A Double-blind, Placebo-controlled, Relapse Prevention Study of Pimavanserin for the Treatment of Hallucinations and Delusions Associated With Dementia-related Psychosis

Inclusion criteria: 1. Is a male or female =50 and =90 years of age 2. 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: a. The subject’s legally acceptable representative (LAR) (or study partner/caregiver, if local regulations allow) must provide written informed consent b. The subject must provide written (if capable) informed assent 3. Meets criteria for All‐cause Dementia according to NIA‐AA guidelines (Appendix A) 4. Meets clinical criteria for one of the following disorders, with or without cerebrovascular disease (CVD): a. Dementia associated with Parkinson’s disease (Appendix B) b. Dementia with Lewy bodies (Appendix C) c. Possible or probable Alzheimer’s disease (Appendix A) d. Frontotemporal degeneration spectrum disorders, including possible or probable: i Behavioral variant frontotemporal dementia (Appendix D) ii Progressive supranuclear palsy (Appendix E) iii Corticobasal degeneration (Appendix F) e. Vascular dementia, including post‐stroke dementia, multi‐infarct dementia and/or subcortical ischemic vascular dementia (SIVD) (Appendix G) 5. Has an MMSE score =6 and =24 6. Has sufficient verbal and written ability to understand and answer questions and comply with procedures, with corrective measures such as hearing aids and reading glasses if necessary, and is willing and able to participate in all scheduled evaluations and complete all required tests 7. Has had psychotic symptoms for at least 2 months 8. Has all of the following scores at Visit 1 (Screening) and Visit 2 (open‐label Baseline): a. SAPS‐H+D total score =10; AND b. CGI‐S =4 (moderately ill); AND c. SAPS‐H+D global item (H7 or D13) score =4 (marked) 9. Has lived at the current place of residence for at least 3 weeks prior to Visit 1 (Screening) and there are no plans to move to a different location 10. Has a designated study partner/caregiver who meets the following requirements: a. In the Investigator’s opinion, is in contact with the subject frequently enough to accurately report on the subject’s symptoms and whether or not the subject is taking the study drug b. Is fluent in the local language in which study assessments will be administered c. Agrees to participate in study assessments and provides written consent to participate in the study 11. Can come to the clinic for study visits with a study partner/caregiver 12. Has an MRI or CT scan of the brain (completed within past 3 years) taken during or subsequent to the onset of dementia. If not available, a non‐contrast brain MRI or non‐contrast head CT must be done during screening. 13. If the subject is taking a cholinesterase inhibitor, memantine, or both, the dose of the medication(s) must be stable for at least 12 weeks prior to Visit 2 (open‐label Baseline) and there must be no current plan to change the dose 14. If the subject is taking an antipsychotic medication at the time of screening, the antipsychotic must be discontinued 2 weeks or 5 half‐lives (whichever is longer) prior to Visit 2. Investigators should not withdraw a subject’s prohibited medication for the purpose of enrolling them into the study unless discontinuation of the medication is deemed to be clinically appropriate (e.g., symptoms are not well‐controlled or the subject cannot tolerate the current medication). 15. If the subject is female, she must be Exclusion criteria: 1. Is in hospice or end‐of‐life care 2. Is confined to bed (subjects who can attend clinic visits using a wheelchair or other ambulatory assistive device are permitted) 3. Requires skilled nursing care (procedures that can only be administered by a registered nurse or doctor, such as but not limited to, intravenous administration of medication, procedures related to insertion or care of suprapubic catheters, and nasopharyngeal/tracheostomy aspiration) 4. Has psychotic symptoms that are primarily attributable to delirium, substance abuse, or a medical or psychiatric condition (e.g., schizophrenia, bipolar disorder, delusional disorder) other than dementia 5. Has a current major depressive episode (within 3 months of Screening), according to the Diagnostic and Statistical Manual of Mental Disorders‐Fifth Edition (DSM‐5) criteria 6. Has a Global Clinician Assessment of