Neuropsychiatric Symptoms Related to Neurodegenerative Disease
Conditions
Brief summary
The purpose of this study is to assess the safety and tolerability of pimavanserin compared to placebo in adult and elderly subjects with neuropsychiatric symptoms related to neurodegenerative disease.
Interventions
DRUGPimavanserin
Pimavanserin 34 mg total daily dose, tablets, once daily by mouth (provided as two 17 mg NUPLAZID® tablets)
DRUGPlacebo
Placebo, tablets, once daily by mouth (provided as two placebo tablets)
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
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Can understand the nature of the trial and protocol requirements and provide written informed consent. If the subject is deemed not competent to provide informed consent, the following requirements for consent must be met: 1. The subject's legally acceptable representative (LAR) (or study partner/caregiver, if local regulations allow) must provide written informed consent 2. The subject must provide written (if capable) informed assent 2. Subject requires some or complete assistance with one or more of the following: 1. Instrumental activities of daily living (communication, transportation, meal preparation, shopping, housework, managing medications, managing personal finances) OR 2. Basic activities of daily living (personal hygiene, dressing, eating, maintaining continence or transferring) 3. Meets clinical criteria for at least one of the following disorders, with or without cerebrovascular disease (CVD): 1. Parkinson's disease with or without dementia as defined by the Movement Disorder Society's Task Force 2. Dementia with Lewy bodies (DLB) 3. All-cause dementia, possible or probable Alzheimer's disease (AD) 4. Frontotemporal degeneration spectrum disorders, including possible or probable: i. Behavioral variant frontotemporal dementia ii. Progressive supranuclear palsy iii. Corticobasal degeneration e. Vascular dementia, including post-stroke dementia multi-infarct dementia and/or subcortical ischemic vascular dementia (SIVD) 4. Has a designated study partner/caregiver 5. Can come to the clinic for study visits with a study partner/caregiver 6. If the subject is female, she must not be pregnant or breastfeeding. She must also be of non-childbearing potential (defined as either surgically sterilized or at least 1 year postmenopausal) or must agree to use a clinically acceptable method of contraception or be abstinent. 7. If the subject is taking an antipsychotic medication at the time of screening, the antipsychotic medication must be discontinued 2 weeks or 5 half-lives (whichever is longer)
Exclusion criteria
1. Is in hospice, is receiving end-of-life palliative care, or is bedridden 2. Has psychotic symptoms that are primarily attributable to delirium or substance abuse (i.e., neuropsychiatric symptoms not related to neurodegenerative disease) 3. Has current evidence of an unstable neurological, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including cancer or malignancies that, in the judgment of the Investigator, would jeopardize the safe participation of the subject in the study or significantly interfere with the conduct or interpretation of the study 4. Has a known personal or family history of long QT syndrome or family history of sudden cardiac death 5. Has a clinical significant CNS abnormality that is most likely contributing to the dementia or findings on MRI or CT including: 1. intracranial mass lesion 2. vascular malformation 3. evidence of \>4 hemosiderin deposits 6. The urine drug screen result at Visit 1 (Screening) indicates the presence of amphetamine/methamphetamine, barbiturates, cocaine, or phencyclidine (PCP). Subjects who test positive for amphetamines and who have a valid prescription may be retested if they agree to abstain from the medication for the length of their participation in the study. The presence of benzodiazepines, marijuana (THC), or opiates does not necessarily exclude the subject from the study, as assessed by the Investigator in consultation with the Medical Monitor. 7. Has previously been enrolled in any prior clinical study with pimavanserin or is currently taking pimavanserinIs judged by the Investigator or the Medical Monitor to be inappropriate for the study for any reason Additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent Adverse Events (TEAEs) | Treatment Period: 8 weeks | Number (%) of patients with treatment-emergent AEs |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 8 in Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) | Treatment Period: 8 weeks | The ESRS is a questionnaire to assess drug induced movement disorders, including parkinsonism; the ESRS-A is an accepted modified form of the original ESRS. The ESRS-A consists of 4 subscales and 4 clinical global impression movement severity scales of Parkinsonism, dyskinesia, dystonia, and akathisia. The Parkinsonism scale consists of 10 items, the dyskinesia subscale of 6 items, the dystonia subscale of 6 items, and the akathisia subscale of 2 items. Each item is scored on a 6-point scale from 0 (absent) to 5 (extreme). The ESRS-A total score is the sum of the 24 item scores with a possible range of 0 to 120. Higher scores denote more severe drug-induced movement disorders. |
