Cohen-Mansfield Agitation Inventory (CMAI) | Week 12 change from baseline | -16.8 score on a scale | Standard Error 5 |
| Pimavanserin 20 mg | Cohen-Mansfield Agitation Inventory (CMAI) | Week 12 | 52.5 score on a scale | Standard Error 4.3 |
| Pimavanserin 20 mg | Cohen-Mansfield Agitation Inventory (CMAI) | Baseline | 56.9 score on a scale | Standard Error 2.2 |
| Pimavanserin 20 mg | Cohen-Mansfield Agitation Inventory (CMAI) | Week 12 change from baseline | -3.7 score on a scale | Standard Error 3.7 |
| Pimavanserin 34 mg | Cohen-Mansfield Agitation Inventory (CMAI) | Baseline | 68.0 score on a scale | Standard Error 3.3 |
| Pimavanserin 34 mg | Cohen-Mansfield Agitation Inventory (CMAI) | Week 12 change from baseline | -12.3 score on a scale | Standard Error 2.7 |
| Pimavanserin 34 mg | Cohen-Mansfield Agitation Inventory (CMAI) | Week 12 | 53.7 score on a scale | Standard Error 3 |
Comparison: Mixed-effect model repeated measures (MMRM), with the dependent variable being the change from Baseline in CMAI total score.95% CI: [-4.8, 15]
Comparison: Mixed-effect model repeated measures (MMRM), with the dependent variable being the change from Baseline in CMAI total score.95% CI: [-8.5, 10.5]
Secondary
Zarit Burden Interview
The Zarit Burden Interview (ZBI) assess the stresses experienced by caregivers of patients with dementia. It assesses 22 questions about the impact of the patient's disabilities on the caregiver's life, each rated from least (0) to most (4) frequent. Items are summed to calculate the ZBI total score. The ZBI total score ranges from 0 to 88; higher scores denoting more stresses experienced by caregivers.
Time frame: Baseline to 12 weeks
Population: Full Analysis set, i.e. patients who had been randomized and treated and had both a baseline value and at least 1 post-baseline value for the CMAI total score.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Zarit Burden Interview | Week 12 | 37.0 score on a scale | Standard Error 3.2 |
| Placebo | Zarit Burden Interview | Baseline | 41.5 score on a scale | Standard Error 2.6 |
| Placebo | Zarit Burden Interview | Week 12 change from baseline | -6.5 score on a scale | Standard Error 2.3 |
| Pimavanserin 20 mg | Zarit Burden Interview | Week 12 | 36.8 score on a scale | Standard Error 3.7 |
| Pimavanserin 20 mg | Zarit Burden Interview | Baseline | 40.8 score on a scale | Standard Error 2.4 |
| Pimavanserin 20 mg | Zarit Burden Interview | Week 12 change from baseline | -4.9 score on a scale | Standard Error 2.3 |
| Pimavanserin 34 mg | Zarit Burden Interview | Baseline | 41.7 score on a scale | Standard Error 2.5 |
| Pimavanserin 34 mg | Zarit Burden Interview | Week 12 change from baseline | -5.5 score on a scale | Standard Error 2.5 |
| Pimavanserin 34 mg | Zarit Burden Interview | Week 12 | 35.7 score on a scale | Standard Error 3.5 |