Suicidality (GCAS) score of 3 or 4 based on Investigator’s assessment of behavior within the 3 months prior to Visit 1 (Screening) or since‐last‐visit at Visit 2 (open‐label Baseline) 7. Has evidence of a non‐neurologic medical comorbidity or medication use that could substantially impair cognition 8. Has a history of ischemic stroke within the last 12 months or any evidence of hemorrhagic stroke 9. Has a known history of cerebral amyloid angiopathy (CAA), epilepsy, CNS neoplasm, or unexplained syncope 10. Has atrial fibrillation unless adequately anticoagulated 11. Has greater than New York Heart Association (NYHA) Class 2 congestive heart failure or Class 2 angina pectoris, sustained ventricular tachycardia, ventricular fibrillation, or torsade de pointes, or syncope due to an arrhythmia 12. Had a myocardial infarction within the 6 months prior to Visit 1 (Screening) 13. Has a known personal or family history or symptoms of long QT syndrome 14. Has any of the following ECG results at Visit 1 (Screening) or Visit 2 (open‐label Baseline): a. QTcF >450 ms, if QRS duration <120 ms b. QTcF >470 ms, if QRS duration =120 ms 15. Has a heart rate <50 beats per minute 16. Has a significant unstable medical condition that could interfere with subject’s ability to complete the study or comply with study procedures 17. Has a clinically significant laboratory abnormality that in the judgment of the Investigator or Medical Monitor will interfere with the conduct or interpretation of safety or efficacy evaluations in the study 18. Has one of the following screening laboratory results: a. Platelets =75,000/mm3 b. Hemoglobin =9.5 g/dL if male, or =8.5 g/dL if female c. Neutrophils, absolute =1000/mm3 d. Aspartate aminotransferase (AST) >2×upper limit of normal e. Alanine aminotransferase (ALT) >2×upper limit of normal f. Creatinine =2 mg/dL g. Hemoglobin A1c (HbA1c) =8.5% h. Abnormal free thyroxine (T4) i. Vitamin B12 deficiency 19. Has a history of a positive test result for HIV or hepatitis C 20. Has a clinically significant CNS abnormality that is most likely contributing to the dementia or findings on MRI or CT including: a. intracranial mass lesion (including but not limited to meningioma [>1 cm3 with evidence of peritumoral edema] or glioma) b. vascular malformation c. evidence of >4 hemosiderin deposits (definite microhemorrhage or superficial siderosis) 21. Requires treatment with a medication or other substance that is prohibited by the protocol 22. Has a body mass index (BMI) <18.5 or known unintentional weight loss =7% of body weight over past Hallucinations and Delusions Associated With Dementia‐related Psychosis MedDRA version: 20.0 Level: PT Classification code 10012295 Term: Dementia of the Alzheimer's type, with delusions System Organ Class: 10029205 ‐ Nervous system disorders MedDRA version: 20.0 Level: LLT Classification code 10019077 Term: Hallucinations System Organ Class: 100000004873 ;Therapeutic area: Psychiatry and Psychology [F] ‐ Mental Disorders [F03] Product Name: Pimavanserin 10 mg Product Code: ACP‐103 Pharmaceutical Form: Tablet INN or Proposed INN: Pimavanserin Current Sponsor code: ACP‐103 Other descriptive name: PIMAVANSERIN TARTRATE Concentration unit: mg/g milligram(s)/gram Concentration type: equal Concentration number: 10‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Product Name: Pimavanserin 17 mg Product Code: ACP‐103 Pharmaceutical Form: Tablet INN or Proposed INN: Pimavanserin Current Sponsor code: ACP‐103 Other descriptive name: PIMAVANSERIN TARTRATE Concentration unit: mg/g milligram(s)/gram Concentration type: equal Concentration number: 17‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Main Objective: To evaluate relapse prevention in subjects with dementia‐related psychosis treated with pimavanserin compared to placebo;Secondary Objective: To evaluate the time to discontinuation of the study for any reason in subjects with dementia‐related psychosis treated with pimavanserin compared to placebo;Primary end point(s): Time from randomization to relapse in the double‐blind period;Timepoint(s) of evaluation of this end point: Week 38 (end of 26 week double blind period) Secondary end point(s): Time from randomization to discontinuation from the double‐blind period for any reason;Timepoint(s) of evaluation of this end point: Week 38 (end of 26 week double blind period)