| Change From Baseline to Week 8 in Mini-Mental State Examination (MMSE) | Treatment Period: 8 weeks | The MMSE is a 30-item questionnaire to quantitatively assess cognition, focusing on questions related to time and place of testing, repeating lists of words, arithmetic, language use and comprehension, and copying a drawing. Each of the 30 items has 2 possible values of 0 (incorrect) or 1 (correct). The MMSE total score is derived as the sum of the 30 item scores; thus, it can range from 0 to 30. Lower scores indicate more severe cognitive impairment. |
Countries
Bulgaria, Colombia, Czechia, Georgia, Mexico, Poland, Romania, Russia, Serbia, South Africa, Ukraine, United States
Participant flow
Recruitment details
This was a multicenter study in adult and elderly patients with neuropsychiatric symptoms related to neurodegenerative disease.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Pimavanserin matching placebo (administered as 2 capsules) once daily | 392 |
| Pimavanserin 34 mg Pimavanserin 34 mg (administered as 2 x 17 mg capsules) once daily | 392 |
| Total | 784 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 10 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Lack of Efficacy | 2 | 1 |
| Overall Study | Lost to Follow-up | 3 | 0 |
| Overall Study | Not further specified | 5 | 7 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Study drug noncompliance | 1 | 2 |
| Overall Study | Withdrawal by Subject | 5 | 6 |
Baseline characteristics
| Characteristic | Placebo | Pimavanserin 34 mg | Total |
|---|---|---|---|
| Age, Continuous | 72.1 years STANDARD_DEVIATION 7.13 | 72.7 years STANDARD_DEVIATION 6.91 | 72.4 years STANDARD_DEVIATION 7.02 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 5 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 00 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 16 Participants | 32 Participants |
| Race (NIH/OMB) White | 367 Participants | 368 Participants | 735 Participants |
| Region of Enrollment Bulgaria | 29 participants | 29 participants | 58 participants |
| Region of Enrollment Colombia | 13 participants | 11 participants | 24 participants |
| Region of Enrollment Czechia | 21 participants | 17 participants | 38 participants |
| Region of Enrollment Georgia | 8 participants | 19 participants | 27 participants |
| Region of Enrollment Mexico | 6 participants | 8 participants | 14 participants |
| Region of Enrollment Poland | 54 participants | 55 participants | 109 participants |
| Region of Enrollment Romania | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Russia | 55 participants | 55 participants | 110 participants |
| Region of Enrollment Serbia | 18 participants | 27 participants | 45 participants |
| Region of Enrollment South Africa | 6 participants | 8 participants | 14 participants |
| Region of Enrollment Ukraine | 62 participants | 45 participants | 107 participants |
| Region of Enrollment United States | 117 participants | 115 participants | 232 participants |
| Sex: Female, Male Female | 213 Participants | 240 Participants | 453 Participants |
| Sex: Female, Male Male | 179 Participants | 152 Participants | 331 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 392 | 2 / 392 |
| other Total, other adverse events | 16 / 392 | 25 / 392 |
| serious Total, serious adverse events | 6 / 392 | 8 / 392 |
Outcome results
Primary
Treatment-emergent Adverse Events (TEAEs)
Number (%) of patients with treatment-emergent AEs
Time frame: Treatment Period: 8 weeks
Population: All patients randomised and treated
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Treatment-emergent Adverse Events (TEAEs) | 115 Participants |
| Pimavanserin 34 mg | Treatment-emergent Adverse Events (TEAEs) | 119 Participants |
Secondary
Change From Baseline to Week 8 in Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A)
The ESRS is a questionnaire to assess drug induced movement disorders, including parkinsonism; the ESRS-A is an accepted modified form of the original ESRS. The ESRS-A consists of 4 subscales and 4 clinical global impression movement severity scales of Parkinsonism, dyskinesia, dystonia, and akathisia. The Parkinsonism scale consists of 10 items, the dyskinesia subscale of 6 items, the dystonia subscale of 6 items, and the akathisia subscale of 2 items. Each item is scored on a 6-point scale from 0 (absent) to 5 (extreme). The ESRS-A total score is the sum of the 24 item scores with a possible range of 0 to 120. Higher scores denote more severe drug-induced movement disorders.
Time frame: Treatment Period: 8 weeks
Population: All patients randomised and treated
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) | -0.6 score on a scale | Standard Error 0.19 |
| Pimavanserin 34 mg | Change From Baseline to Week 8 in Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) | -0.5 score on a scale | Standard Error 0.19 |
Secondary
Change From Baseline to Week 8 in Mini-Mental State Examination (MMSE)
The MMSE is a 30-item questionnaire to quantitatively assess cognition, focusing on questions related to time and place of testing, repeating lists of words, arithmetic, language use and comprehension, and copying a drawing. Each of the 30 items has 2 possible values of 0 (incorrect) or 1 (correct). The MMSE total score is derived as the sum of the 30 item scores; thus, it can range from 0 to 30. Lower scores indicate more severe cognitive impairment.
Time frame: Treatment Period: 8 weeks
Population: All patients randomised and treated
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 8 in Mini-Mental State Examination (MMSE) | 1.2 score on a scale | Standard Error 0.15 |
| Pimavanserin 34 mg | Change From Baseline to Week 8 in Mini-Mental State Examination (MMSE) | 1.3 score on a scale | Standard Error 0.15 |